Chapter 27: Multiple Myeloma

Epidemiology

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Epidemiology

Incidence:

24,050 (male: 13,500; female: 10,550.

Durie-Salmon Stage at presentation

Estimated new cases for 2014 in the United States)

Stage I

7.5 per 100,000 males, 4.8 per 100,000 females

Stage II

21%

Deaths:

Estimated 11,090 in 2014 (male: 6,110; female: 4,980)

Stage III

73%

Median age:

69 years

Male to female ratio:

1.4:1

Durie BGM, Salmon SE. Cancer 1975;36:842–854

Siegel R et al. CA Cancer J Clin 2014;64:9–29

Surveillance, Epidemiology and End Results (SEER) Program, available from http://seer.cancer.gov (accessed in 2013)

Pathology

Monoclonal gammopathy of uncertain significance (MGUS)

Stable serum M-protein level <3 g/dL and bone marrow clonal plasma cells <10%
Urine Bence Jones protein absent or minimal
No related organ/tissue impairment (ROTI)^✫
No evidence of other B-lymphoproliferative disorders
Progression to multiple myeloma (MM) in ~1% per year (median 10 years)

Smoldering (asymptomatic) myeloma

M-protein in serum ≥30 g/L and/or bone marrow clonal plasma cells ≥10%
No ROTI or symptoms

Active (symptomatic) myeloma^†

Requires one or more of the following (CRAB criteria):
Calcium elevation (>11.5 mg/dL [>2.88 mmol/L])
Renal insufficiency (creatinine >2 mg/dL [>177 μmol/L])
Anemia (hemoglobin <10 g/dL or 2 g less than normal)
Bone disease (lytic or osteopenic)

Extramedullary plasmacytoma

Extramedullary tumor of clonal plasma cells
Normal bone marrow
Normal skeletal survey
M-protein absent or disappears from blood/urine after excision or irradiation of solitary lesion
Absence of ROTI^✫
Progression to MM in ~15%

Solitary plasmacytoma of bone

Three to 5% of plasma cell dyscrasias
Isolated bone tumor consisting of monoclonal plasma cells
Normal bone marrow
M-protein absent or disappears from blood/urine after excision or irradiation of solitary lesion
Absence of other myeloma ROTI^✫
Multiple or recurrent in up to 5% of patients
Progression to MM in ~50%

Plasma cell leukemia

Five percent of newly presenting MM patients
Peripheral blood absolute plasma cell count ≥2000/mm³
More than 20% plasma cells in differential count of peripheral blood leukocytes

Work-up

All patients

H&P
CBC with differential; serum electrolytes, BUN, creatinine, calcium and albumin, LDH
Quantitative immunoglobulins, serum protein electrophoresis, and immunofixation
Twenty-four–hour urine protein electrophoresis, immunofixation, and Bence Jones quantitation
Serum free light-chain assay
Skeletal survey
Unilateral bone marrow aspirate and biopsy with flow and immunohistochemistry
Bone marrow cytogenetics and interphase FISH
Albumin and β₂-microglobulin (see staging system)

Selected patients

MRI of the spine (evaluate for solitary plasmacytoma of bone or suspected cord compression)
FDG-PET/CT scan in selected patients to evaluate for increased uptake
Tissue biopsy (evaluate for solitary plasmacytoma)
Serum viscosity (if M-protein level is markedly elevated or symptoms of hyperviscosity are present)
Additional tests (prognostic markers): plasma cell labeling index, C-reactive protein, and LDH

Staging

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Staging

Durie-Salmon Staging System

Stage I

Stage II^✫

Stage III^†

Myeloma cell mass

Low

Intermediate

High

Hemoglobin

>10 g/dL

8.5–10 g/dL

<8.5 g/dL

Serum calcium

≤12 mg/dL (≤3 mmol/L)

Fitting neither stage I nor stage II

>12 mg/dL (>3 mmol/L)

Skeletal survey

Normal^‡

Advanced lytic bone lesions

Serum M-protein levels: IgG

<5 g/dL

5–7 g/dL

>7 g/dL

Serum M-protein levels: IgA

<3 g/dL

3–5 g/dL

>5 g/dL

24-hour urinary light chain excretion

<4 g/24 hours

4–12 g/24 hours

>12 g/24 hours

^✫Not meeting criteria for either stage I or stage III

^†Need to meet 1 or more of the criteria listed

^‡Or solitary plasmacytoma

Note: Subclassification: For each stage, "A" denotes serum creatinine <2 mg/dL (<177 μmol/L) and "B" denotes serum creatinine ≥2 mg/dL (≥177 μmol/L)

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Staging

International Staging System

Stage I

Stage II

Stage III

Serum β₂-microglobulin

<3.5 mg/L

3.5 to <5.5 mg/mL

≥5.5 mg/L

Serum albumin

≥3.5 g/dL (≥35 g/L)

<3.5 g/dL

—

Durie BGM, Salmon SE. Cancer 1975;36:842–854

Greipp PR et al. J Clin Oncol 2005;23:3412–3420

Response Criteria

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Response Criteria

International Myeloma Working Group Uniform Response Criteria

CR and Other Response Categories

CR = Complete Response

Negative immunofixation on the serum and urine
Disappearance of any soft tissue plasmacytomas
≤5% plasma cells in bone marrow

sCR = Stringent Complete Response

CR as described above, PLUS:

Normal free light chain (FLC) ratio AND
Absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence

VGPR = Very Good Partial Response

Serum and urine M-protein detectable by immunofluorescence but not on electrophoresis OR
≥90% reduction in serum M-protein + urine M-protein level <100 mg/24 hours

PR = Partial Response

≥50% reduction of serum M-protein + reduction in 24-hour urinary M-protein by ≥90% or to <200 mg/24 hours

If the serum and urine M-protein are unmeasurable:
A ≥50% decrease in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria

If serum and urine M-protein are unmeasurable, and serum FLC assay is also unmeasurable:

≥50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was ≥30%

Note: In addition to the above listed criteria, if present at baseline, a ≥50% reduction in the size of soft-tissue plasmacytomas is also required

SD = Stable Disease^✫

Not meeting criteria for CR, VGPR, PR, or progressive disease

^✫Not recommended for use as an indicator of response; stability of disease is best described by providing the time-to-progression estimates

Median Survival

Treatments for myeloma have expanded in the last decade. A recent study¹ examined the survival trends over time of 2 groups of patients seen at Mayo Clinic, one from time of diagnosis and the other from the time of relapse:

Among 387 patients who relapsed after stem cell transplantation, a clear improvement was seen in overall survival from the time of relapse. Patients whose disease relapsed after the year 2000 had a median overall survival of 23.9 months versus 11.8 months (P <0.001) for those who relapsed prior to this date. This improvement was independent of other prognostic factors
Patients treated with 1 or more of the newer drugs (thalidomide, lenalidomide, bortezomib) had longer survival from relapse (30.9 vs. 14.8 months; P <0.001)
In a larger group of 2981 patients with newly diagnosed myeloma, those diagnosed during the last decade had a 50% improvement in overall survival (44.8 vs. 29.9 months; P <0.001)

A second study^2,3 estimated trends in age-specific 5- and 10-year relative survival of patients with multiple myeloma (MM) in the United States from 1990–1992 to 2002–2004 from the 1973–2004 database of the Surveillance, Epidemiology, and End Results (SEER) Program. Techniques of period analysis were used to show most recent developments:

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Five- and 10-Year Estimates of Relative Survival of Patients with MM by Age Group and Calendar Period

1990–1992

2002–2004

Increase^†

P ^‡

PE^✫

SE^✫

5-Year Relative Survival

All ages

28.8

0.9

34.7

0.9

5.9

<0.001

Younger than 50 years

44.8

3.5

56.7

3.0

11.9

0.001

50 to 59 years

38.8

2.5

48.2

2.1

9.4

0.001

60 to 69 years

30.6

1.8

36.3

1.8

5.7

0.09

70 to 79 years

27.1

1.7

28.7

1.6

0.21

80 years and older

13.8

2.0

15.2

1.9

1.4

0.96

10-Year Relative Survival

All ages

11.1

0.8

17.4

0.8

6.3

<0.001

Younger than 50 years

24.5

3.4

41.3

3.2

16.8

<0.001

50 to 59 years

17.2

2.1

28.6

2.2

11.4

<0.001

60 to 69 years

10.8

1.3

15.4

1.5

4.6

0.03

70 to 79 years

7.4

1.4

10.4

1.4

3.0

0.09

80 years and older

7.1

2.3

5.7

1.7

−1.4

0.94

^✫PE indicates point estimate; and SE, standard error

^†Increase from 1990–1992 to 2002–2004 in percentage points

^‡P for trend from 1990–1992 to the last period 2002–2004

A recent update (Pulte et al. Leuk Lymphoma 2013 Sep 3. [Epub ahead of print]) continues to demonstrate increased survival for patients with myeloma, but with a disparity in survival between non-Hispanic whites and minorities that has been persistent or slightly increasing over time, especially for younger patients. The reasons for these differences cannot be definitively ascertained from the SEER database, the source of the data since it lacks important information concerning several critical factors including cytogenetics, staging of myeloma, chemotherapeutic regimens employed and insurance data.

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Number of Cases and Median Age at Presentation, Overall and by Ethnic Group^✫

Period

Case Numbers

Median Age

1998–2001

2002–2005

2006–2009

1998–2001

2002–2005

2006–2009

All

6443

6993

7120

NHW

4227

4378

4283

All nonwhite

2174

2551

2702

1075

1245

1354

Hispanic

631

736

780

API

414

491

514

AA, African American; API, Asian and Pacific Islander; NWH, non-Hispanic white

^✫Note that number of NHW plus all nonwhites does not equal total case number because patients with missing information on ethnicity/race and more than 1 race or ethnic group were not included in analysis of individual racial groups

Adapted from Pulte et al. Leuk Lymphoma 2013; Early Online: 1–7

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Five- and 10-Year Relative Survival by Ethnic/Racial Group for All Age Groups

Period

Unadjusted Relative Survival (SE)

Adjusted Relative Survival (SE)^✫

1998–2001

2002–2005

2006–2009

1998–2001

2002–2005

2006–2009

5-Year Survival

All

34.8 (0.6)

39.7 (0.4)

44.6 (0.6)

35.6 (0.6)

39.8 (0.4)

44 (0.6)

δ/p Value^†

+9.8/<0.0001

+8.4/<0.0001

NHW

34.2 (0.7)

39.6 (0.5)

44.9 (0.8)

36.4 (0.7)

40.9 (0.5)

45.3 (0.7)

δ/p Value^†

+10.7/<0.0001

+8.9/<0.0001

All nonwhite

35.4 (1)

39.5 (0.7)

43.5 (1)

33.8 (1)

37.6 (0.7)

41.4 (1)

δ/p Value^†

+8.1/<0.0001

+7.6/<0.0001

35.1 (1.5)

39.7 (1)

44.3 (1.4)

33.4 (1.4)

37.4 (0.9)

41.5 (1.4)

δ/p Value^†

+9.2/<0.0001

+8.1/<0.0001

Hispanic

35.3 (1.9)

38.9 (1.2)

42.5 (1.8)

32.6 (1.8)

36.2 (1.2)

39.8 (1.8)

δ/p Value^†

+7.2/0.01

+7.2/0.007

API

37.3 (2.5)

39.8 (1.6)

42.4 (2.3)

37.5 (2.3)

40.4 (1.5)

43.3 (2.2)

δ/p Value^†

+5.1/0.16

+5.8/0.09

10-Year Survival

All

16.1 (0.5)

20.4 (0.4)

25 (0.6)

16.6 (0.5)

20.2 (0.4)

24.1 (0.5)

δ/p Value^†

+8.9/<0.0001

+7.7/<0.0001

NHW

15.3 (0.6)

19.7 (0.5)

24.5 (0.7)

17 (0.6)

20.5 (0.5)

24.6 (0.7)

δ/p Value^†

+9.2/<0.0001

+7.8/<0.0001

All nonwhite

17.4 (1)

21.3 (0.8)

25.6 (1.2)

16.1 (0.8)

19.4 (0.6)

23 (0.9)

δ/p Value^†

+8.2/<0.0001

+7.3/<0.0001

16.1 (1.2)

20.1 (1)

24.5 (1.4)

14.8 (1.1)

18.2 (0.9)

21.6 (1.2)

δ/p Value^†

+8.4/<0.0001

+7.0/<0.0001

Hispanic

17.4 (1.7)

21.1 (1.3)

25.2 (1.8)

15.3 (1.5)

18.6 (1.2)

22 (1.6)

δ/p Value^†

+7.8/0.001

+6.9/0.0006

API

22 (2.3)

24.9 (1.7)

27.8 (2.3)

21.4 (2.1)

24.4 (1.6)

28.1 (2.2)

δ/p Value^†

+5.8/0.07

+7.0/0.03

AA, African American; API, Asian and Pacific Islander; NHW, non-Hispanic white

^✫Age adjusted to International Cancer Survival Standard

^†δ = Delta or difference between 1998–2001 and 2006–2009 periods and p value for trend

Adapted from Pulte et al. Leuk Lymphoma 2013; Early Online: 1–7

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Five- and 10-year Relative Survival by Ethnic and Age Groups

15–49

50–69

70 and Older

5-Year Relative Survival (SE)

Period

1998–2001

2006–2009

1998–2001

2006–2009

1998–2001

2006–2009

5-Year Survival

All

52.9 (1.9)

66.1 (1.7)

39.9 (0.9)

52.2 (0.9)

26 (0.8)

30.8 (0.9)

δ/p Value^✫

+13.2/<0.0001

+12.5/<0.0001

+4.8/<0.0001

NHW

54.4 (2.6)

71.2 (2.2)

40.8 (1.2)

53.7 (1.1)

25.6 (1)

31 (1.1)

δ/p Value^✫

+16.8/<0.0001

+13.3/<0.0001

+5.4/<0.0001

All nonwhite

50.7 (2.9)

60.1 (2.6)

38.1 (1.5)

49 (1.4)

26.7 (1.9)

29.9 (1.8)

δ/p Value^✫

+9.4/0.03

+11.7/<0.0001

+3.2/0.23

46.1 (4)

60.5 (3.6)

39 (2.1)

48.9 (2)

25.9 (2.3)

30 (2.3)

δ/p Value^✫

+14.4/0.01

+10.3/0.0007

+4.1/0.21

Hispanic

52.4 (5)

58.2 (4.5)

36.6 (2.7)

47.4 (2.6)

25.2 (3.1)

29.3 (2.9)

δ/p Value^✫

+5.8/0.42

+9.2/0.02

+4.1/0.34

API

60.3 (7.3)

63.4 (8)

39 (3.8)

51.3 (3.4)

30.1 (3.5)

30.5 (3.2)

δ/p Value^✫

+3.1/0.79

+14.2/0.01

+0.4/0.93

10-Year Survival

All

34.6 (1.9)

47.3 (1.9)

17.6 (0.8)

30 (0.9)

9.8 (0.6)

13 (0.7)

δ/p Value^✫

+12.7/<0.0001

+12.4/<0.0001

+3.2/<0.0001

NHW

36.6 (2.7)

53.7 (2.6)

17.7 (1)

30.1 (1.1)

9 (0.7)

12.4 (0.9)

δ/p Value^✫

+17.1/<0.0001

+12.4/<0.0001

+3.4/<0.0001

All nonwhite

30 (3.3)

39.4 (3.4)

17.4 (1.5)

29.6 (1.7)

12.5 (1.6)

14.7 (1.7)

δ/p Value^✫

+9.4/0.06

+12.2/<0.0001

+2.2/0.25

27 (3.6)

38.9 (3.9)

16.6 (1.7)

27.5 (2)

10.5 (1.8)

12.7 (2)

δ/p Value^✫

+11.9/0.03

+10.9/<0.0001

+2.2/0.31

Hispanic

36.6 (5.5)

41.3 (4.7)

16.4 (2.3)

28.2 (2.6)

8.5 (2.4)

11.8 (2.6)

δ/p Value^✫

+4.7/0.54

+1.8/<0.0001

+3.3/0.24

API

37.8 (7.3)

39.3 (7.8)

21.6 (3.5)

35 (3.6)

18 (3.4)

19.2 (3.1)

δ/p Value^✫

+1.5/0.89

+13.4/0.008

+1.2/0.78

AA, African American; API, Asian and Pacific Islander; NHW, non-Hispanic white

^✫δ = Delta or difference between 1998–2001 and 2006–2009 periods and p value for trend

Adapted from Pulte et al. Leuk Lymphoma 2013; Early Online: 1–7

International Myeloma Working Group Uniform Response Criteria

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International Myeloma Working Group Uniform Response Criteria

Disease Progression and Relapse

Progressive Disease^✫

Any one or more of the following:

Increase of ≥25% from baseline in serum M-component (absolute increase must be ≥0.5 g/dL)
Increase of ≥25% from baseline in urine M-component (absolute increase must be ≥200 mg/24 hours)
Increase of ≥25% from baseline in the difference between involved and uninvolved FLC levels—only in patients without measurable serum and urine M-protein levels (absolute increase must be ≥10 mg/dL)
Increase of ≥25% from baseline in bone marrow plasma cell percentage (absolute percentage must be ≥10%)
Definite development of new bone lesions or soft-tissue plasmacytomas or definite increase in the size of existing bone lesions or soft-tissue plasmacytomas
Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or >2.88 mmol/L) that can be attributed solely to the plasma cell proliferative disorder

Clinical Relapse

One or more of the following:

Development of new soft-tissue plasmacytomas or bone lesions
Definite increase in the size of existing plasmacytomas or bone lesions. A definite increase is defined as a 50% (and at least 1 cm) increase as measured serially by the sum of the products of the cross-diameters of the measurable lesion
Hypercalcemia >11.5 mg/dL (>2.88 mmol/L)
Decrease in hemoglobin of ≥2 g/dL
Rise in serum creatinine by ≥2 mg/dL (≥177 μmol/L)

Relapse from CR^†

One or more of the following:

Reappearance of serum or urine M-protein by immunofixation or electrophoresis
Development of ≥5% plasma cells in the bone marrow
Appearance of any other sign of progression (ie, new plasmacytoma, lytic bone lesion, or hypercalcemia)

^✫Used for calculation of time to progression and progression-free survival outcomes for all patients, including those in CR (includes primary progressive and disease progression on or off therapy)

^†Used only if the outcome studied is disease-free survival (DFS)

Durie BGM et al. International uniform response criteria for multiple myeloma. Leukemia 2006;20:1467–1473

Expert Opinion

1. Treatment by stage:

Asymptomatic MGUS, smoldering MM, and Stage I MM

These patients do not need primary therapy and should be monitored without therapy unless they have evidence of disease progression. Clinical trials are being conducted in these stages. Follow-up every 3 to 6 months is recommended. Progression of the disease to stage II or higher, is defined by:
- 25% increase in the monoclonal component (serum or urine)
- >25% increase in plasma cells bone marrow infiltration
- Increased size of bone lesions or development of new lytic lesions
- Hypercalcemia
- Increased plasmacytoma tumor volume
Symptomatic patients (Stages II and III MM)

These patients should be treated with combination therapy followed by consideration for stem cell transplantation if eligible. Determine whether a patient is a candidate for high-dose therapy with autologous peripheral blood stem cell (PBSC) transplantation before initiating chemotherapy. Avoid alkylating agents in such patients before autologous PBSCs are collected, because exposure to alkylating agents may prevent the collection of an adequate number of PBSCs for autologous transplantation

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Regimens

Newly Diagnosed Multiple Myeloma—Transplantation Candidates

Lenalidomide + low-dose dexamethasone

Rajkumar SV et al. Lancet Oncol 2010;11:29–37

Bortezomib + dexamethasone

Harousseau J-L et al. J Clin Oncol 2010;28:4621–4629

Bortezomib + lenalidomide + dexamethasone

Richardson PG et al. Blood 2010;116:679–686

Bortezomib + thalidomide + dexamethasone

Cavo M et al. Lancet 2010;376:2075–2085

Kaufman JL et al. Cancer 2010;116:3143–3151

Bortezomib + doxorubicin + dexamethasone

Sonneveld P et al. J Clin Oncol 2012;30:2946–2955

Cyclophosphamide + bortezomib + dexamethasone

Reeder CB et al. Leukemia 2009;23:1337–1341

Carfilzomib + lenalidomide + dexamethasone

Jakubowlak AJ et al. Blood 2012;120:1801–1809

Thalidomide + dexamethasone

Rajkumar SV et al. J Clin Oncol 2006;24:431–436

Newly Diagnosed Multiple Myeloma—Those Not Transplantation Candidates

Melphalan + prednisone + thalidomide

Palumbo A et al. Lancet 2006;367:825–831

Palumbo A et al. Blood 2008;112:3107–3114

Bortezomib + melphalan + prednisone

San Miguel JFS et al. N Engl J Med 2008;359:906–917

Melphalan + prednisone + lenalidomide

Palumbo A et al. J Clin Oncol 2007;25:4459–4465

Relapsed/Refractory Multiple Myeloma

Richardson PG et al. N Engl J Med 2003;348:2609–2617

Lenalidomide + dexamethasone

Dimopoulos M et al. N Engl J Med 2007;357:2123–2132

Weber DM et al. N Engl J Med 2007;357:2133–2142

Carfilzomib (bortezomib-naïve)

Vij R et al. Blood 2012;119:5661–5670

Carfilzomib (prior bortezomib)

Vij R et al. Br J Haematol 2012;158:739–748

Pomalidomide + dexamethasone

Lacy MQ et al. Leukemia 2010;24:1934–1939

Leleu X et al. Blood 2013;121:1968–1975

Pomalidomide + cyclophosphamide + prednisone

Larocca A et al. Blood 2013;122:2799–2806

Bortezomib + liposomal doxorubicin HCl

Orlowski RZ et al. J Clin Oncol 2007;25:3892–3901

High-Dose Conditioning for Stem Cell Transplantation in Relapsed/Refractory Multiple Myeloma

High-dose melphalan

Moreau P et al. Blood 2002;99:731–735

Maintenance Therapy Multiple Myeloma

Sonneveld P et al. J Clin Oncol 2012;30:2946–2955

Attal M et al. N Engl J Med 2012;366:1782–1791

Dimopoulos MA et al. Haematologica 2013;98:784–788

McCarthy PL et al. N Engl J Med 2012;366:1770–1781

Palumbo A et al. N Engl J Med 2012;366:1759–1769

Thalidomide

Morgan GJ et al. Blood 2012;119:7–15

2. Indications for treatment:
- Monoclonal plasma cells in the bone marrow >10% and/or presence of a biopsy-proven plasmacytoma
- Monoclonal protein present in the serum and/or urine^✫
- Myeloma-related organ dysfunction (≥1)^†
  
  [C] Calcium elevation in the blood (serum calcium >10.5 mg/dL [>2.63 mmol/L] or greater than the upper limit of normal range)
  
  [R] Renal insufficiency (serum creatinine >2 mg/dL [>177 μmol/L])
  
  [A] Anemia (hemoglobin <10 g/dL or 2 g less than the lower limit of normal range)
  
  [B] Lytic bone lesions or osteoporosis^‡
Note: THESE CRITERIA IDENTIFY STAGE IB and STAGES II and III A/B MYELOMA BY DURIE/SALMON STAGE. Stage IA becomes smoldering or indolent myeloma
3. Solitary plasmacytoma:
- Primary radiation therapy (≥45 Gy) to the involved fields represents the initial treatment for patients diagnosed with osseous plasmacytoma
- Same approach and/or surgery represent the initial treatment for patients with extraosseous plasmacytomas
- Follow-up for either solitary or extraosseous plasmacytomas includes blood and urine tests every 4 weeks to monitor response to radiation treatment
- If a complete disappearance of the monoclonal component is demonstrated, blood and urine tests will be performed every 3–6 months
- If the monoclonal component persists, follow-up should continue every 4 weeks
- If a progression in the disease is documented, a reevaluation for recurrent extraosseous plasmacytomas and/or myeloma should be considered
Dimopoulos MA et al. J Clin Oncol 1992;10:587–590

Hu K, Yahalom J. Oncology (Williston Park) 2000;14:101–108, 111; discussion 111–112, 115
4. Treatment with a bisphosphonate is recommended to reduce skeletal complications for all myeloma patients with skeletal lesions. Alternatives that have demonstrated efficacy in this setting include:
- Pamidronate, or
- Zoledronic acid, or
- Clodronate
Notes:
- Because renal toxicity can result from bisphosphonate therapy, renal function should be monitored closely. Bisphosphonate doses may need to be modified or discontinued in renally impaired individuals
- Myeloma patients with bone lesions should receive treatment with a bisphosphonate. Whether to administer bisphosphonates to myeloma patients without evidence of bone disease is unclear. Some research has shown bisphosphonates may have a clinical benefit even in patients without bone disease. Recommendations on how often bisphosphonates should be administered will likely evolve over time. Current recommendations are to administer standard doses of bisphosphonates every 3–4 weeks. The duration for which repeated doses should be administered is also unclear. Currently, there are no data from randomized studies to guide bisphosphonate use for more than 2 years. The risks and benefits of continuing bisphosphonate treatment after 2 years must be considered in each patient. To prevent osteonecrosis of the jaw, patients treated with bisphosphonates should maintain good dental hygiene and should stop bisphosphonate treatment for 90 days before and after invasive dental procedures. Caregivers must ensure that myeloma patients get enough vitamin D and calcium. This is a concern because 60% of myeloma patients are vitamin D and calcium deficient. U.S. Food and Drug Administration product labeling for both zoledronic acid and pamidronate disodium recommend vitamin D and calcium supplementation in conjunction with bisphosphonate treatment, but calcium supplementation should be used cautiously for patients with kidney problems
5. Anemia is present in most patients with multiple myeloma. Reversible causes of anemia should be evaluated and treated. Patients with symptomatic anemia may benefit from therapy with recombinant erythropoietin (see Chapter 43)
6. Waldenström macroglobulinemia presents with lymphoplasmacytic bone marrow infiltration and IgM paraproteinemia. Therapy usually consists of rituximab along with an alkylating agent such as cyclophosphamide, or bortezomib or nucleoside analogs such as fludarabine. Other management considerations focus on complications caused by macroglobulinemia, such as hyperviscosity, cryoglobulinemia, and hemolytic anemia
7. Primary amyloidosis is characterized by organ dysfunction resulting from monoclonal light-chain production and tissue deposition. Carefully selected patients may benefit from high-dose melphalan with autologous PBSC support, which can result in hematologic remission, regression of light-chain deposition, and improvement in organ function. Other options include the use of bortezomib- or lenalidomide-based regimens
8. The optimal prophylaxis strategy for thromboembolic complications of IMiD therapy (thalidomide and lenalidomide) is not clear. Therapy with low-molecular-weight heparins or full-dose warfarin anticoagulation are standard treatments for DVT and pulmonary embolism in the general population. However, in patients with multiple myeloma, data exist supporting the protective effect of aspirin against VTE, despite its mechanism of arterial anticoagulation. Until more is known about the nature and mechanism of thromboembolism induced by the IMiDs, it is difficult to say which agent is most appropriate. At this time, any of the agents may be considered reasonable; however, all patients receiving combination therapy with lenalidomide or thalidomide should have some form of thromboembolic prophylaxis incorporated into therapy

Palumbo A et al. Enoxaparin or aspirin for the prevention of recurrent thromboembolism in newly diagnosed myeloma patients treated with melphalan and prednisone plus thalidomide or lenalidomide. J Thromb Haemost 2006;4:1842–1845

Palumbo A et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia 2008;22:414–423

REGIMEN: NEWLY DIAGNOSED MULTIPLE MYELOMA (TRANSPLANTATION CANDIDATES): INDUCTION PRIOR TO AUTOLOGOUS STEM CELL TRANSPLANTATION (ASCT) LENALIDOMIDE + LOW-DOSE DEXAMETHASONE

Regimen: Newly Diagnosed Multiple Myeloma (Transplantation Candidates): Induction Prior to Autologous Stem Cell Transplantation (ASCT) Lenalidomide + Low-Dose Dexamethasone

Rajkumar SV et al. Lancet Oncol 2010;11:29–37

Lenalidomide 25 mg/day; administer orally, continually, for 21 consecutive days on days 1–21, every 28 days (total dose/cycle = 525 mg)

Dexamethasone 40 mg/dose; administer orally for 4 doses on days 1, 8, 15, and 22, every 28 days (total dose/cycle = 160 mg)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL–LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is INTERMEDIATE

Antimicrobial primary prophylaxis to be considered:

Antibacterial—consider a fluoroquinolone or no prophylaxis; P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—consider concomitant use of clotrimazole during periods of neutropenia
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

Caution: Acyclovir and famciclovir accumulate in patients with impaired renal function and may exacerbate renal dysfunction (valacyclovir is a prodrug for acyclovir). Monitor kidney function serially during acyclovir, valacyclovir, and famciclovir use

Acyclovir and famciclovir elimination is inversely related to renal function
Acyclovir, famciclovir, and valacyclovir utilization is modified in renally impaired individuals (consult product labeling or Summary of Product Characteristics for guidance about dose/dosage and administration frequency modifications, and, when relevant, recommendations for drug dilution, administration rate, concurrent fluid administration, and fluid supplementation as a function of urine output)
Impaired acyclovir elimination is associated with neurologic adverse effects, including agitation, ataxia, coma, confusion, dizziness, dysarthria, encephalopathy, hallucinations, paresthesia, seizure, somnolence, and tremors

See Chapter 47 for more information

Thromboprophylaxis

Risk assessment and recommendations for VTE prophylaxis in patients with multiple myeloma with individual or myeloma-related risk factors, or risk factors related to treatment

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Individual risk factors

Obesity (BMI ≥30 kg/m²)
H/O VTE
CVC or pacemaker
Comorbid pathologies

Cardiac disease

Chronic renal disease

Diabetes

Acute infection

Immobilization
Surgery

General surgery

Any anesthesia

Trauma
Medications

Erythropoietin (epoetin alfa, darbepoetin)

Estrogenic compounds

Bevacizumab
Clotting disorders

Thrombophilia

Myeloma-related risk factors

Diagnosis of multiple myeloma
Hyperviscosity

≤1 Individual or myeloma risk factor present:

Aspirin 81–325 mg daily

≥2 Individual or myeloma risk factors present:

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or
Warfarin, targeting an INR = 2–3

Concomitant treatment-related risk factors

Thalidomide or lenalidomide in combination with:

High-dose dexamethasone (≥480 mg/month)

Doxorubicin
Multiagent chemotherapy

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or

Warfarin, targeting an INR = 2–3

CVC, central venous catheter; INR, international normalized ratio; LMWH, low-molecular-weight heparin; VTE, venous thromboembolic disease

^✫LMWHs should be used with caution in individuals with impaired renal function (creatinine clearance <30 mL/min). Refer to product labeling for information about doses and administration schedules in renally impaired patients, and guidance for monitoring anti-Factor Xa concentrations

Geerts WH et al. Chest 2008;133(6 Suppl):381S–453S

Multiple Myeloma, V.1.2014. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Palumbo A et al. Leukemia 2008;22:414–423

Venous Thromboembolic Disease, V.2.2013. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Bisphosphonates

All patients receiving primary therapy for symptomatic multiple myeloma should receive a bisphosphonate adjunctively; for example:

Pamidronate disodium 90 mg; administer intravenously over 2–4 hours, every month, or
Zoledronic acid 4 mg; administer intravenously over 15 minutes, every month

Consider baseline bone densitometry evaluation

See Chapter 43 for more information

Treatment Modifications

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Treatment Modifications

Adverse Event

Treatment Modification

Platelet count <30,000/mm³

Interrupt lenalidomide treatment, follow CBC weekly. Resume lenalidomide at 15 mg/day after platelet count is ≥30,000/mm³

For each subsequent platelet count <30,000/mm³

Interrupt lenalidomide treatment, follow CBC weekly. After platelet count recovers to ≥30,000/mm³, resume lenalidomide at a dose decreased from the previous dose by 5 mg/day, but the daily dose should not be less than 5 mg/day

ANC <1000/mm³

Interrupt lenalidomide treatment, follow CBC weekly. Resume lenalidomide at 15 mg/day after ANC ≥1000/mm³

For each subsequent ANC <1000/mm³

Interrupt lenalidomide treatment, follow CBC weekly. After ANC recovers to ≥1000/mm³, resume lenalidomide at a dose decreased from the previous dose by 5 mg/day, but the daily dose should not be less than 5 mg/day

Febrile neutropenia

Interrupt lenalidomide treatment, follow closely, and resume lenalidomide at 15 mg/day after fever abates

G3/4 nonhematologic toxicity

Interrupt lenalidomide treatment, follow clinically. After toxicity abates to G ≤2, resume lenalidomide at a dose decreased from the previous dose by 5 mg/day, but the daily dose should not be less than 5 mg/day

Toxicities ascribed to dexamethasone such as severe manifestations of hypercorticism, including hyperglycemia, irritability, insomnia, and oral candidiasis

Reduce dexamethasone dose to 20 mg per day

Lenalidomide starting dose adjustment for Renal Impairment in Multiple Myeloma (Days 1–21 of Each 28-day Cycle)

Moderate renal impairment

CrCl 30–60 mL/min (0.5–1 mL/s)

10 mg lenalidomide every 24 hours

Severe renal impairment

CrCl <30 mL/min (<0.5 mL/s), not requiring dialysis

15 mg lenalidomide every 48 hours

End-stage renal disease

CrCl <30 mL/min (<0.5 mL/s), requiring dialysis

5 mg/day. On dialysis days, administer a daily dose following dialysis

CrCl, Creatinine clearance

Patient Population Studied

Randomized phase III trial of 445 patients with newly diagnosed multiple myeloma. Patients were eligible if they had previously untreated symptomatic multiple myeloma, bone marrow plasmacytosis (≥10% plasma cells or sheets of plasma cells), or a biopsy-proven plasmacytoma, and measurable disease defined as serum monoclonal protein >10 g/L or urine monoclonal protein ≥0.2 g/day or more. Study eligibility also required hemoglobin >7 g/dL, platelet count ≥75,000/mm³, ANC ≥1000/mm³, and an acceptable serum creatinine. Patients were excluded if they had G ≥2 peripheral neuropathy, active infection, current or prior deep vein thrombosis, or Eastern Cooperative Oncology Group performance status = 3/4

Efficacy (N = 208)

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Efficacy (N = 208)

Best overall Response to Therapy

Percent of Patients

Overall response rate (partial response or better)

70%

Complete plus very good partial response

40%

Complete response

Immunofixation-negative complete response

10%

Very good partial response

26%

Partial response

30%

Minimal response

13%

No response/stable disease

Progressive disease

Unevaluable

1-year overall survival^✫

96% (95% CI, 94–99)

2-year overall survival^✫

87% (95% CI, 81–93)

1-year overall survival, ages <65 years old

98% (95% CI, 92–99)

1-year overall survival, ages ≥65 years old

94% (95% CI, 89–99)

Median time to partial response or better

1 month^†

Median response duration

24.1 months (95% CI, 21.5–28.1)

Median progression-free survival

25.3 months (22.3–not reached)

^✫Overall survival was not a protocol-specified end point in this study. However, the study was stopped on recommendations of the independent data monitoring committee at a median follow-up of 12.5 months (95% CI, 11.5–14.6), because overall survival was significantly higher with low-dose dexamethasone than with high-dose dexamethasone (p = 0.0002). All patients in the high-dose group were instructed to crossover to receive low-dose dexamethasone

^†Among patients who responded

Toxicity

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Toxicity

G ≥3 Toxicities (N = 220)

Toxicity

Percent of patients

Hematologic

Hemoglobin

Platelets

Neutrophils

20%

Nonhematologic

Deep vein thrombosis or pulmonary embolism

12%

Infection or pneumonia

Hyperglycemia

Cardiac ischemia

<1%

Atrial fibrillation or flutter

<1%

Fatigue

Neuropathy

Nonneuropathic weakness

Summary

Any G ≥3 toxicity in first 4 months

35%

Any G ≥3 nonhematologic toxicity at any time during therapy

48%

Any G ≥4 nonhematologic toxicity at any time during therapy

14%

Early mortality (first 4 months)

<1%

Reason for Discontinuation (N = 222)

Treatment completed per protocol

25%

Disease progression

17%

Adverse events or complications

23%

Death on study

Patient withdrawal or refusal

Alternative therapy

17%

Other complicating disease

Other

Therapy Monitoring

Before each cycle: CBC with differential and blood chemistries (including BUN, creatinine, and calcium)
Every 6 weeks to 3 months: Measure serum and urine M-protein

REGIMEN: NEWLY DIAGNOSED MULTIPLE MYELOMA (TRANSPLANTATION CANDIDATES): INDUCTION PRIOR TO AUTOLOGOUS STEM CELL TRANSPLANTATION (ASCT) BORTEZOMIB + DEXAMETHASONE

Regimen: Newly Diagnosed Multiple Myeloma (Transplantation Candidates): Induction Prior to Autologous Stem Cell Transplantation (ASCT) Bortezomib + Dexamethasone

Harousseau J-L et al. J Clin Oncol 2010;28:4621–4629

Bortezomib 1.3 mg/m² per dose; administer by intravenous injection over 3–5 seconds for 4 doses on days 1, 4, 8, and 11, every 3 weeks for 4 cycles (total dosage/cycle = 5.2 mg/m²)

Dexamethasone 40 mg/dose; administer orally, as follows:

Cycles 1 and 2: For 4 consecutive days on days 1–4, and for 4 consecutive days on days 9–12, every 3 weeks for 2 cycles (total dose/cycle = 320 mg)
Cycles 3 and 4: For 4 consecutive days on days 1–4, every 3 weeks for 2 cycles (total dose/cycle = 160 mg)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is HIGH

Antimicrobial primary prophylaxis is recommended:

Antibacterial—consider fluoroquinolone prophylaxis; P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—recommended
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

Acyclovir and famciclovir elimination is inversely related to renal function
Acyclovir, famciclovir, and valacyclovir utilization is modified in renally impaired individuals (consult product labeling or Summary of Product Characteristics for guidance about dose/dosage and administration frequency modifications, and, when relevant, recommendations for drug dilution, administration rate, concurrent fluid administration, and fluid supplementation as a function of urine output)
Impaired acyclovir elimination is associated with neurologic adverse effects, including agitation, ataxia, coma, confusion, dizziness, dysarthria, encephalopathy, hallucinations, paresthesia, seizure, somnolence, and tremors

See Chapter 47 for more information

Thromboprophylaxis

Risk assessment and recommendations for VTE prophylaxis in patients with multiple myeloma with individual or myeloma-related risk factors, or risk factors related to treatment

| Download (.pdf) | Print

Individual risk factors

Obesity (BMI ≥30 kg/m²)
H/O VTE
CVC or pacemaker
Comorbid pathologies

Cardiac disease

Chronic renal disease

Diabetes

Acute infection

Immobilization
Surgery

General surgery

Any anesthesia

Trauma
Medications

Erythropoietin (epoetin alfa, darbepoetin)

Estrogenic compounds

Bevacizumab

Clotting disorders

Thrombophilia

Myeloma-related risk factors

Diagnosis of multiple myeloma
Hyperviscosity

≤1 Individual or myeloma risk factor present:

Aspirin 81–325 mg daily

≥2 Individual or myeloma risk factors present:

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or
Warfarin, targeting an INR = 2–3

Concomitant treatment-related risk factors

Thalidomide or lenalidomide in combination with:

High-dose dexamethasone (≥480 mg/month)
Doxorubicin
Multiagent chemotherapy

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or

Warfarin, targeting an INR = 2–3

CVC, central venous catheter; INR, international normalized ratio; LMWH, low-molecular-weight heparin; VTE, venous thromboembolic disease

Geerts WH et al. Chest 2008;133(6 Suppl):381S–453S

Multiple Myeloma, V.1.2014. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Palumbo A et al. Leukemia 2008;22:414–423

Venous Thromboembolic Disease, V.2.2013. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Bisphosphonates

All patients receiving primary therapy for symptomatic multiple myeloma should receive a bisphosphonate adjunctively; for example:

Pamidronate disodium 90 mg; administer intravenously over 2–4 hours, every month, or
Zoledronic acid 4 mg; administer intravenously over 15 minutes, every month

Consider baseline bone densitometry evaluation

See Chapter 43 for more information

Treatment Modifications

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Treatment Modifications

Adverse Event

Treatment Modification

Febrile neutropenia

Withhold therapy until fever abates, then resume therapy at the same dosages and schedules

G4 hematologic toxicity

Withhold therapy until counts recover to ANC >750/mm³ and platelets >50,000/mm³, then resume therapy

G3/4 nonhematologic toxicity

Interrupt therapy, follow clinically and resume therapy when toxicity G ≤2

Toxicities ascribed to dexamethasone such as severe manifestations of hypercorticism, including hyperglycemia, irritability and insomnia, oral candidiasis

Reduce dexamethasone dose to 20 mg per dose

Treatment Modification for Bortezomib-Induced Peripheral Neuropathy^✫

Severity of Peripheral Neuropathy

Modification of Dose and Schedule

G1 (paresthesias or loss of reflexes) without pain or loss of function

No action

G1 with pain or G2 (interferes with function, but not with activities of daily living)

Reduce bortezomib dosage to 1 mg/m² per dose

G2 with pain or G3 (interferes with activities of daily living)

Withhold bortezomib treatment until toxicity resolves, then reinitiate at a dosage of 0.7 mg/m² per dose once weekly

G4 (permanent sensory loss that interferes with function)

Discontinue treatment

^✫Richardson PG et al. J Clin Oncol 2006;24:3113–3120

Patient Population Studied

Phase III study of 482 patients with multiple myeloma who were ≤65 years of age and eligible for autologous stem cell transplantation. All patients had untreated symptomatic MM with measurable paraprotein in serum (>10 g/L) or urine (>0.2 g/24 hours). Key eligibility criteria, included Eastern Cooperative Oncology Group PS ≤2, adequate renal function (no end-stage renal failure requiring dialysis), and hematologic (platelets ≥50,000/mm³, neutrophils ≥750/mm³), and hepatic (bilirubin ≤3 times the upper limit of normal range [ULN] and AST and ALT ≤4 times ULN) indices. Patients with confirmed diagnosis of amyloidosis and G ≥2 peripheral neuropathy were excluded

Efficacy

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Efficacy

Response to Induction Therapy Overall and According to Baseline Disease Stage and Prognostic Factors

Evaluable Population (N = 223)

ORR (at least PR)

78.5%

At least VGPR

37.7%

CR/nCR

14.8%

5.8%

MR + SD

12.6%

4.5%

Death

0.5%

Not assessable

ORR and at Least VGPR and CR/nCR Response Rates by Disease Stage

ISS 1

ORR

81.4%

At least VGPR

37.3%

CR/nCR

15.7%

ISS 2

ORR

71.6%

At least VGPR

35.8%

CR/nCR

14.8%

ISS 3

ORR

76.9%

At least VGPR

40.4%

CR/nCR

13.5%

Response to First Transplantation and Overall at Least VGPR and CR/nCR Rates, Including Second Transplantation, Among All Evaluable Patients

Response to First Transplantation

ORR (at least PR)

80.3%

At least VGPR

54.3%

CR/nCR

35%

16.1%

MR + SD + PD

2.7%

Death

0.5%

No transplantation

11.7%

Overall, Including Second Transplantation

At least VGPR

67.7%

CR/nCR

39.5%

CR, complete response; CR/nCR, complete response/near complete response; ISS, International Staging System; MR, minimal response; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease; VGPR, very good partial response

Toxicity (N = 239)

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Toxicity (N = 239)

Toxicity

Percent of Patients

Any AE

96.7%

Any grade ≥3 AE

46.9%

Any grade ≥4 AE

11.3%

Any serious AE

27.2%

Toxicity leading to study drug discontinuation or delay

18.4%

Toxicity leading to bortezomib dose reduction

6.9% (64/931 cycles)

Death related to toxicity

Hematologic Toxicity

G1–4

G3/4

Anemia

15.9%

4.2%

Neutropenia

Thrombocytopenia

10.9%

2.9%

Infections

48.1%

8.8%

Herpes zoster^✫

9.2%

—

Thrombosis

4.6%

1.7%

Nonhematologic Toxicities

G1–4

Fatigue

28.5%

Rash

11.7%

GI symptoms

26.8%

Cardiac disorders

5.9%

Pneumopathy

3.4%

G1 Peripheral neuropathy^†

21.3%

G2 Peripheral neuropathy^†

15.5%

G3 Peripheral neuropathy^†

7.1%

^✫No antiviral prophylaxis for Herpes zoster was specified in the protocol

^†Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms used by investigators that were considered related to neurologic toxicity included accommodation disorder, anosmia, areflexia, difficulty in walking, dysesthesia, fall, formication, hypoesthesia, hyporeflexia, muscle spasms, pain in limb, paraparesis, paresthesia, peripheral motor neuropathy, peripheral neuropathy, sensory loss, vertigo, and vision blurred

Therapy Monitoring

Before each cycle: CBC with differential and blood chemistries (including BUN, creatinine, and calcium)
Every 6 weeks to 3 months: Measure serum and urine M-protein

REGIMEN: NEWLY DIAGNOSED MULTIPLE MYELOMA (TRANSPLANTATION CANDIDATES): INDUCTION PRIOR TO AUTOLOGOUS STEM CELL TRANSPLANTATION (ASCT) BORTEZOMIB + LENALIDOMIDE + DEXAMETHASONE

Regimen: Newly Diagnosed Multiple Myeloma (Transplantation Candidates): Induction Prior to Autologous Stem Cell Transplantation (ASCT) Bortezomib + Lenalidomide + Dexamethasone

Richardson PG et al. Blood 2010;116:679–686

All Cycles:

Bortezomib 1–1.3 mg/m² per dose; administer by intravenous injection over 3–5 seconds for 4 doses on days 1, 4, 8, and 11, every 3 weeks for 8 cycles (total dosage/cycle for 1 mg/m² per dose = 4 mg/m²; total dosage/cycle for 1.3 mg/m² per dose = 5.2 mg/m²)

Lenalidomide 15–25 mg per day; administer orally for 14 consecutive days on days 1–14, every 3 weeks for 8 cycles (total dose/cycle for 15 mg/day = 210 mg; total dose/cycle for 25 mg/day = 350 mg)

Cycles 1–4:

Dexamethasone 40 mg per dose; administer orally for 8 doses on days 1, 2, 4, 5, 8, 9, 11, and 12, every 3 weeks for 4 cycles (total dose/cycle = 320 mg), then

Cycles 5–8:

Dexamethasone 20 mg per dose; administer orally for 8 doses on days 1, 2, 4, 5, 8, 9, 11, and 12, every 3 weeks for 4 cycles (total dose/cycle = 160 mg)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is HIGH

Antimicrobial primary prophylaxis is recommended:

Antibacterial—consider fluoroquinolone prophylaxis; P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—recommended
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

Acyclovir and famciclovir elimination is inversely related to renal function
Acyclovir, famciclovir, and valacyclovir utilization is modified in renally impaired individuals (consult product labeling or Summary of Product Characteristics for guidance about dose/dosage and administration frequency modifications, and, when relevant, recommendations for drug dilution, administration rate, concurrent fluid administration, and fluid supplementation as a function of urine output)
Impaired acyclovir elimination is associated with neurologic adverse effects, including agitation, ataxia, coma, confusion, dizziness, dysarthria, encephalopathy, hallucinations, paresthesia, seizure, somnolence, and tremors

See Chapter 47 for more information

Decreased bowel motility prophylaxis

Give a bowel regimen to prevent constipation based initially on stool softeners

Thromboprophylaxis

Risk assessment and recommendations for VTE prophylaxis in patients with multiple myeloma with individual or myeloma-related risk factors, or risk factors related to treatment

| Download (.pdf) | Print

Individual risk factors

Obesity (BMI ≥30 kg/m²)
H/O VTE
CVC or pacemaker
Comorbid pathologies

Cardiac disease

Chronic renal disease

Diabetes

Acute infection

Immobilization
Surgery

General surgery

Any anesthesia

Trauma
Medications

Erythropoietin (epoetin alfa, darbepoetin)

Estrogenic compounds

Bevacizumab
Clotting disorders

Thrombophilia

Myeloma-related risk factors

Diagnosis of multiple myeloma
Hyperviscosity

≤1 Individual or myeloma risk factor present:

Aspirin 81–325 mg daily

≥2 Individual or myeloma risk factors present:

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or
Warfarin, targeting an INR = 2–3

Concomitant treatment-related risk factors

Thalidomide or lenalidomide in combination with:

High-dose dexamethasone (≥480 mg/month)
Doxorubicin
Multiagent chemotherapy

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or

Warfarin, targeting an INR = 2–3

CVC, central venous catheter; INR, international normalized ratio; LMWH, low-molecular-weight heparin; VTE, venous thromboembolic disease

Geerts WH et al. Chest 2008;133(6 Suppl):381S–453S

Multiple Myeloma, V.1.2014. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Palumbo A et al. Leukemia 2008;22:414–423

Venous Thromboembolic Disease, V.2.2013. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Bisphosphonates

All patients receiving primary therapy for symptomatic multiple myeloma should receive a bisphosphonate adjunctively; for example:

Pamidronate sodium 90 mg; administer intravenously over 2–4 hours, every month, or
Zoledronic acid 4 mg; administer intravenously over 15 minutes, every month

Consider baseline bone densitometry evaluation

See Chapter 43 for more information

Treatment Modifications

| Download (.pdf) | Print

Treatment Modifications

Adverse Event

Treatment Modification

Platelet count <30,000/mm³

Interrupt lenalidomide treatment, follow CBC weekly. Resume lenalidomide at 15 mg/day after platelet count is ≥30,000/mm³

For each subsequent platelet count <30,000/mm³

ANC <1000/mm³

Interrupt lenalidomide treatment, follow CBC weekly. Resume lenalidomide at 15 mg/day after ANC ≥1000/mm³

For each subsequent ANC <1000/mm³

Febrile neutropenia

Interrupt lenalidomide treatment, follow closely, and resume lenalidomide at 15 mg/day after fever abates

G3/4 non-hematologic toxicity

Interrupt lenalidomide treatment and follow clinically. After toxicity abates to G ≤2, resume lenalidomide at a dose decreased from the previous dose by 5 mg/day, but the daily dose should not be less than 5 mg/day

Toxicities ascribed to dexamethasone such as severe manifestations of hypercorticism, including hyperglycemia, irritability, insomnia, and oral candidiasis

Reduce dexamethasone dose to 20 mg per day

Treatment Modification for Bortezomib-Induced Peripheral Neuropathy^✫

Severity of Peripheral Neuropathy

Modifications of Dose and Schedule

G1 (paresthesias or loss of reflexes) without pain or loss of function

No action

G1 with pain or G2 (interferes with function but not with activities of daily living)

Reduce bortezomib dosage to 1 mg/m² per dose

G2 with pain or G3 (interferes with activities of daily living)

Withhold bortezomib treatment until toxicity resolves, then reinitiate at a dosage of 0.7 mg/m² per dose once weekly

G4 (permanent sensory loss that interferes with function)

Discontinue treatment

Lenalidomide Starting Dose Adjustment for Renal Impairment in Multiple Myeloma (Days 1–21 of Each 28-Day Cycle)

Moderate renal impairment CrCl 30–60 mL/min (0.5–1 mL/s)

10 mg lenalidomide every 24 hours

Severe renal impairment

CrCl <30 mL/min (<0.5 mL/s), not requiring dialysis

15 mg lenalidomide every 48 hours

End-stage renal disease

CrCl <30 mL/min (<0.5 mL/s), requiring dialysis

Lenalidomide 5 mg/day. On dialysis days, administer a daily dose following dialysis

CrCl, Creatinine clearance

^✫Richardson PG et al. J Clin Oncol 2006;24:3113–3120

Efficacy

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Efficacy

Best Response to Treatment for Treated and Phase II Populations

Response

All Patients (N = 66)

Phase II Population (N = 35)

Percentage

90% CI

Percentage

90% CI

20–39

24–52

nCR

5–19

10–34

VGPR

18–38

8–31

24–44

14–41

CR + nCR

29–50

42–71

CR + nCR + VGPR

56–76

59–86

At least PR

100

96–100

100

92–100

Estimated 18-month duration of response

68% (95% CI, 55–79%)

Percentages of Patients Achieving a Best Response of VGPR or Better, and Estimated 18-Month PFS Rates

Characteristic/Value

Response ≥VGPR n (%)

Estimated 18-Month PFS, % (95% CI)

Baseline Characteristic

All patients

100 (96–100)

75 (63–84)

ISS disease stage I

21 (72)

89 (70–96)

ISS disease stage II/III

23 (62)

65 (47–78)

Durie-Salmon disease stage I

12 (55)

82 (59–93)

Durie-Salmon disease stage II/III

32 (73)

72 (56–83)

β₂-Microglobulin

<3.5 mg/L

32 (73)

77 (61–87)

β₂-Microglobulin

≥3.5 mg/L

12 (55)

73 (49–87)

Albumin <3.5 g/dL

17 (71)

63 (40–78)

Albumin ≥3.5 g/dL

27 (64)

83 (67–91)

Cytogenetics Present

Abnormal metaphase cytogenetics = Yes

5 (83)

(27–97)

Abnormal metaphase cytogenetics = No

39 (65)

75 (62–84)

Del 13/13q by FISH = Yes

79 (57–91)

18 (75)

Del 13/13q by FISH = No

16 (59)

65 (43–80)

Del 17p by FISH = Yes

3 (60)

100

Del 17p by FISH = No

30 (67)

68 (52–80)

t(4;14) by FISH = Yes

2 (100)

100

t(4;14) by FISH = No

24 (62)

63 (46–77)

Cytogenetics Present

t(11;14) by FISH = Yes

7 (64)

73 (37–90)

t(11;14) by FISH = No

28 (70)

72 (55–83)

Del 17p and/or t(4;14) by FISH = Yes

4 (67)

100

Del 17p and/or t(4;14) by = No

29 (66)

68 (51–79)

Estimated 18-month OS (with/without ASCT)

97% (95% CI, 88–99%)

CI, confidence interval; CR, complete response; FISH, fluorescence in situ hybridization; ISS, International Staging System; nCR, near-complete response; OS, overall survival; PFS, progression-free survival; PR, partial response; VGPR, very good partial response

Note: Per European Group for Blood and Marrow Transplant criteria, all response categories required 2 confirmatory assessments at least 6 weeks apart

Patient Population Studied

A phase I/II study of 66 patients with newly diagnosed symptomatic multiple myeloma who had not previously received systemic antimyeloma therapy, and had a Karnofsky Performance Status ≥60%. Patients were excluded if they had G ≥2 peripheral neuropathy, serum creatinine >2.5 mg/dL (>221 μmol/L), platelets <50,000/mm³, ANC <1000/mm³, hemoglobin <8 g/dL, or transaminases ≥2 times the upper limit of normal range

Toxicity

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Toxicity

Adverse Events in ≥15% of Patients and All G3/4 (N = 66)

Event

% Total

% G3

% G4

Neuropathy, sensory^✫

Fatigue

Constipation

Edema limb

Muscle pain

Rash/desquamation

Diarrhea

Nausea

Neuropathic pain

Extremity, limb pain

Insomnia

Hyperglycemia

Dizziness

Constitutional

Dyspnea

Neuropathy, motor

Platelets

Pruritus/itching

Neutrophils

Anxiety

Dry skin

Lymphopenia

Vision, blurred

Alanine transaminase

Hypokalemia

Mental status

Hyperkalemia

Hyponatremia

Hypophosphatemia

Pulmonary/upper respiratory, other

Agitation

Hearing

Hemoglobin

QTc interval

Thrombosis/thrombus/embolism

Creatinine

Leukocytes

Atrial fibrillation

Infection, other

Stomach hemorrhage

^✫Including 34 (52%) = G1 and 18 (27%) = G2

Therapy Monitoring

Before each cycle: CBC with differential and blood chemistries (including BUN, creatinine, and calcium)
Every 6 weeks to 3 months: Measure serum and urine M-protein

REGIMEN: NEWLY DIAGNOSED MULTIPLE MYELOMA (TRANSPLANTATION CANDIDATES): INDUCTION PRIOR TO AUTOLOGOUS STEM CELL TRANSPLANTATION (ASCT) BORTEZOMIB + THALIDOMIDE + DEXAMETHASONE

Regimen: Newly Diagnosed Multiple Myeloma (Transplantation Candidates): Induction Prior to Autologous Stem Cell Transplantation (ASCT) Bortezomib + Thalidomide + Dexamethasone

Cavo M et al. Lancet 2010;376:2075–2085

Bortezomib 1.3 mg/m² per dose; administer by intravenous injection over 3–5 seconds for 4 doses on days 1, 4, 8, and 11, every 21 days for 3 cycles (total dosage/cycle = 5.2 mg/m²)

Thalidomide 200 mg/day; administer orally, continually, for 21 consecutive days on days 1–21, every 21 days for 3 cycles (total dose/cycle = 4200 mg)

Dexamethasone 40 mg per dose; administer orally for 8 doses on days 1, 2, 4, 5, 8, 9, 11, and 12, every 21 days for 3 cycles (total dose/cycle = 320 mg)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is HIGH

Antimicrobial primary prophylaxis is recommended:

Antibacterial—consider fluoroquinolone prophylaxis; P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—recommended
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

Acyclovir and famciclovir elimination is inversely related to renal function
Acyclovir, famciclovir, and valacyclovir utilization is modified in renally impaired individuals (consult product labeling or Summary of Product Characteristics for guidance about dose/dosage and administration frequency modifications, and, when relevant, recommendations for drug dilution, administration rate, concurrent fluid administration, and fluid supplementation as a function of urine output)
Impaired acyclovir elimination is associated with neurological adverse effects, including agitation, ataxia, coma, confusion, dizziness, dysarthria, encephalopathy, hallucinations, paresthesia, seizure, somnolence, and tremors

See Chapter 47 for more information

Thromboprophylaxis

Risk assessment and recommendations for VTE prophylaxis in patients with multiple myeloma with individual or myeloma-related risk factors, or risk factors related to treatment

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Individual risk factors

Obesity (BMI ≥30 kg/m²)
H/O VTE
CVC or pacemaker
Comorbid pathologies
Cardiac disease

Chronic renal disease

Diabetes

Acute infection

Immobilization
Surgery

General surgery

Any anesthesia

Trauma
Medications

Erythropoietin (epoetin alfa, darbepoetin)

Estrogenic compounds

Bevacizumab
Clotting disorders

Thrombophilia

Myeloma-related risk factors

Diagnosis of multiple myeloma
Hyperviscosity

≤1 Individual or myeloma risk factor present:

Aspirin 81–325 mg daily

≥2 Individual or myeloma risk factors present:

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or
Warfarin, targeting an INR = 2–3

Concomitant treatment-related risk factors

Thalidomide or lenalidomide in combination with:

High-dose dexamethasone (≥480 mg/month)
Doxorubicin
Multiagent chemotherapy

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or

Warfarin, targeting an INR = 2–3

CVC, central venous catheter; INR, international normalized ratio; LMWH, low-molecular-weight heparin; VTE, venous thromboembolic disease

Geerts WH et al. Chest 2008;133(6 Suppl):381S–453S

Multiple Myeloma, V.1.2014. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Palumbo A et al. Leukemia 2008;22:414–423

Venous Thromboembolic Disease, V.2.2013. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Bisphosphonates

All patients receiving primary therapy for symptomatic multiple myeloma should receive a bisphosphonate adjunctively; for example:

Pamidronate disodium 90 mg; administer intravenously over 2–4 hours, every month, or
Zoledronic acid 4 mg; administer intravenously over 15 minutes, every month

Consider baseline bone densitometry evaluation

See Chapter 43 for more information

Treatment Modifications

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Treatment Modifications

Bortezomib Dosage Levels

Dose Level 1

1.3 mg/m²

Dose Level −1

1 mg/m²

Dose Level −2

0.7 mg/m²

Thalidomide Dose Levels

Dose Level 1

200 mg daily

Dose Level –1

100 mg daily

Dose Level –2

50 mg daily

Adverse Event

Treatment Modification

Febrile neutropenia

Withhold therapy until fever abates then resume therapy

G4 hematologic toxicity

Withhold therapy until ANC >750/mm³ and platelets >50,000/mm³, then resume therapy at a dose decreased by 1 dose level

G3/4 nonhematologic toxicity

Interrupt therapy, follow clinically. After toxicity abates to G ≤2, resume therapy at a dose decreased by 1 dose level

G ≥3 thalidomide neuropathy

Interrupt therapy and follow clinically. After toxicity abates to G ≤2, resume therapy at a dose decreased by 1 dose level

Toxicities ascribed to dexamethasone such as severe manifestations of hypercorticism, including hyperglycemia, irritability, insomnia, and oral candidiasis

Reduce dexamethasone dose to 20 mg per dose

Treatment Modification for Bortezomib-Induced Peripheral Neuropathy^✫

Severity of Peripheral Neuropathy

Modification of Dose and Schedule

G1 (paresthesias or loss of reflexes) without pain or loss of function

No action

G1 with pain or G2 (interferes with function, but not with activities of daily living)

Reduce bortezomib dosage to 1 mg/m² per dose

G2 with pain or G3 (interferes with activities of daily living)

Withhold bortezomib treatment until toxicity resolves, then reinitiate at a dosage of 0.7 mg/m² per dose once weekly

G4 (permanent sensory loss that interferes with function)

Discontinue treatment

^✫Richardson PG et al. J Clin Oncol 2006;24:3113–3120

Patient Population Studied

A phase III study of 480 patients, ages 18 to 65 years, with previously untreated, symptomatic newly diagnosed multiple myeloma who were eligible for stem cell transplantation

Eligible subjects demonstrated a Karnofsky performance status ≥60%, adequate hematologic function (ANC ≥1000/mm³ and platelet count ≥70,000/mm³), and serum creatinine ≤2 mg/dL (≤177 μmol/L). Patients with peripheral neuropathy G ≥2, a history of venous thromboembolism, or a previous diagnosis of thrombophilic alterations, were ineligible

Efficacy

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Efficacy

Response to Different Treatment Phases and Best Response

N = 236

% (95% CI)

After Induction Therapy

Complete response

19% (13.7–23.6)

Complete or near complete response

31% (25–36.8)

Very good partial response or better

62% (55.7–68.1)

Partial response or better

93% (90–96.4)

Minimal response or stable disease

7% (3.6–10)

Progressive disease

5% (2.3–7.8)

After First Autologous Stem Cell Transplantation

Complete response

38% (31.5–43.9)

Complete or near complete response

52% (45.7–58.5)

Very good partial response or better

79% (73.6–84)

Partial response or better

93% (90–96.4)

Minimal response or stable disease

6% (3.2–9.5)

Progressive disease

<1% (0–1.3)

After Second Autologous Stem Cell Transplantation

Complete response

42% (35.2–47.8)

Complete or near complete response

55% (48.7–61.4)

Very good partial response or better

82% (76.9–86.7)

Partial response or better

93% (90–96.4)

Minimal response or stable disease

6% (2.9–8.9)

Progressive disease

8% (4.9–11.9)

After Consolidation Therapy

Complete response

49% (42.8–55.5)

Complete or near complete response

62% (56.1–68.5)

Very good partial response or better

85% (80.6–89.7)

Partial response or better

92% (89–95.8)

Minimal response or stable disease

5% (2.3–7.9)

Progressive disease

9% (5.2–12.4)

Best Response to Overall Treatment Protocol

Complete response

58% (51.3–63.9)

Complete or near complete response

71% (65.4–77)

Very good partial response or better

89% (85–93)

Partial response or better

96% (93.7–98.6)

Minimal response, stable disease, or progressive disease

4% (1.4–6.3)

Toxicity

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Toxicity

Serious and G3/4 Adverse Events Reported in ≥2% of Patients During Induction Therapy

Any serious adverse event

13%

Any grade 3 or 4 adverse event

56%

Any grade 3 or 4 nonhematologic adverse event

51%

Skin rash

10%

Peripheral neuropathy

10%

Deep vein thrombosis

Constipation

Infections excluding herpes zoster

Gastrointestinal events (excluding constipation)

Cardiac toxicity

Liver toxicity

Discontinuation during or after induction therapy

Toxic effects

Disease progression

Other reasons

Early death

<1%

Nonhematologic Adverse Events of Any Grade Reported in at Least 10% of Patients During Induction Therapy (N = 236)

% G1–4

% G3/4

Constipation

Neuropathy

Skin rash

Fever

Infections

Edema

Gastrointestinal events (excluding constipation)

Therapy Monitoring

Before each cycle: CBC with differential and blood chemistries (including BUN, creatinine, and calcium)
Every 6 weeks to 3 months: Measure serum and urine M-protein

REGIMEN: NEWLY DIAGNOSED MULTIPLE MYELOMA (TRANSPLANTATION CANDIDATES): INDUCTION PRIOR TO AUTOLOGOUS STEM CELL TRANSPLANTATION (ASCT) BORTEZOMIB + DOXORUBICIN + DEXAMETHASONE

Regimen: Newly Diagnosed Multiple Myeloma (Transplantation Candidates): Induction Prior to Autologous Stem Cell Transplantation (ASCT) Bortezomib + Doxorubicin + Dexamethasone

Sonneveld P et al. J Clin Oncol 2012;30:2946–2955

Induction:

Bortezomib 1.3 mg/m² per dose intravenously over 3–5 seconds for 4 doses on days 1, 4, 8, and 11, every 28 days for 3 cycles (total dosage/cycle = 5.2 mg/m²)

Doxorubicin 9 mg/m² per day by slow intravenous injection over 3–5 minutes for 4 consecutive days on days 1–4, every 28 days for 3 cycles (total dosage/cycle = 36 mg/m²)

Dexamethasone 40 mg/dose orally for 12 doses on days 1–4, days 9–12, and days 17–20 for 3 cycles (total dose/cycle = 480 mg)

Notes:

Stem cell collection was performed 4–6 weeks after induction
High-dose melphalan (HDM) 200 mg/m², and autologous stem cell transplantation (ASCT) were administered
Starting 4 weeks after HDM, patients received maintenance with bortezomib 1.3 mg/m² intravenously every 2 weeks for 2 years
Patients with an HLA-identical sibling could proceed to nonmyeloablative allogeneic stem cell transplantation (alloSCT) after HDM
Maintenance therapy was not given after alloSCT

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days with doxorubicin is LOW

Emetogenic potential on days with bortezomib ± dexamethasone is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is INTERMEDIATE

Antimicrobial primary prophylaxis to be considered:

Antibacterial—consider a fluoroquinolone or no prophylaxis; Pneumocystis jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—recommended; consider use during periods of neutropenia
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir) throughout bortezomib induction

See Chapter 47 for more information

Steroid-associated gastritis

Add a proton pump inhibitor during steroid use to prevent gastritis and duodenitis

Thromboprophylaxis

Risk assessment and recommendations for VTE prophylaxis in patients with multiple myeloma with individual or myeloma-related risk factors, or risk factors related to treatment

| Download (.pdf) | Print

Individual risk factors

Obesity (BMI ≥30 kg/m²)
H/O VTE
CVAD or pacemaker
Comorbid pathologies

Cardiac disease

Chronic renal disease

Diabetes

Acute infection

Immobilization
Surgery

General surgery

Any anesthesia

Trauma
Medications

Erythropoietin (epoetin alfa, darbepoetin)

Estrogenic compounds

Bevacizumab
Clotting disorders

Thrombophilia

Myeloma-related risk factors

Diagnosis of multiple myeloma
Hyperviscosity

≤1 Individual or myeloma risk factor present:

Aspirin 81–325 mg daily

≥2 Individual or myeloma risk factors present:

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or
Warfarin, targeting an INR = 2–3

Concomitant treatment-related risk factors

Thalidomide or lenalidomide in combination with:

High-dose dexamethasone (≥480 mg/month)
Doxorubicin
Multiagent chemotherapy

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or

Warfarin, targeting an INR = 2–3

CVAD, central vascular access device; INR, international normalized ratio; LMWH, low-molecular-weight heparin; VTE, venous thromboembolic disease

Geerts WH et al. Chest 2008;133(6 Suppl):381S–453S

Multiple Myeloma, V.1.2014. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Palumbo A et al. Leukemia 2008;22:414–423

Venous Thromboembolic Disease, V.2.2013. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Bisphosphonates

All patients receiving primary therapy for symptomatic multiple myeloma should receive a bisphosphonate adjunctively; for example:

Pamidronate disodium 90 mg; administer intravenously over 2–4 hours, every month, or
Zoledronic acid 4 mg; administer intravenously over at least 15 minutes, every month

Consider baseline bone densitometry evaluation

See Chapter 43 for more information

Treatment Modifications

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Treatment Modifications

Adverse Event

Treatment Modification

G3 nonhematologic toxicity or G4 hematologic toxicity

Hold treatment until toxicity resolves to G ≤1, then resume with bortezomib 1 mg/m² per dose and/or 25% reduction in doxorubicin dosage

G3 nonhematologic toxicity or G4 hematologic toxicity in a patient receiving bortezomib 1 mg/m²

Hold treatment until toxicity resolves to G ≤1, then resume with bortezomib 0.7 mg/m² per dose and/or 25% reduction in doxorubicin dosage

Severe manifestations of hypercorticism, including severe hyperglycemia, irritability, insomnia, or oral candidiasis

Reduce daily dexamethasone dose by 20% for G3 toxicity, and by 40% for G4 or recurrent G3 toxicity

Treatment Modification for Bortezomib-Induced Peripheral Neuropathy^✫

Severity of Peripheral Neuropathy

Modification of Dose and Schedule

G1 (paresthesias or loss of reflexes) without pain or loss of function

No action

G1 with pain or G2 (interferes with function but not with activities of daily living)

Reduce bortezomib dosage to 1 mg/m² per dose

G2 with pain or G3 (interferes with activities of daily living)

Withhold bortezomib treatment until toxicity resolves, then reinitiate with bortezomib 0.7 mg/m² per dose once weekly

G4 (permanent sensory loss that interferes with function)

Discontinue treatment

^✫Richardson PG et al. J Clin Oncol 2006;24:3113–3120

Patient Population Studied

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Patient Population Studied

Patients 18–65 years of age with newly diagnosed MM (Durie-Salmon stages II to III) WHO performance status 0 to 2, or WHO 3 when caused by MM. Exclusion criteria were systemic amyloid light chain amyloidosis, nonsecretory MM, neuropathy G ≥2, serum bilirubin ≥1.8 mg/dL (≥30 μmol/L) or aminotransferases ≥2.5 times the upper limit of normal range. Prior corticosteroids were allowed for a maximum of 5 days. Patients with renal impairment were not excluded. Local radiotherapy for painful MM lesions was allowed

Patient Characteristic (N = 413)

No (%)

ISIS Stage

144 (35)

150 (36)

III

81 (20)

38 (9)

M-Protein Isotype

IgA

92 (22)

IgG

251 (61)

IgD

5 (1)

LCD

63 (15)

Other

M-Protein Light Chain [unknown = 1 (0%)]

Kappa

277 (67)

Lambda

135 (33)

Creatinine, mg/dL [unknown = 1 (0%)]

≤2

376 (91)

36 (9)

Number of Skeletal Lesions [unknown 5 12 (3%)]

102 (25)

1–2

44 (11)

≥3

255 (62)

Serum LDH [unknown = 12 (3%)]

≤ULN

329 (80)

>ULN

72 (17)

Genetic Abnormalities

del(13q) done in 361 (88%)

148/361 (41)

t(4;14) done in 250 (615)

35/250 (14)

del(17p13) done in 289 (70%)

25/289 (9)

Hematologic Abnormalities

Median β₂-microglobulin, mg/L

3.40

Median hemoglobin, mmol/L

6.6

Median calcium, mmol/L

2.34

Median number of bone marrow plasma cells

Efficacy (N = 413)

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Efficacy (N = 413)

Response

Number (%)

Response After Induction

29 (7)

≥nCR

46 (11)

≥VGPR

174 (42)

≥PR

322 (78)

Response After High-Dose Melphalan (HDM)

85 (21)

≥nCR

127 (31)

≥VGPR

254 (62)

≥PR

363 (88)

Response Overall

147 (36)

≥nCR

201 (49)

≥VGPR

312 (76)

≥PR

373 (90)

Response Upgrade During Maintenance

Any response upgrade^✫

93 (23)

CR → CR

48 (12)

nCR → nCR

23 (6)

VGPR → VGPR

20 (5)

PR → PR

2^✫

ISS Stage I (n = 144)

59 (41)

≥nCR

78 (54)

≥VGPR

115 (80)

≥PR

132 (92)

ISS Stage II (n = 150)

51 (34)

≥nCR

70 (47)

≥VGPR

109 (73)

≥PR

134 (89)

ISS Stage III (n = 81)

26 (32)

≥nCR

35 (43)

≥VGPR

56 (69)

≥PR

70 (86)

ISS Stage Unknown (n = 38)

11 (29)

≥nCR

18 (47)

≥VGPR

32 (84)

≥PR

37 (97)

β₂-Microglobulin >3 mg/L (n = 223)

77 (35)

≥nCR

103 (46)

≥VGPR

163 (73)

≥PR

189 (79)

Creatinine >2 mg/dL (n = 36)

13 (36)

≥nCR

19 (53)

≥VGPR

28 (78)

≥PR

31 (86)

Genetic Abnormalities

del(13/13q14) (n = 148)

≥nCR

76 (51)

≥VGPR

124 (84)

t(4;14) (n = 35)

≥nCR

20 (57)

≥VGPR

30 (86)

del(17p13) (δ = 25)

≥nCR

13 (52)

≥VGPR

18 (72)

CR, complete response; ISS, International Staging System; nCR, near complete response; PR, partial response; VGPR, very good partial response

^✫Median time to any response upgrade after start of maintenance was 7 months (range: 1–57 months)

Median PFS

35 months

Median PFSA (ie, without censoring of alloSCT)

34 months

Median OS

Not reached at 66 months

5-year OS

61%

PFS calculated from the time of last HDM

31 months

Toxicity

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Toxicity

Variable

Induction (n = 410)

Bortezomib Maintenance (n = 229)

No.

Any AE

400

222

AE G3/4

258

110

AE classified as SAE

187

AE leading to discontinuation, dose reduction, or delay of bortezomib

112

Death from AE

All Grades

G3/4

All Grades

G3/4

Hematologic Toxicities (%)

Anemia

Neutropenia

Thrombocytopenia

Infections

Herpes zoster

Nonhematologic Toxicities (%)

Wasting, fatigue

GI symptoms

Cardiac disorders

Thrombosis

Peripheral neuropathy

AE, adverse event (including infection); N/A, not applicable; SAE, serious adverse event

Therapy Monitoring

Blood counts and physical examinations on day 1 of each cycle
Serum and urinary protein electrophoresis studies on day 1 of each cycle as indicated and at the end of treatment

REGIMEN: NEWLY DIAGNOSED MULTIPLE MYELOMA (TRANSPLANTATION CANDIDATES): INDUCTION PRIOR TO AUTOLOGOUS STEM CELL TRANSPLANTATION (ASCT) CYCLOPHOSPHAMIDE + BORTEZOMIB + DEXAMETHASONE (CyBorD)

Regimen: Newly Diagnosed Multiple Myeloma (Transplantation Candidates): Induction Prior to Autologous Stem Cell Transplantation (ASCT) Cyclophosphamide + Bortezomib + Dexamethasone (CyBorD)

Reeder CB et al. Leukemia 2009;23:1337–1341

Bortezomib 1.3 mg/m² per dose intravenously over 3–5 seconds for 4 doses on days 1, 4, 8, and 11, every 28 days, for 4 cycles (total dosage/cycle = 5.2 mg/m²)

Cyclophosphamide 300 mg/m² per dose orally for 4 doses on days 1, 8, 15, and 22, every 28 days, for 4 cycles (total dosage/cycle = 1200 mg/m²)

Dexamethasone 40 mg/dose orally for 12 doses on days 1–4, days 9–12, and days 17–20 for 3 cycles (total dose/cycle = 480 mg)

Notes:

Dose escalation was not allowed
At the end of 4 cycles patients proceeded to stem cell mobilization and harvest

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days with cyclophosphamide is MODERATE–HIGH

Emetogenic potential on days with bortezomib ± dexamethasone is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis may be indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is INTERMEDIATE

Antimicrobial primary prophylaxis to be considered:

Antibacterial—consider a fluoroquinolone or no prophylaxis; Pneumocystis jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—recommended; consider use during periods of neutropenia
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir) throughout bortezomib induction

See Chapter 47 for more information

Steroid-associated gastritis

Add a proton pump inhibitor during steroid use to prevent gastritis and duodenitis

Thromboprophylaxis

Risk assessment and recommendations for VTE prophylaxis in patients with multiple myeloma with individual or myeloma-related risk factors, or risk factors related to treatment

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Individual risk factors

Obesity (BMI ≥30 kg/m²)
H/O VTE
CVAD or pacemaker
Comorbid pathologies

Cardiac disease

Chronic renal disease

Diabetes

Acute infection

Immobilization
Surgery

General surgery

Any anesthesia

Trauma
Medications

Erythropoietin (epoetin alfa, darbepoetin)

Estrogenic compounds

Bevacizumab
Clotting disorders

Thrombophilia

Myeloma-related risk factors

Diagnosis of multiple myeloma
Hyperviscosity

≤1 Individual or myeloma risk factor present:

Aspirin 81–325 mg daily

≥2 Individual or myeloma risk factors present:

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or
Warfarin, targeting an INR = 2–3

Concomitant treatment-related risk factors

Thalidomide or lenalidomide in combination with:

High-dose dexamethasone (≥480 mg/month)
Doxorubicin
Multiagent chemotherapy

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or

Warfarin, targeting an INR = 2–3

CVAD, central vascular access device; INR, international normalized ratio; LMWH, low-molecular-weight heparin; VTE, venous thromboembolic disease

Geerts WH et al. Chest 2008;133(6 Suppl):381S–453S

Multiple Myeloma, V.1.2014. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Palumbo A et al. Leukemia 2008;22:414–423

Venous Thromboembolic Disease, V.2.2013. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Bisphosphonates

All patients receiving primary therapy for symptomatic multiple myeloma should receive a bisphosphonate adjunctively; for example:

Pamidronate disodium 90 mg; administer intravenously over 2–4 hours, every month, or
Zoledronic acid 4 mg; administer intravenously over at least 15 minutes, every month

Consider baseline bone densitometry evaluation

See Chapter 43 for more information

Treatment Modifications

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Treatment Modifications

Note: Dose reduction was allowed after the first cycle, but cyclophosphamide and bortezomib can be held during cycle 1 for neutropenia or thrombocytopenia G ≥3

Cyclophosphamide Dose Levels

Starting dose

300 mg/m² per dose on days 1, 8, 15, and 22

Level –1

300 mg/m² per dose on days 1, 8, and 15

Level –2

300 mg/m² per dose on days 1 and 8

Level –3

300 mg/m² on day 1

Adverse Event

Treatment Modification

G3 hematologic toxicity

Reduce cyclophosphamide 1 dose level

G1/2 cystitis

Reduce cyclophosphamide 1 dose level

G3/4 cystitis

Discontinue cyclophosphamide

Bortezomib Dose Levels

Starting dose

1.3 mg/m² per dose on days 1, 4, 8, and 11

Level –1

1 mg/m² per dose on days 1, 4, 8, and 11

Level –2

0.7 mg/m² per dose on days 1, 4, 8, and 11

Level –3

1.3 mg/m² per dose on days 1 and 8

Adverse Event

Treatment Modification

G3 thrombocytopenia (platelet count <50,000/mm³)

Reduce bortezomib dosage by 1 dose level

Treatment Modification for Bortezomib-Induced Peripheral Neuropathy^✫

Severity of Peripheral Neuropathy

Modification of Dose and Schedule

G1 (paresthesias or loss of reflexes) without pain or loss of function

No action

G1 with pain or G2 (interferes with function but not with activities of daily living)

Reduce bortezomib dosage 1 dose level

G2 with pain or G3 (interferes with activities of daily living)

Withhold bortezomib treatment until toxicity resolves, then reinitiate reducing bortezomib dosage 1 dose level

G4 (permanent sensory loss that interferes with function)

Discontinue treatment

Dexamethasone Dose Levels

Starting dose

40 mg per dose on days 1–4, 9–12, and 17–20

Level –1

20 mg per dose on days 1–4, 9–12, and 17–20

Level –2

20 mg per dose on days 1–4

Level –3

10 mg per dose on days 1–4

Adverse Event

Treatment Modification

G2 muscle weakness, G3 gastrointestinal tract, hyperglycemia, confusion or mood alteration

Reduce dexamethasone dose by 1 dose level

^✫Richardson PG et al. J Clin Oncol 2006;24:3113–3120

Efficacy

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Efficacy

Responses

By ITT (N = 33)

By ITT if Completed 4 Cycles (N = 28)

After SCT (N = 23)

ORR (≥PR)

29 (88%)

27 (96%)

23 (100%)

≥VGPR

20 (61%)^✫

20 (71%)

17 (74%)

9 (27%)

7 (25%)

6 (26%)

ITT, intention to treat; ORR, overall response (partial response or better); PR, partial response; SCT, stem cell transplantation; ≥VGPR, very good partial response or better

^✫One in CR, 12 in nCR, and 7 in VGPR

Risk Category as Assessed by Bone Marrow Plasma Cell Fish Analysis and ISS Stage, and Corresponding Response After 4 Cycles

Risk Category

Frequency

ORR

≥VGPR

Deletion 13

50% (16/32)

94% (15/16)

63% (10/16)

Deletion 17

13% (4/31)

75% (3/4)

50% (2/4)

t(4;14)

18% (6/33)

83% (5/6)

50% (3/6)

Hyperdiploid

21% (7/33)

100% (7/7)

71% (5/7)

ISS stage 3

30% (10/33)

80% (8/10)

60% (6/10)

FISH, fluorescent in situ hybridization; ISS, international staging system; ORR, overall response; VGPR, very good partial response

Therapy Monitoring

Blood counts and physical examinations on day 1 of each cycle
Serum and urinary protein electrophoresis studies on day 1 of each cycle as indicated and at the end of treatment

Patient Population Studied

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Patient Population Studied

Newly diagnosed, symptomatic MM of Durie–Salmon stage II or III, Eastern Cooperative Oncology Group performance status ≤2, creatinine ≤3.5 mg/dL (≤309 μmol/L), absolute neutrophil count ≥1000/mm³, platelets ≥100,000/mm³

Patient Characteristics

Mean age

60 (38–75) years

Gender: M/F

52%/48%

International Staging System, stages I/II/III,

33/36/30%

Durie–Salmon stage II or III; symptomatic disease

100%

del13 in 16/32

16/32 (50%)

del17^✫

4/31 (13%)

t(4;14)^✫

6/33 (18%)

Favorable hyperdiploid karyotype

7/33 (21%)

^✫Genetic high-risk categories

Toxicity

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Toxicity

Adverse Events

G3/4^✫

Anemia

12%

Neutropenia

13%

Thrombocytopenia

25%

Hyperglycemia

13%

Diarrhea

Hypokalemia

Neuropathy

Thrombosis

^✫National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0) severity grades

REGIMEN: NEWLY DIAGNOSED MULTIPLE MYELOMA (TRANSPLANTATION CANDIDATES): INDUCTION PRIOR TO AUTOLOGOUS STEM CELL TRANSPLANTATION (ASCT) CARFILZOMIB + LENALIDOMIDE + DEXAMETHASONE (CRd)

Regimen: Newly Diagnosed Multiple Myeloma (Transplantation Candidates): Induction Prior to Autologous Stem Cell Transplantation (ASCT) Carfilzomib + Lenalidomide + Dexamethasone (CRd)

Jakubowlak AJ et al. Blood 2012;120:1801–1809

Hydration with carfilzomib: During cycle 1, days 1 and 2, administer intravenously 250–500 mL 0.9% NS before each carfilzomib dose, and an additional 250–500 mL of fluid after carfilzomib. During repeated treatments, continue intravenous hydration as needed. Encourage oral hydration

Carfilzomib 36 mg/m² per dose intravenously in 50-mL 5% dextrose injection over 30 minutes

Cycles 1–8: for 6 doses, on days 1, 2, 8, 9, 15, and 16, every 28 days (total dosage/cycle = 216 mg/m²)
Cycle 9 and subsequent cycles: for 4 doses, on days 1, 2, 15, and 16, every 28 days (total dosage/cycle = 144 mg/m²)

Lenalidomide 25 mg/day orally, continually for 21 consecutive days on days 1–21, every 28 days (total dose/cycle = 525 mg)

Dexamethasone administer orally or intravenously for 4 doses on days 1, 8, 15, and 22, every 28 days

Cycles 1–4: 40 mg/dose (total dose/cycle = 160 mg)
Cycle 5 and subsequent cycles: 20 mg/dose (total dose/cycle = 80 mg)

Notes:

After cycle 4, transplantation-eligible candidates underwent stem cell collection (SCC) then continued CRd with the option of transplantation
Thirty-five patients underwent SCC, 7 proceeded to transplantation, and the remainder resumed CRd
After 8 cycles, patients received maintenance CRd. Per initial design, CRd maintenance was planned for an indefinite period of time, but because progression events were limited and no maintenance treatments were discontinued because of toxicity, the study was amended to 24 total cycles of CRd. After completion of 24 cycles, single-agent lenalidomide off protocol was recommended

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days with lenalidomide ± carfilzomib is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis may be indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is INTERMEDIATE

Antimicrobial primary prophylaxis to be considered:

Antibacterial—consider a fluoroquinolone or no prophylaxis; Pneumocystis jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—recommended; consider use during periods of neutropenia
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

Steroid-associated gastritis

Add a proton pump inhibitor during steroid use to prevent gastritis and duodenitis

Thromboprophylaxis

Risk assessment and recommendations for VTE prophylaxis in patients with multiple myeloma with individual or myeloma-related risk factors, or risk factors related to treatment

| Download (.pdf) | Print

Individual risk factors

Obesity (BMI ≥30 kg/m²)
H/O VTE
CVAD or pacemaker
Comorbid pathologies

Cardiac disease

Chronic renal disease

Diabetes

Acute infection

Immobilization
Surgery

General surgery

Any anesthesia

Trauma
Medications

Erythropoietin (epoetin alfa, darbepoetin)

Estrogenic compounds

Bevacizumab
Clotting disorders

Thrombophilia

Myeloma-related risk factors

Diagnosis of multiple myeloma
Hyperviscosity

≤1 Individual or myeloma risk factor present:

Aspirin 81–325 mg daily

≥2 Individual or myeloma risk factors present:

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or
Warfarin, targeting an INR = 2–3

Concomitant treatment-related risk factors

Thalidomide or lenalidomide in combination with:

High-dose dexamethasone (≥480 mg/month)
Doxorubicin
Multiagent chemotherapy

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or

Warfarin, targeting an INR = 2–3

CVAD, central vascular access device; INR, international normalized ratio; LMWH, low-molecular-weight heparin; VTE, venous thromboembolic disease

Geerts WH et al. Chest 2008;133(6 Suppl):381S–453S

Multiple Myeloma, V.1.2014. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Palumbo A et al. Leukemia 2008;22:414–423

Venous Thromboembolic Disease, V.2.2013. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Bisphosphonates

All patients receiving primary therapy for symptomatic multiple myeloma should receive a bisphosphonate adjunctively; for example:

Pamidronate disodium 90 mg; administer intravenously over 2–4 hours, every month, or
Zoledronic acid 4 mg; administer intravenously over at least 15 minutes, every month

Consider baseline bone densitometry evaluation

See Chapter 43 for more information

Diarrhea management

Loperamide 4 mg orally initially after the first loose or liquid stool, then

Loperamide 2 mg orally every 2 hours during waking hours, plus

Loperamide 4 mg orally every 4 hours during hours of sleep

Continue for at least 12 hours after diarrhea resolves
Recurrent diarrhea after a 12-hour diarrhea-free interval is treated as a new episode
Rehydrate orally with fluids and electrolytes during a diarrheal episode
If a patient develops blood or mucus in stool, dehydration, or hemodynamic instability, or if diarrhea persists >48 hours despite loperamide, stop loperamide and hospitalize the patient for IV hydration

Alternatively, a trial of Diphenoxylate hydrochloride 2.5 mg with Atropine sulfate 0.025 mg (eg, Lomotil)

Initial adult dose is 2 tablets 4 times daily until control has been achieved, after which the dose may be reduced to meet individual requirements. Control may often be maintained with as little as 2 tablets daily
Clinical improvement of acute diarrhea is usually observed within 48 hours. If improvement of chronic diarrhea after treatment with a maximum daily dose of 8 tablets is not observed within 10 days, control is unlikely with further administration

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Lenalidomide Starting Dose Adjustment for Renal Impairment in Multiple Myeloma (Days 1–21 of Each 28-Day Cycle)^✫

Moderate renal impairment: CrCl 30–60 mL/min (0.5–1 mL/s)

Lenalidomide 10 mg q24h

Severe renal impairment: CrCl <30 mL/min (<30 mL/s), not requiring dialysis

Lenalidomide 15 mg q48h

End-stage renal disease: requiring dialysis

Lenalidomide 5 mg/day. On dialysis days, administer the daily dose following dialysis

CrCl, creatinine clearance

^✫Richardson PG et al. J Clin Oncol 2006;24:3113–3120

Treatment Modifications

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Treatment Modifications

Carfilzomib Dose Levels

Starting dose

36 mg/m² per dose

Level –1

27 mg/m² per dose

Level –2

20 mg/m² per dose

Level –3

15 mg/m² per dose

Level –4

11 mg/m² per dose

Level –5

Discontinue

Adverse Event

Treatment Modification

Hematologic Toxicity

G3/4 neutropenia

Hold carfilzomib dosing for up to 21 days to resolve toxicity and then restart at the same dosage, or reduce the carfilzomib dosage by 1 dose level. If counts recover to G2 neutropenia or G3 thrombocytopenia, reduce carfilzomib dosage by 1 dose level. If tolerated, the reduced dose may be escalated to the previous dose level

Febrile neutropenia (ANC <1000/mm³ with fever ≥38°C)

G4 thrombocytopenia

G3/4 thrombocytopenia associated with bleeding

Nonhematologic Toxicity

G3/4 cardiac toxicity

New onset or worsening:

Congestive heart failure
Decreased left ventricular function
Myocardial ischemia

Hold carfilzomib dosing for up to 21 days to resolve toxicity and then restart at the same dosage or reduce the carfilzomib dosage by 1 dose level. If tolerated, the reduced dosage may be escalated to the previous dose level

Pulmonary hypertension

G3/4 pulmonary complications

G3/4 elevation of transaminases, bilirubin, or other liver abnormalities

Nonhematologic Toxicity

Serum creatinine ≥2× baseline

If attributable to carfilzomib, hold carfilzomib doses for up to 21 days to resolve toxicity to G1 or to baseline and then restart at the same dosage, or reduce the carfilzomib dosage by 1 dose level. If tolerated, the reduced dosage may be escalated to the previous dose level

G2 neuropathy with pain

Hold carfilzomib dosing for up to 21 days to resolve toxicity and then restart at the same dose, or reduce the carfilzomib dosage by 1 dose level. If tolerated, the reduced dosage may be escalated to the previous dose level

G3/4 peripheral neuropathy

Other G3/4 nonhematologic toxicities

If attributable to carfilzomib, hold carfilzomib doses for up to 21 days to resolve toxicity to G1 or to baseline and then restart at the same dosage or reduce the carfilzomib dosage by 1 dose level. If tolerated, the reduced dosage may be escalated to the previous dose level

Lenalidomide Dose Levels

Starting dose

25 mg/day

Level –1

20 mg/day

Level –2

15 mg/day

Level –3

10 mg/day

Level –4

5 mg/day

Level –5

Discontinue

Adverse Event

Treatment Modification

G3/4 neutropenia

Hold lenalidomide dosing for up to 21 days to resolve toxicity and then restart at the same dosage or reduce the lenalidomide dosage by 1 dose level

Febrile neutropenia (ANC <1000/mm³ with fever ≥38°C)

G3/4 nonhematologic toxicity

Hold lenalidomide dosing for up to 21 days to resolve toxicity to G ≤2 and then restart at the same dosage or reduce the lenalidomide dosage by 1 dose level

Any adverse event G ≥3 (excluding nausea, vomiting, diarrhea, lenalidomide-induced maculopapular rash or dexamethasone-induced hyperglycemia)
G ≥3 nausea, vomiting, or diarrhea despite maximal therapy
G4 fatigue lasting >7 days

Hold carfilzomib and lenalidomide dosing for up to 21 days to resolve toxicity to G ≤2 and then, depending on presumed attribution of toxicity, restart at the same dosage or reduce the carfilzomib dosage and/or lenalidomide daily dose by 1 dose level

Toxicities ascribed to dexamethasone such as severe manifestations of hypercorticism, including hyperglycemia, irritability, insomnia, or oral candidiasis

Hold dexamethasone dosing for up to 21 days to resolve toxicity and then restart at the same dose, or reduce dexamethasone doses by 50%

Patient Population Studied

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Patient Population Studied

Enrolled both transplantation-eligible and -ineligible patients with newly diagnosed, symptomatic MM. Patients were required to have an Eastern Cooperative Oncology Group performance status of 0–2. Patients were ineligible if they had G3/4 neuropathy, and an estimated creatinine clearance <50 mL/min (<0.83 mL/s) or serum creatinine ≥2 g/dL (>177 μmol/L)

Baseline Characteristics

Characteristics

N = 53

Age

Median, years (range)

59 (35–81)

≥65 years, n (%)

23 (43)

Sex

Male, n (%)

39 (74)

Female

14 (26)

ISS Stage, n (%)

21 (40)

18 (34)

III

14 (26)

Durie-Salmon Stage, n (%)

7 (13)

12 (24)

III

34 (63)

Unfavorable cytogenetics, n (%)^✫

17/51 (33)

del 13^†/hypodiploidy

10/50 (20)

t(4;14)

5/49 (10)

t(14;16)

0/48

del 17p

7/48 (15)

ISS, International Staging System

^✫One or more of the abnormalities listed

^†del 13 by metaphase only

Efficacy

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Efficacy

Best Response to Treatment in Evaluable Patients

Responses, n (%)

≥PR

≥VGPR

≥nCR

sCR

All patients (N = 53)

52 (98)

43 (81)

33 (62)

22 (42)

Treatment Duration

>4 cycles (n = 49)

49 (100)

43 (88)

33 (67)

22 (45)

>8 cycles (n = 36)

36 (100)

33 (92)

28 (78)

22 (61)

>12 cycles (n = 29)

29 (100)

25 (86)

21 (72)

18 (62)

nCR, near-complete response; PR, partial response; sCR, stringent complete response; VGPR, very good partial response

Best Response to Treatment by Carfilzomib Dose, ISS Stage, and Cytogenetics (N = 53)^✫

Responses, n (%)

≥PR

≥VGPR

≥nCR

sCR

Carfilzomib Dose, mg/m²

20 (n = 4)

4 (100)

3 (75)

1 (25)

27 (n = 13)

13 (100)

10 (77)

7 (54)

36 (n = 36)

35 (97)

26 (72)

20 (55)

14 (39)

ISS Stage

I (n = 21)

21 (100)

16 (76)

12 (57)

7 (33)

II (n = 18)

18 (100)

15 (75)

10 (55)

8 (44)

III (n = 14)

13 (93)

12 (86)

11 (79)

7 (50)

Cytogenetics

Normal/favorable (n = 34)^†

34 (100)

26 (76)

20 (59)

13 (38)

Unfavorable (n = 17)^†

16 (94)

13 (76)

11 (65)

9 (53)

ISS, International Staging System; nCR, near-complete response; PR, partial response; sCR, stringent complete response; VGPR, very good partial response

^✫Assessed by Modified International Myeloma Working Group (IMWG) Uniform Criteria with the addition of nCR

^†Any of del 13 by metaphase or hypodiploidy or t(4;14) or t(14;16) or del 17p considered as unfavorable; all others considered normal/favorable

Toxicity

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Toxicity

Treatment-Emergent Adverse Events During Induction (Cycles 1–8; N = 53)

Any Grade, n (%)

G3/4, n (%)

Nonhematologic

Hyperglycemia

38 (72)

12 (23)

Edema

25 (47)

2 (4)

Hypophosphatemia

24 (45)

13 (25)

Fatigue

20 (38)

1 (2)

Muscle cramping

17 (32)

Rash

15 (28)

4 (8)

Elevated liver function test

15 (28)

4 (8)

Diarrhea

14 (26)

Infection^✫

12 (23)

2 (4)

Phlebitis

12 (23)

Peripheral neuropathy

12 (23)^†

Dyspnea

8 (15)

2 (4)

Deep vein thrombosis

6 (11)

2 (4)

Pulmonary embolism

3 (6)

Nausea

7 (13)

Renal

5 (9)

1 (2)

Constipation

5 (9)

Mood alterations

5 (9)

1 (2)

Hematologic

Thrombocytopenia

36 (68)

9 (17)

Anemia

32 (60)

11 (21)

Neutropenia

16 (30)

9 (17)

^✫Grade 3/4 events were pneumonia, and grade 1/2 events were upper respiratory infections

^†Three (6%) grade 2, remaining grade 1

Therapy Monitoring

Blood counts and physical examinations on day 1 of each cycle
Serum and urinary protein electrophoresis studies on day 1 of each cycle as indicated and at the end of treatment

REGIMEN: NEWLY DIAGNOSED MULTIPLE MYELOMA (TRANSPLANTATION CANDIDATES): INDUCTION PRIOR TO AUTOLOGOUS STEM CELL TRANSPLANTATION (ASCT) THALIDOMIDE + DEXAMETHASONE

Regimen: Newly Diagnosed Multiple Myeloma (Transplantation Candidates): Induction Prior to Autologous Stem Cell Transplantation (ASCT) Thalidomide + Dexamethasone

Rajkumar SV et al. J Clin Oncol 2006;24:431–436

Four-week cycles:

Thalidomide 200 mg/day; administer orally, continually, for 4 weeks (total dose/4-week cycle = 5600 mg)

Dexamethasone 40 mg/dose; administer orally for three 4-day periods on days 1 to 4, 9 to 12, and 17 to 20, every 4 weeks (total dose/4-week cycle = 480 mg)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL - LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is INTERMEDIATE

Antimicrobial primary prophylaxis to be considered:

Antibacterial—consider a fluoroquinolone or no prophylaxis; P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—consider concomitant use of clotrimazole during periods of neutropenia
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

Caution: Acyclovir and famciclovir accumulate in patients with impaired renal function and may exacerbate renal dysfunction (valacyclovir is a prodrug for acyclovir). Monitor kidney function serially during acyclovir, valacyclovir, and famciclovir use
- Acyclovir and famciclovir elimination is inversely related to renal function
- Acyclovir, famciclovir, and valacyclovir utilization is modified in renally impaired individuals (consult product labeling or Summary of Product Characteristics for guidance about dose/dosage and administration frequency modifications, and, when relevant, recommendations for drug dilution, administration rate, concurrent fluid administration, and fluid supplementation as a function of urine output)
- Impaired acyclovir elimination is associated with neurologic adverse effects, including: agitation, ataxia, coma, confusion, dizziness, dysarthria, encephalopathy, hallucinations, paresthesia, seizure, somnolence, and tremors

See Chapter 47 for more information

Thromboprophylaxis

Risk assessment and recommendations for VTE prophylaxis in patients with multiple myeloma with individual or myeloma-related risk factors, or risk factors related to treatment

| Download (.pdf) | Print

Individual risk factors

Obesity (BMI ≥30 kg/m²)
H/O VTE
CVC or pacemaker
Comorbid pathologies

Cardiac disease

Chronic renal disease

Diabetes

Acute infection

Immobilization
Surgery

General surgery

Any anesthesia

Trauma
Medications

Erythropoietin (epoetin alfa, darbepoetin)

Estrogenic compounds

Bevacizumab
Clotting disorders

Thrombophilia

Myeloma-related risk factors

Diagnosis of multiple myeloma
Hyperviscosity

≤1 Individual or myeloma risk factor present:

Aspirin 81–325 mg daily

≥2 Individual or myeloma risk factors present:

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or
Warfarin, targeting an INR = 2–3

Concomitant treatment-related risk factors

Thalidomide or lenalidomide in combination with:

High-dose dexamethasone (≥480 mg/month)
Doxorubicin
Multiagent chemotherapy

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or

Warfarin, targeting an INR = 2–3

CVC, central venous catheter; INR, international normalized ratio; LMWH, low-molecular-weight heparin; VTE, venous thromboembolic disease

Geerts WH et al. Chest 2008;133(6 Suppl):381S–453S

Multiple Myeloma, V.1.2014. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Palumbo A et al. Leukemia 2008;22:414–423

Venous Thromboembolic Disease, V.2.2013. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Bisphosphonates

All patients receiving primary therapy for symptomatic multiple myeloma should receive a bisphosphonate adjunctively; for example:

Pamidronate disodium 90 mg; administer intravenously over 2–4 hours, every month, or
Zoledronic acid 4 mg; administer intravenously over 15 minutes, every month

Consider baseline bone densitometry evaluation

See Chapter 43 for more information

Treatment Modifications

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Treatment Modifications

Thalidomide Dose Levels

Dose Level 1

200 mg daily

Dose Level −1

100 mg daily

Dose Level −2

50 mg daily

Adverse Event

Treatment Modification

Febrile neutropenia

Withhold therapy until fever abates, then resume therapy

G4 hematologic toxicity

Withhold therapy until ANC >750/mm³ and platelets >50,000/mm³, then resume therapy with thalidomide dose decreased by 1 dose level

G3/4 nonhematologic toxicity

Interrupt therapy and follow clinically. After toxicity abates to G ≤2, resume therapy with thalidomide dose decreased by 1 dose level

G ≥3 thalidomide neuropathy

Toxicities ascribed to dexamethasone such as severe manifestations of hypercorticism, including hyperglycemia, irritability, insomnia, and oral candidiasis

Reduce dexamethasone dose to 20 mg per dose

Efficacy

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Efficacy

Best response within 4 cycles of therapy

63%

Complete response within 4 cycles of therapy

Disease progression within 4 cycles of therapy

Stem cell harvest efficiency

90%

Patient Population Studied

Phase III trial of 207 patients with newly diagnosed, previously untreated, measurable myeloma. Patients were eligible to enter onto the study if they had previously untreated symptomatic multiple myeloma, bone marrow plasmacytosis (≥10% plasma cells or sheets of plasma cells), or a biopsy-proven plasmacytoma, and measurable disease defined as serum monoclonal protein >1 g/dL and/or urine monoclonal protein ≥200 mg/24 hours. Study eligibility criteria also included hemoglobin >7 g/dL, platelet count >50,000 cells/mm³, absolute neutrophil count >1000 cells/mm³, creatinine <3 mg/dL (<265 μmol/L), bilirubin ≤1.5 mg/dL (≤26 μmol/L), and ALT and AST ≤2.5-times the upper limit of normal. No prior systemic therapy was permitted with the exception of bisphosphonates

Toxicity (N = 102)

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Toxicity (N = 102)

Grade 3/4 neutropenia

Deep venous thrombosis (G ≥3)

17%

Skin rash (G ≥3)

Sinus bradycardia (G ≥3)

Peripheral neuropathy (G ≥3)

Toxicity of any type (G ≥4)

34%

Treatment-related deaths

G ≥3 Thrombosis/embolism

20%

G ≥3 Hyperglycemia

15%

G ≥3 Fatigue

15%

G ≥3 Dyspnea

11%

G ≥3 Hypocalcemia

G ≥3 Confusion

G ≥3 Constipation

G ≥3 Neuropathy-motor

G ≥3 Muscle weakness

G ≥3 Edema

G ≥3 Pneumonitis/pulmonary infiltrates

G ≥3 Hyponatremia

G ≥3 Hypotension

G ≥3 Dehydration

G ≥3 Neuropathy-sensory

G ≥3 Rash/desquamation

G ≥3 Nausea

G ≥3 Hypoxia

G ≥3 Depressed level of consciousness

G ≥3 Anorexia

G ≥3 Seizure

Therapy Monitoring

Before each cycle: CBC with differential and blood chemistries (including BUN, creatinine, and calcium)
Every 6 weeks to 3 months: Measure serum and urine M-protein

REGIMEN: NEWLY DIAGNOSED MULTIPLE MYELOMA (ELDERLY AND THOSE NOT TRANSPLANTATION CANDIDATES): MELPHALAN + PREDNISONE + THALIDOMIDE (MPT)

Regimen: Newly Diagnosed Multiple Myeloma (Elderly and Those Not Transplantation Candidates): Melphalan + Prednisone + Thalidomide (MPT)

Palumbo A et al. Lancet 2006;367:825–831

Palumbo A et al. Blood 2008;112:3107–3114

Induction:

Melphalan 4 mg/m² per day; administer orally for 7 consecutive days on days 1–7, every 4 weeks, for 6 cycles (total dosage/cycle = 28 mg/m²)

Prednisone 40 mg/m² per day; administer orally for 7 consecutive days on days 1–7, every 4 weeks, for 6 cycles (total dosage/cycle = 280 mg/m²)

Thalidomide 100 mg/day; administer orally for 28 consecutive day on days 1–28, every 4 weeks for 6 cycles (total dose/cycle = 2800 mg)

Maintenance:

Thalidomide 100 mg/day; administer orally, continually, until confirmation of relapsed or refractory disease (total dose/week = 700 mg)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL–LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is INTERMEDIATE

Antimicrobial primary prophylaxis to be considered:

Antibacterial—consider a fluoroquinolone or no prophylaxis; P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—consider concomitant use of clotrimazole during periods of neutropenia
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

Acyclovir and famciclovir elimination is inversely related to renal function
Acyclovir, famciclovir, and valacyclovir utilization is modified in renally impaired individuals (consult product labeling or Summary of Product Characteristics for guidance about dose/dosage and administration frequency modifications, and, when relevant, recommendations for drug dilution, administration rate, concurrent fluid administration, and fluid supplementation as a function of urine output)
Impaired acyclovir elimination is associated with neurologic adverse effects, including agitation, ataxia, coma, confusion, dizziness, dysarthria, encephalopathy, hallucinations, paresthesia, seizure, somnolence, and tremors

See Chapter 47 for more information

Thromboprophylaxis

Risk assessment and recommendations for VTE prophylaxis in patients with multiple myeloma with individual or myeloma-related risk factors, or risk factors related to treatment

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Individual risk factors

Obesity (BMI ≥30 kg/m²)
H/O VTE
CVC or pacemaker
Comorbid pathologies

Cardiac disease

Chronic renal disease

Diabetes

Acute infection

Immobilization
Surgery

General surgery

Any anesthesia

Trauma
Medications

Erythropoietin (epoetin alfa, darbepoetin)

Estrogenic compounds

Bevacizumab
Clotting disorders

Thrombophilia

Myeloma-related risk factors

Diagnosis of multiple myeloma
Hyperviscosity

≤1 Individual or myeloma risk factor present:

Aspirin 81–325 mg daily

≥2 Individual or myeloma risk factors present:

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or
Warfarin, targeting an INR = 2–3

Concomitant treatment-related risk factors

Thalidomide or lenalidomide in combination with:

High-dose dexamethasone (≥480 mg/month)
Doxorubicin
Multiagent chemotherapy

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or

Warfarin, targeting an INR = 2–3

CVC, central venous catheter; INR, international normalized ratio; LMWH, low-molecular-weight heparin; VTE, venous thromboembolic disease

Geerts WH et al. Chest 2008;133(6 Suppl):381S–453S

Multiple Myeloma, V.1.2014. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Palumbo A et al. Leukemia 2008;22:414–423

Venous Thromboembolic Disease, V.2.2013. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Bisphosphonates

All patients receiving primary therapy for symptomatic multiple myeloma should receive a bisphosphonate adjunctively; for example:

Pamidronate sodium 90 mg; administer intravenously over 2–4 hours, every month, or
Zoledronic acid 4 mg; administer intravenously over 15 minutes, every month

Consider baseline bone densitometry evaluation

See Chapter 43 for more information

Treatment Modifications

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Treatment Modifications

Melphalan Dosage Levels

Dosage Level 1

4 mg/m²

Dosage Level −1

3 mg/m²

Dosage Level −2

2 mg/m²

Adverse Event

Treatment Modification

Febrile neutropenia

Withhold therapy until fever abates, then resume therapy

G4 hematologic toxicity

Withhold therapy until ANC >750/mm³ and platelets >50,000/mm³, then resume therapy with the melphalan dose decreased by 1 dose level

G3/4 nonhematologic toxicity

Interrupt therapy and follow clinically. After toxicity abates to G ≤2, resume therapy with thalidomide dose decreased by 1 dose level

G ≥3 thalidomide neuropathy

If ANC nadir is ≤1000/mm³ or platelets nadir is ≤50,000/mm³

Continue treatment, but reduce melphalan dosage by 1 level

G2 nonhematologic toxicity

Reduce thalidomide dose by 50% to 50 mg/day

G ≥3 nonhematologic toxicity

Discontinue thalidomide

G3 toxicities ascribed to prednisone such as severe manifestations of hypercorticism, including hyperglycemia, irritability, insomnia, and oral candidiasis

Reduce daily prednisone dosage by 20%

G4 or recurrent G3 toxicities ascribed to prednisone such as severe manifestations of hypercorticism, including hyperglycemia, irritability, insomnia, and oral candidiasis

Reduce daily prednisone dosage by 40%

Patient Population Studied

A multicenter randomized trial of 331 previously untreated patients with Durie and Salmon stage II or III multiple myeloma who were older than 65 years (or younger but unable to undergo transplantation), and had measurable disease. Exclusion criteria included any G2 peripheral neuropathy. Abnormal cardiac function, chronic respiratory disease, and abnormal liver or renal function were not criteria for exclusion

Efficacy (N = 129)

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Efficacy (N = 129)

Complete or partial response

76%

Complete response

15.5%

Partial response

60.4%

Near-complete response

12.4%

90% to 99% myeloma protein reduction

8.5%

50% to 89% myeloma protein reduction

39.5%

Minimal response

5.4%

No response

5.4%

Progressive disease

7.8%

Responses not available

5.4%

Progression free survival^✫

21.8 months

Median overall survival^†

45 months

^✫After a median follow-up of 38.1 months. The magnitude of PFS benefit was consistent irrespective of age, serum concentrations of β₂-microglobulin, or high International Staging System

^†The median OS of 45 months for melphalan + prednisone (MP) + thalidomide (T) compared to a median OS of 47.6 months for MP was not statistically significant (P = 0.79). New agents in the management of relapsed disease could explain this finding

Toxicity (N = 129)

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Toxicity (N = 129)

Adverse Event

G3/4 Adverse Events

Percent of Patients

≥1 Event

48%

Hematologic

22%

Neutropenia

16%

Anemia

Thrombocytopenia

Thrombosis/embolism

12%

Deep venous thrombosis

Pulmonary embolism

Neurologic

10%

Peripheral neuropathy

Somnolence or fatigue

Infection

10%

Pneumonia

Fever of unknown origin

Herpes zoster

Upper respiratory

Cardiac

Arrhythmia

Myocardial infarction/angina

Cardiac failure

Hypertension

Gastrointestinal

Constipation

Mucositis

Dermatologic

Rash

Toxic epidermal necrolysis

Renal

Creatinine increase

Edema

Bleeding

Therapy Monitoring

Before each cycle: CBC with differential and blood chemistries (including BUN, creatinine, and calcium)
Every 6 weeks to 3 months: Measure serum and urine M-protein

REGIMEN: NEWLY DIAGNOSED MULTIPLE MYELOMA (NOT TRANSPLANTATION CANDIDATES): BORTEZOMIB + MELPHALAN + PREDNISONE

Regimen: Newly Diagnosed Multiple Myeloma (Not Transplantation Candidates): Bortezomib + Melphalan + Prednisone

San Miguel JF et al. N Engl J Med 2008;359:906–917

All Cycles:

Melphalan 9 mg/m² per day; administer orally for 4 consecutive days on days 1–4, every 6 weeks, for 9 cycles (total dosage/cycle = 36 mg/m²)

Prednisone 60 mg/m² per day; administer orally for 4 consecutive days on days 1–4, every 6 weeks, for 9 cycles (total dosage/cycle = 240 mg/m²), plus

Cycles 1–4:

Bortezomib 1.3 mg/m² per dose; administer by intravenous injection over 3–5 seconds for 8 doses, on days 1, 4, 8, 11, 22, 25, 29, and 32, every 6 weeks, for 4 cycles (total dosage/cycle = 10.4 mg/m²)

Cycles 5–9:

Bortezomib 1.3 mg/m² per dose; administer by intravenous injection over 3–5 seconds for 4 doses on days 1, 8, 22, and 29, every 6 weeks, for 5 cycles (total dosage/cycle = 5.2 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL–LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is HIGH

Antimicrobial primary prophylaxis is recommended:

Antibacterial—consider fluoroquinolone prophylaxis; P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—recommended
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

Acyclovir and famciclovir elimination is inversely related to renal function
Acyclovir, famciclovir, and valacyclovir utilization is modified in renally impaired individuals (consult product labeling or Summary of Product Characteristics for guidance about dose/dosage and administration frequency modifications, and, when relevant, recommendations for drug dilution, administration rate, concurrent fluid administration, and fluid supplementation as a function of urine output)
Impaired acyclovir elimination is associated with neurologic adverse effects, including agitation, ataxia, coma, confusion, dizziness, dysarthria, encephalopathy, hallucinations, paresthesia, seizure, somnolence, and tremors

See Chapter 47 for more information

Decreased bowel motility prophylaxis

Give a bowel regimen to prevent constipation based initially on stool softeners

Thromboprophylaxis

Risk assessment and recommendations for VTE prophylaxis in patients with multiple myeloma with individual or myeloma-related risk factors, or risk factors related to treatment

| Download (.pdf) | Print

Individual risk factors

Obesity (BMI ≥30 kg/m²)
H/O VTE
CVC or pacemaker
Comorbid pathologies

Cardiac disease

Chronic renal disease

Diabetes

Acute infection

Immobilization
Surgery

General surgery

Any anesthesia

Trauma
Medications

Erythropoietin (epoetin alfa, darbepoetin)

Estrogenic compounds

Bevacizumab
Clotting disorders

Thrombophilia

Myeloma-related risk factors

Diagnosis of multiple myeloma
Hyperviscosity

≤1 Individual or myeloma risk factor present:

Aspirin 81–325 mg daily

≥2 Individual or myeloma risk factors present:

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or
Warfarin, targeting an INR = 2–3

Concomitant treatment-related risk factors

Thalidomide or lenalidomide in combination with:

High-dose dexamethasone (≥480 mg/month)
Doxorubicin
Multiagent chemotherapy

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or

Warfarin, targeting an INR = 2–3

CVC, central venous catheter; INR, international normalized ratio; LMWH, low-molecular-weight heparin; VTE, venous thromboembolic disease

Geerts WH et al. Chest 2008;133(6 Suppl):381S–453S

Multiple Myeloma, V.1.2014. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Palumbo A et al. Leukemia 2008;22:414–423

Venous Thromboembolic Disease, V.2.2013. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Bisphosphonates

All patients receiving primary therapy for symptomatic multiple myeloma should receive a bisphosphonate adjunctively; for example:

Pamidronate sodium 90 mg; administer intravenously over 2–4 hours, every month, or
Zoledronic acid 4 mg; administer intravenously over 15 minutes, every month

Consider baseline bone densitometry evaluation

See Chapter 43 for more information

Treatment Modifications

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Treatment Modifications

Bortezomib Dosage Levels (per dose)

Dosage Level 1

1.3 mg/m²

Dosage Level −1

1 mg/m²

Dosage Level −2

0.7 mg/m²

Melphalan Dose Levels (per day)

Dosage Level 1

9 mg/m²

Dosage Level −1

6.75 mg/m²

Dosage Level −2

4.5 mg/m²

Adverse Event

Treatment Modification

Febrile neutropenia

Withhold therapy until fever abates then resume therapy

G4 hematologic toxicity

Withhold therapy until ANC >750/mm³ and platelets >50,000/mm³, then resume therapy with bortezomib and mel-pha-lan dosages decreased by 1 dose level

G3/4 nonhematologic toxicity

Withhold therapy. After toxicity abates to G ≤2, resume therapy with bortezomib and melphalan dosages decreased by 1 dose level

G≥3 thalidomide neuropathy

Continue treatment, but reduce thalidomide dose by 1 dose level

If ANC nadir is ≤1000/mm³ or platelets nadir is ≤50,000/mm³

Continue treatment, but reduce borte-zomib and melphalan dosages by 1 level

G3 toxicities ascribed to prednisone such as severe manifestations of hypercorticism, including hyper-glycemia, irritability, insomnia, or oral candidiasis

Reduce daily prednisone dosage by 20%

G4 or recurrent G3 toxicities ascribed to prednisone such as severe manifestations of hypercorticism, including hyperglycemia, irritability, insomnia, or oral candidiasis

Reduce daily prednisone dosage by 40%

Treatment Modification for Bortezomib-Induced Peripheral Neuropathy^✫

Severity of Peripheral Neuropathy

Modification of Dose and Schedule

G1 (paresthesias or loss of reflexes) without pain or loss of function

No action

G1 with pain, or G2 (interferes with function but not with activities of daily living)

Reduce bortezomib dosage to 1 mg/m² per dose

G2 with pain, or G3 (interferes with activities of daily living)

Withhold bortezomib treatment until toxicity resolves, then reinitiate at a dosage of 0.7 mg/m² per dose once weekly

G4 (permanent sensory loss that interferes with function)

Discontinue treatment

^✫Richardson PG et al. J Clin Oncol 2006;24:3113–3120

Patient Population Studied

A randomized, open-label, phase III trial of 682 patients with newly diagnosed, untreated, symptomatic, measurable myeloma who, because of age (≥65 years), were not candidates for high-dose therapy plus stem cell transplantation

Efficacy (N = 337)

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Efficacy (N = 337)^✫

European Group for Blood and Marrow Transplantation (EBMT) Criteria

Complete or partial response

71%

Complete response

30%

Partial response

40%

Minimal response

Stable disease

18%

Progressive disease

Time to Event

Median time to response^†

First response (months)

1.4

Complete response

4.2

Median duration of response^†

Complete or partial response

19.9

Complete response

Time to subsequent myeloma therapy^‡

Not reached

Treatment-free interval^‡

Not reached

International Uniform Response Criteria^§

Complete, very good partial, or partial response

74%

Complete response

33%

Very good partial response

Partial response

33%

Stable disease

23%

Progressive disease

^✫Seven patients could not be evaluated for a response. Among patients evaluated, responses were not determined for 4. Percentages may not total 100 because of rounding

^†Data determined by computer algorithm, applying EBMT criteria

^‡Data based on 344 patients

^§Of 79 patients considered to have stable disease on the basis of International Uniform Response Criteria who could be evaluated, 4 patients (1%) had negative results on immunofixation (complete response) and 19 (6%) had a reduction of at least 50% in M-protein (partial response). These patients were not recorded as having a complete or partial response because confirmatory results were missing. If these patients are included, the response rate is 81% and the complete-response rate is 34%. Patients could not be assessed for the category of stringent complete response because immunohistochemical, immunofluorescence, and free light-chain assays were not performed. International Uniform Response Criteria do not require changes in M-protein be confirmed a minimum of 6 weeks after the initial assessment

Toxicity (N = 340)^✫

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Toxicity (N = 340)^✫

G1/2

Any Event

Hematologic Events^†

Thrombocytopenia

Neutropenia

Anemia

Leukopenia

Lymphopenia

Gastrointestinal Events

Nausea

Diarrhea

Constipation

Vomiting

Infections

Pneumonia

Herpes zoster

Nervous System Disorders

Peripheral sensory neuropathy

Neuralgia

Dizziness

Other Conditions

Pyrexia

Fatigue

Asthenia

Cough

Insomnia

Peripheral edema

Rash

Back pain

Dyspnea

Hypokalemia

Arthralgia

Deep venous thrombosis

^✫Listed adverse events were reported in ≥15% of patients, and G3 or G4 events were reported in ≥5% of patients. Patients may have more than 1 adverse event. Included are all patients who received at least 1 dose of a study drug

^†Rates of red cell transfusions were 26%; erythropoiesis-stimulating agents for treatment-related anemia were used in 30% of patients

Therapy Monitoring

Before each cycle: CBC with differential and blood chemistries (including BUN, creatinine, and calcium)
Every 6 weeks to 3 months: Measure serum and urine M-protein

REGIMEN: NEWLY DIAGNOSED MULTIPLE MYELOMA NOT TRANSPLANTATION CANDIDATES: MELPHALAN + PREDNISONE + LENALIDOMIDE

Regimen: Newly Diagnosed Multiple Myeloma Not Transplantation Candidates: Melphalan + Prednisone + Lenalidomide

Palumbo A et al. J Clin Oncol 2007;25:4459–4465

Induction:

Melphalan 0.18 mg/kg per day; administer orally for 4 consecutive days on days 1–4, every 4 weeks, for 9 cycles (total dosage/cycle = 0.72 mg/kg)

Prednisone 2 mg/kg per day; administer orally for 4 consecutive days on days 1–4, every 4 weeks, for 9 cycles (total dosage/cycle = 8 mg/kg)

Lenalidomide 10 mg per day; administer orally for 21 consecutive days on days 1–21, every 4 weeks, for 9 cycles (total dose/cycle = 210 mg)

Maintenance:

Lenalidomide 10 mg/day; administer orally for 21 consecutive days on days 1–21, every 4 weeks until signs of relapse or disease progression (total dose/cycle = 210 mg)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL–LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is INTERMEDIATE

Antimicrobial primary prophylaxis to be considered:

Antibacterial—consider a fluoroquinolone or no prophylaxis; P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—consider concomitant use of clotrimazole during periods of neutropenia
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

Acyclovir and famciclovir elimination is inversely related to renal function
Acyclovir, famciclovir, and valacyclovir utilization is modified in renally impaired individuals (consult product labeling or Summary of Product Characteristics for guidance about dose/dosage and administration frequency modifications, and, when relevant, recommendations for drug dilution, administration rate, concurrent fluid administration, and fluid supplementation as a function of urine output)
Impaired acyclovir elimination is associated with neurological adverse effects, including agitation, ataxia, coma, confusion, dizziness, dysarthria, encephalopathy, hallucinations, paresthesia, seizure, somnolence, and tremors

See Chapter 47 for more information

Decreased bowel motility prophylaxis

Give a bowel regimen to prevent constipation based initially on stool softeners

Thromboprophylaxis

Risk assessment and recommendations for VTE prophylaxis in patients with multiple myeloma with individual or myeloma-related risk factors, or risk factors related to treatment

| Download (.pdf) | Print

Individual risk factors

Obesity (BMI ≥30 kg/m²)
H/O VTE
CVC or pacemaker
Comorbid pathologies

Cardiac disease

Chronic renal disease

Diabetes

Acute infection

Immobilization
Surgery

General surgery

Any anesthesia

Trauma
Medications

Erythropoietin (epoetin alfa, darbepoetin)

Estrogenic compounds

Bevacizumab
Clotting disorders

Thrombophilia

Myeloma-related risk factors

Diagnosis of multiple myeloma
Hyperviscosity

≤1 Individual or myeloma risk factor present:

Aspirin 81–325 mg daily

≥2 Individual or myeloma risk factors present:

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or
Warfarin, targeting an INR = 2–3

Concomitant treatment-related risk factors

Thalidomide or lenalidomide in combination with:

High-dose dexamethasone (≥480 mg/month)
Doxorubicin
Multiagent chemotherapy

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or

Warfarin, targeting an INR = 2–3

CVC, central venous catheter; INR, international normalized ratio; LMWH, low-molecular-weight heparin; VTE, venous thromboembolic disease

Geerts WH et al. Chest 2008;133(6 Suppl):381S–453S

Multiple Myeloma, V.1.2014. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Palumbo A et al. Leukemia 2008;22:414–423

Venous Thromboembolic Disease, V.2.2013. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Bisphosphonates

All patients receiving primary therapy for symptomatic multiple myeloma should receive a bisphosphonate adjunctively; for example:

Pamidronate sodium 90 mg; administer intravenously over 2–4 hours, every month, or
Zoledronic acid 4 mg; administer intravenously over 15 minutes, every month

Consider baseline bone densitometry evaluation

See Chapter 43 for more information

Treatment Modifications

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Treatment Modifications

Lenalidomide Dose Levels

Dose Level 1

10 mg/day

Dose Level −1

5 mg/day

Melphalan Dose Levels

Dosage Level 1

0.18 mg/kg

Dosage Level −1

0.135 mg/kg

Adverse Event

Treatment Modification

Febrile neutropenia

Withhold therapy until fever abates, then resume therapy

G4 neutropenia for ≥7 days despite filgrastim administration, any other G4 hematologic toxicities, or any G ≥3 nonhematologic toxicities

Withhold therapy until toxicities resolve to G ≤2 then resume therapy with a subsequent dose/dosage reduction in lenalidomide and melphalan at the start of the following cycle

G ≥3 neuropathy

Interrupt therapy and follow clinically. After toxicity abates to G ≤2, resume lenalidomide with a dose decreased by 1 dose level

G3/4 non-hematologic toxicity

Interrupt lenalidomide treatment and follow clinically. Resume lenalidomide at 5 mg/day after toxicity abates to G ≤2

ANC <1000/mm³, platelet count <50,000/mm³, or nonhematologic adverse events G ≥2

Withhold therapy as long as 2 weeks until ANC ≥1000/mm³, platelet count is ≥50,000/mm³, and nonhematologic toxicities are G ≤1, then resume therapy. A delay of 2 weeks is allowed without any dose modification. A new cycle delay beyond a maximum of 2 weeks requires a dose/dosage reduction in lenalidomide and melphalan by 1 dose level

Toxicities ascribed to prednisone such as severe manifestations of hypercorticism, including: hyperglycemia, irritability, insomnia, or oral candidiasis

Reduce prednisone dose to 20 mg/day

Lenalidomide Starting Dose Adjustment for Renal Impairment in Multiple Myeloma (Days 1–21 of Each 28-Day Cycle)^✫

Moderate renal impairment

CrCl 30–60 mL/min (0.5–1 mL/s)

10 mg lenalidomide every 24 hours

Severe renal impairment

CrCl <30 mL/min, not requiring dialysis

15 mg lenalidomide every 48 hours

End-stage renal disease

CrCl <30 mL/min, requiring dialysis

Lenalidomide 5 mg/day. On dialysis days, administer a daily dose following dialysis

CrCl, Creatinine clearance

^✫Richardson PG et al. J Clin Oncol 2006;24:3113–3120

Patient Population Studied

Phase I/II trial of 54 patients ages ≥65 years or younger if ineligible for high-dose therapy for newly diagnosed multiple myeloma. Karnofsky performance status ≥60%; platelet count ≥75,000/mm³; absolute neutrophil count ≥1500/mm³; corrected serum calcium ≤3.5 mmol/L (≤14 mg/dL)

Therapy Monitoring

Before each cycle: CBC with differential and blood chemistries (including BUN, creatinine, and calcium)
Every 6 weeks to 3 months: Measure serum and urine M-protein

Efficacy

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Efficacy

Dose Levels Evaluated

3 (MTD)

Lenalidomide (mg)

Melphalan (mg/kg)

0.18

0.25

0.18

0.25

Number of patients

Complete or partial response

66.7

83.3

CR, immunofixation negative

—

23.8

VGPR

—

33.3

23.8

Partial response

66.7

33.3

Minimal response

33.3

16.7

No response

—

Progressive Disease

—

Median time to best response

4 months

PR > first cycle

52.9%

PR > third cycle

66%

PR > sixth cycle

79.2%

1-year event-free survival

92.3% (95% CI, 85.1 to 99.5)

1-year event-free survival at MTD

95.2% (95% CI, 93.2 to 97.3).

1-year overall survival in all patients

100% (95% CI, 91.8% to 100%)

CR, complete response; MTD, Maximum tolerated doses; PR, partial response; VGPR, very good partial response

Toxicity

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Toxicity

Total G3/4 Events

Total G1/2 Events

Hematologic Events

Neutropenia

67.9%

Thrombocytopenia

32.1%

Anemia

17%

Nonhematologic Events

Infective

Febrile neutropenia

9.4%

—

Pneumonia

1.9%

5.7%

Upper respiratory

—

13.2%

Dermatologic events

Rash

3.8%

35.8%

Vasculitis

3.8%

1.9%

Thromboembolism

Deep venous thrombosis

3.8%

—

Pulmonary embolism

1.9%

—

Constitutional events

Fatigue

3.8%

43.4%

Fever

—

18.9%

Gastrointestinal events

Constipation

—

24.5%

Diarrhea

1.9%

22.6%

Nausea

—

18.9%

Anorexia

—

17%

Neurologic events

Mood alterations

1.9%

9.4%

Dizziness

—

3.8%

ND, Not determined

Note: G1/2 adverse events reported by ≥10% of patients or G3/4 adverse events reported by ≥3% of patients

REGIMEN: RELAPSED/REFRACTORY MULTIPLE MYELOMA: BORTEZOMIB ± DEXAMETHASONE

Regimen: Relapsed/Refractory Multiple Myeloma: Bortezomib ± Dexamethasone

Richardson PG et al. N Engl J Med 2003;348:2609–2617

Bortezomib 1.3 mg/m² per dose; administer by intravenous injection over 3–5 seconds for 4 doses on days 1, 4, 8, and 11, every 21 days (total dosage/cycle = 5.2 mg/m²)

In patients with disease progression after 2 cycles, or stable disease after 4 cycles, add:

Dexamethasone 20 mg per dose; administer orally for 8 doses on days 1, 2, 4, 5, 8, 9, 11, and 12, every 21 days (total dose/cycle = 160 mg)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is HIGH

Antimicrobial primary prophylaxis is recommended:

Antibacterial—consider fluoroquinolone prophylaxis; P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—recommended
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

Acyclovir and famciclovir elimination is inversely related to renal function
Acyclovir, famciclovir, and valacyclovir utilization is modified in renally impaired individuals (consult product labeling or Summary of Product Characteristics for guidance about dose/dosage and administration frequency modifications, and, when relevant, recommendations for drug dilution, administration rate, concurrent fluid administration, and fluid supplementation as a function of urine output)
Impaired acyclovir elimination is associated with neurological adverse effects, including agitation, ataxia, coma, confusion, dizziness, dysarthria, encephalopathy, hallucinations, paresthesia, seizure, somnolence, and tremors

See Chapter 47 for more information

Decreased bowel motility prophylaxis

Give a bowel regimen to prevent constipation based initially on stool softeners

Thromboprophylaxis

Risk assessment and recommendations for VTE prophylaxis in patients with multiple myeloma with individual or myeloma-related risk factors, or risk factors related to treatment

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Individual risk factors

Obesity (BMI ≥30 kg/m²)
H/O VTE
CVC or pacemaker
Comorbid pathologies

Cardiac disease

Chronic renal disease

Diabetes

Acute infection

Immobilization
Surgery

General surgery

Any anesthesia

Trauma
Medications

Erythropoietin (epoetin alfa, darbepoetin)

Estrogenic compounds

Bevacizumab
Clotting disorders

Thrombophilia

Myeloma-related risk factors

Diagnosis of multiple myeloma
Hyperviscosity

≤1 Individual or myeloma risk factor present:

Aspirin 81–325 mg daily

≥2 Individual or myeloma risk factors present:

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or
Warfarin, targeting an INR = 2–3

Concomitant treatment-related risk factors

Thalidomide or lenalidomide in combination with:

High-dose dexamethasone (≥480 mg/month)
Doxorubicin
Multiagent chemotherapy

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or

Warfarin, targeting an INR = 2–3

CVC, central venous catheter; INR, international normalized ratio; LMWH, low-molecular-weight heparin; VTE, venous thromboembolic disease

Geerts WH et al. Chest 2008;133(6 Suppl):381S–453S

Multiple Myeloma, V.1.2014. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Palumbo A et al. Leukemia 2008;22:414–423

Venous Thromboembolic Disease, V.2.2013. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Bisphosphonates

All patients receiving primary therapy for symptomatic multiple myeloma should receive a bisphosphonate adjunctively; for example:

Pamidronate disodium 90 mg; administer intravenously over 2–4 hours, every month, or
Zoledronic acid 4 mg; administer intravenously over 15 minutes, every month

Consider baseline bone densitometry evaluation

See Chapter 43 for more information

Treatment Modifications

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Treatment Modifications

Adverse Event

Treatment Modification

G3 nonhematologic toxicity or G4 hematologic toxicity

Hold treatment until toxicity resolves to G ≤1, then resume with bortezomib 1 mg/m²

G3 nonhematologic toxicity or G4 hematologic toxicity in a patient receiving bortezomib 1 mg/m²

Hold treatment until toxicity resolves to G ≤1, then resume with bortezomib 0.7 mg/m²

Severe manifestations of hypercorticism, including severe hyperglycemia, irritability, insomnia, or oral candidiasis

Reduce daily dexamethasone dosage by 20% for G3 toxicity, and by 40% for G4 or recurrent G3 toxicity

Patient Population Studied

Study of 202 patients with relapsed multiple myeloma, refractory to the therapy subjects had most recently received. A multicenter, open-label, nonrandomized, phase II trial

Efficacy (N = 193)

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Efficacy (N = 193)

European Group for Blood and Marrow Transplantation Criteria

Complete response

10%

Partial response

18%

Minimal response

No change

24%

Progressive disease

41%

Median time to first response

1.3 months

Median response duration^✫

12 months

^✫In the 67 patients with a complete, partial, or minimal response to bortezomib alone

Toxicity (N = 202)

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Toxicity (N = 202)

NCI Common Toxicity Criteria, version 2.0

Toxicity

Percentage of Patients

Bortezomib-Related

G3/4

Nonhematologic Toxicity

Nausea

Diarrhea

Fatigue

Peripheral neuropathy

Vomiting

Anorexia

Fever

Headache

Constipation

Rash

Limb pain

Dizziness, not vertigo

Weakness

Dehydration

Hematologic Toxicity

Thrombocytopenia

Anemia

Neutropenia

Note: Ten deaths occurred within 20 days after the last bortezomib dose. Most deaths were attributed to progressive disease; 2 deaths were possibly related to treatment

Therapy Monitoring

Weekly: CBC with differential
Every 2 cycles: Serum BUN, creatinine, and LFTs. Serum and urine M-protein

REGIMEN: RELAPSED/REFRACTORY MULTIPLE MYELOMA: LENALIDOMIDE + DEXAMETHASONE

Regimen: Relapsed/Refractory Multiple Myeloma: Lenalidomide + Dexamethasone

Weber DM et al. N Engl J Med 2007;357:2133–2142

Dimopoulos M et al. N Engl J Med 2007;357:2123–2132

Lenalidomide 25 mg per day; administer orally for 21 consecutive days on days 1–21, every 28 days (total dose/cycle = 525 mg)

Cycles 1–4:

Dexamethasone 40 mg per dose; administer orally for 12 doses on days 1–4, 9–12, and 17–20, every 28 days for 4 cycles (total dose/cycle = 480 mg)

Cycle 5 and subsequently:

Dexamethasone 40 mg per dose; administer orally for 4 doses on days 1–4, every 28 days, until the occurrence of disease progression or unacceptable toxic effects (total dose/cycle = 160 mg)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL–LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is INTERMEDIATE

Antimicrobial primary prophylaxis to be considered:

Antibacterial—consider a fluoroquinolone or no prophylaxis; P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—consider concomitant use of clotrimazole during periods of neutropenia
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

Caution: Acyclovir and famciclovir accumulate in patients with impaired renal function and may exacerbate renal dysfunction (valacyclovir is a prodrug for acyclovir). Monitor kidney function serially during acyclovir, valacyclovir, and famciclovir use
- Acyclovir and famciclovir elimination is inversely related to renal function
- Acyclovir, famciclovir, and valacyclovir utilization is modified in renally impaired individuals (consult product labeling or Summary of Product Characteristics for guidance about dose/dosage and administration frequency modifications, and, when relevant, recommendations for drug dilution, administration rate, concurrent fluid administration, and fluid supplementation as a function of urine output)
- Impaired acyclovir elimination is associated with neurologic adverse effects, including agitation, ataxia, coma, confusion, dizziness, dysarthria, encephalopathy, hallucinations, paresthesia, seizure, somnolence, and tremors

See Chapter 47 for more information

Thromboprophylaxis

Risk assessment and recommendations for VTE prophylaxis in patients with multiple myeloma with individual or myeloma-related risk factors, or risk factors related to treatment

| Download (.pdf) | Print

Individual risk factors

Obesity (BMI ≥30 kg/m²)
H/O VTE
CVC or pacemaker
Comorbid pathologies

Cardiac disease

Chronic renal disease

Diabetes

Acute infection

Immobilization
Surgery

General surgery

Any anesthesia

Trauma
Medications

Erythropoietin (epoetin alfa, darbepoetin)

Estrogenic compounds

Bevacizumab
Clotting disorders

Thrombophilia

Myeloma-related risk factors

Diagnosis of multiple myeloma
Hyperviscosity

≤1 Individual or myeloma risk factor present:

Aspirin 81–325 mg daily

≥2 Individual or myeloma risk factors present:

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or
Warfarin, targeting an INR = 2–3

Concomitant treatment-related risk factors

Thalidomide or lenalidomide in combination with:

High-dose dexamethasone (≥480 mg/month)
Doxorubicin
Multiagent chemotherapy

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or

Warfarin, targeting an INR = 2–3

CVC, central venous catheter; INR, international normalized ratio; LMWH, low-molecular-weight heparin; VTE, venous thromboembolic disease

Geerts WH et al. Chest 2008;133(6 Suppl):381S–453S

Multiple Myeloma, V.1.2014. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Palumbo A et al. Leukemia 2008;22:414–423

Venous Thromboembolic Disease, V.2.2013. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Bisphosphonates

All patients receiving primary therapy for symptomatic multiple myeloma should receive a bisphosphonate adjunctively; for example:

Pamidronate disodium 90 mg; administer intravenously over 2–4 hours, every month, or
Zoledronic acid 4 mg; administer intravenously over 15 minutes, every month

Consider baseline bone densitometry evaluation

See Chapter 43 for more information

Treatment Modifications

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Treatment Modifications

Lenalidomide Dose Levels

Dose Level 1

25 mg

Dose Level −1

15 mg

Dose Level −2

10 mg

Dose Level −3

5 mg

Dexamethasone Dose Levels

Dose Level 1

40 mg/dose for 12 doses on days 1 to 4, 9 to 12, and 17 to 20

Dose Level −1

40 mg daily for 4 days every 2 weeks (days 1–4 and 15–18)

Dose Level −2

40 mg daily for 4 days every 4 weeks (days 1–4)

Dose Level −3

20 mg daily for 4 days every 4 weeks (days 1–4)

Adverse Event

Treatment Modification

G3/4 neutropenia

Interrupt lenalidomide treatment and follow clinically. After ANC recovers to ≥1000/mm³, resume lenalidomide at a dose decreased from the previous dose by 5 mg/day, but the daily dose should not be less than 5 mg/day

Febrile neutropenia

Interrupt lenalidomide treatment and follow closely. After fever abates, resume lenalidomide at a dose decreased from the previous dose by 5 mg/day, but the daily dose should not be less than 5 mg/day

G3/4 nonhematologic toxicity

Toxicities ascribed to dexamethasone such as severe manifestations of hypercorticism, including hyperglycemia, irritability, insomnia, or oral candidiasis

Reduce dexamethasone dose to the next lowest dose level

Lenalidomide Starting Dose Adjustment for Renal Impairment in Multiple Myeloma (Days 1–21 of Each 28-Day Cycle)^✫

Moderate renal impairment

CrCl 30–60 mL/min (0.5–1 mL/s)

10 mg lenalidomide every 24 hours

Severe renal impairment

CrCl <30 mL/min, not requiring dialysis

15 mg lenalidomide every 48 hours

End-stage renal disease

CrCl <30 mL/min, requiring dialysis

Lenalidomide 5 mg/day. On dialysis days, administer a daily dose following dialysis

CrCl, Creatinine clearance

^✫Richardson PG et al. J Clin Oncol 2006;24:3113–3120

Patient Population Studied

Two multicenter, randomized, phase III studies that enrolled patients with progressive multiple myeloma not resistant to dexamethasone who had received at least 1 previous treatment. Patients were considered to have disease that was resistant to dexamethasone if they had had progression during previous therapy containing high-dose dexamethasone (total monthly dose >200 mg). Measurable disease was defined as a serum monoclonal protein (M-protein) level of ≥0.5 g/dL or a urinary Bence Jones protein level ≥0.2 g/day. Additional eligibility criteria included an Eastern Cooperative Oncology Group performance status ≤2

European Study

(Dimopoulos M et al. N Engl J Med 2007;357: 2123–2132)

(351 patients: N = 176 lenalidomide group; N = 175 placebo group)

North America Study

(Weber DM et al. N Engl J Med 2007;357:2133–2142)

(353 patients: N = 177 lenalidomide group; N = 176 placebo group)

Efficacy

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Efficacy

North American Study (Weber et al.)

European Study (Dimopoulos et al.)

Lenalidomide N = 177

Placebo N = 176

Lenalidomide N = 176

Placebo N = 175

Overall response

19.9

60.2

Complete response

14.1

0.6

15.9

3.4

Near-complete response

10.2

1.1

8.5

1.7

Partial response

36.7

18.2

35.8

18.9

Stable disease

30.5

30.1

55.4

Progressive disease

2.8

14.2

1.7

14.3

Response not evaluable

5.6

6.3

Previous Thalidomide, Response Rate, and Time to Progression (TTP)

Yes

56.8

12.5

49.1

16.4

Median TTP (months)

8.5

4.1

8.4

4.6

64.1

28.7

Median TTP (months)

—

13.5

4.7

Beta₂-Microglobulin Level, Response Rate

<2.5 mg/L

27.5

70.6

37.5

≥2.5 mg/L

55.2

16.8

18.9

Previous Therapies (Number), Response Rate, and Time to Progression (TTP)

64.7

22.4

66.1

29.8

Median TTP (months)

5.1

—

≥2

58.7

18.3

57.5

21.2

Median TTP (months)

10.2

4.6

—

Previous Stem Cell Transplant, Response Rate

Yes

66.1

19.4

61.9

28.4

52.9

20.6

58.2

18.8

Previous Use of Bortezomib, Response Rate, and Time to Progression (TTP)

Yes

68.4

—

60.1

21.2

—

Median TTP (months)

10.3

3.3

—

Median TTP, All Patients (Months)

11.1

4.7

11.3

4.7

Median Overall Survival (Months)

26.2

12.9

20.6

NR, not reached; TTP, Time to progression

Toxicity

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Toxicity

North America Study (Weber et al.) G3/4 (N = 177)

European Study (Dimopoulos et al.) G3/4 (N = 176)

Hematologic Events

Neutropenia

41.2

29.5

Anemia

8.6

Thrombocytopenia

14.7

11.4

Febrile neutropenia

3.4

Gastrointestinal Events

Constipation

2.8

1.7

Diarrhea

3.4

2.8

Nausea

2.8

1.1

General Disorders

Asthenia

3.4

6.2

Fatigue

6.2

6.8

Pyrexia

2.3

0.6

Peripheral edema

2.3

1.1

Infections

Upper respiratory

1.1

1.7

Any infection

21.4

9.6

Pneumonia

12.4

Not reported

Neurologic Disorders

Headache

Not reported

0.6

Tremor

Not reported

1.1

Dizziness

Not reported

0.6

Paresthesia

Not reported

0.6

Insomnia

Not reported

1.1

Musculoskeletal or Connective Tissue Disorder

Muscle cramp

Not reported

0.6

Back pain

Not reported

2.3

Bone pain

Not reported

2.8

Muscle weakness

Not reported

7.4

Arthralgia

Not reported

0.6

Vascular Disorders

Deep vein thrombosis

Not reported

Pulmonary embolism

Not reported

4.5

Venous thromboembolism

Not reported

11.4

Therapy Monitoring

Blood counts and physical examinations
- Cycle 1: days 1, 8, and 15
- Cycles 2 and 3: days 1 and 15
- Cycle 4, and subsequently: day 1
Serum and urinary protein electrophoresis studies on day 1 of each cycle and at the end of treatment
Serum electrolytes and creatinine before beginning each treatment cycle

REGIMEN: RELAPSED/REFRACTORY MULTIPLE MYELOMA (PRIOR BORTEZOMIB AND BORTEZOMIB NAÏVE): CARFILZOMIB

Regimen: Relapsed/Refractory Multiple Myeloma (Prior Bortezomib and Bortezomib NaÏve): Carfilzomib

Vij R et al. Blood 2012;119:5661–5670 (Bortezomib-naïve)

Vij R et al. Br J Haematol 2012;158:739–748 (Prior bortezomib)

Hydration with carfilzomib: During cycle 1, days 1 and 2, administer intravenously 250–500 mL 0.9% NS before each carfilzomib dose, and an additional 250–500 mL of fluid intravenously after carfilzomib. During repeated treatments, continue intravenous hydration as needed. Encourage oral hydration

Carfilzomib 36 mg/m² per dose intravenously in 50-mL 5% dextrose injection over 30 minutes for 6 doses, on days 1, 2, 8, 9, 15, and 16, every 28 days for a maximum of 12 cycles (total dosage/cycle = 216 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis may be indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is INTERMEDIATE

Antimicrobial primary prophylaxis to be considered:

Antibacterial—consider a fluoroquinolone or no prophylaxis; Pneumocystis jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—recommended; consider use during periods of neutropenia
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

Thromboprophylaxis

Risk assessment and recommendations for VTE prophylaxis in patients with multiple myeloma with individual or myeloma-related risk factors, or risk factors related to treatment

| Download (.pdf) | Print

Individual risk factors

Obesity (BMI ≥30 kg/m²)
H/O VTE
CVAD or pacemaker
Comorbid pathologies

Cardiac disease

Chronic renal disease

Diabetes

Acute infection

Immobilization
Surgery

General surgery

Any anesthesia

Trauma
Medications

Erythropoietin (epoetin alfa, darbepoetin)

Estrogenic compounds

Bevacizumab
Clotting disorders

Thrombophilia

Myeloma-related risk factors

Diagnosis of multiple myeloma
Hyperviscosity

≤1 Individual or myeloma risk factor present:

Aspirin 81–325 mg daily

≥2 Individual or myeloma risk factors present:

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or
Warfarin, targeting an INR = 2–3

Concomitant treatment-related risk factors

Thalidomide or lenalidomide in combination with:

High-dose dexamethasone (≥480 mg/month)
Doxorubicin
Multiagent chemotherapy

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or

Warfarin, targeting an INR = 2–3

CVAD, central vascular access device; INR, international normalized ratio; LMWH, low-molecular-weight heparin; VTE, venous thromboembolic disease

Geerts WH et al. Chest 2008;133(6 Suppl):381S–453S

Multiple Myeloma, V.1.2014. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Palumbo A et al. Leukemia 2008;22:414–423

Venous Thromboembolic Disease, V.2.2013. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Bisphosphonates

All patients receiving primary therapy for symptomatic multiple myeloma should receive a bisphosphonate adjunctively; for example:

Pamidronate disodium 90 mg; administer intravenously over 2–4 hours, every month, or
Zoledronic acid 4 mg; administer intravenously over at least 15 minutes, every month

Consider baseline bone densitometry evaluation

See Chapter 43 for more information

Diarrhea management

Loperamide 4 mg orally initially after the first loose or liquid stool, then
Loperamide 2 mg orally every 2 hours during waking hours, plus
Loperamide 4 mg orally every 4 hours during hours of sleep
- Continue for at least 12 hours after diarrhea resolves
- Recurrent diarrhea after a 12-hour diarrhea-free interval is treated as a new episode
- Rehydrate orally with fluids and electrolytes during a diarrheal episode
- If a patient develops blood or mucus in stool, dehydration, or hemodynamic instability, or if diarrhea persists >48 hours despite loperamide, stop loperamide and hospitalize the patient for IV hydration
  
  Alternatively, a trial of Diphenoxylate hydrochloride 2.5 mg with Atropine sulfate 0.025 mg (eg, Lomotil)
- Initial adult dose is 2 tablets 4 times daily until control has been achieved, after which the dose may be reduced to meet individual requirements. Control may often be maintained with as little as 2 tablets daily
- Clinical improvement of acute diarrhea is usually observed within 48 hours. If improvement of chronic diarrhea after treatment with a maximum daily dose of 8 tablets is not observed within 10 days, control is unlikely with further administration

Patient Population Studied

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Patient Population Studied

Characteristic

Bortezomib-Naïve^✫ (N = 129)

Prior Bortezomib^† (N = 35)

General

Median age, years (range)

65 (38–85)

63 (40–77)

Male, n (%)

76 (58.9)

18 (51.4)

Median time from diagnosis, years (range)

3.6 (0.7–24.4)

3.6 (1.2–13.2)

Immunoglobulin Subtype, n (%)

IgG

86 (66.7)

24 (68.6)

IgA

33 (25.6)

5 (14.3)

IgD

—

1 (2.9)

Not reported/missing

10 (7.8)

5 (14.3)

Light Chain Subtype, n (%)

Kappa

94 (72.9)

23 (65.7)

Lambda

35 (27.1)

12 (34.3)

ECOG PS, n (%)

52 (40.3)

15 (42.9)

1 or 2

77 (59.7)

19 (54.3)

ISS Stage, n (%)

I or II

94 (72.9)

27 (77.1%)

III

22 (17.1)

7 (20%)

Not reported/missing

13 (10.1)

1 (2.9%)

Others Clinical History

Neuropathy history^‡

90 (69.8)

19 (54.3)^§

CrCl <50 mL/min (<0.83 mL/s)

20 (15.5)

4 (11.4)

Cytogenetic/FISH Prognostic Markers, n (%)

Normal/favorable

103 (79.8)

25 (71.4)

Poor

19 (14.7)

9 (25.7)

Unknown or not done

7 (5.4)

1 (2.9%)

CrCl, creatinine clearance; FISH, fluorescence in situ hybridization

^✫Includes 2 patient cohorts: (a) cohort 1 (n = 59) was treated with 20 mg/m² carfilzomib; (b) cohort 2 (n = 70) was treated with 20/27 mg/m² carfilzomib

^†Patients treated with 20 mg/m² carfilzomib

^‡Baseline peripheral neuropathy (PN): 68 (52.7)

^§Peripheral neuropathy G ≥1

Prior Therapies

Bortezomib-Naïve^✫ (N = 129)

Prior Bortezomib^† (N = 35)

n (%)

Median number of prior regimens (range)

2 (1–4)

3.0 (1–13)

3 (2.3)^‡

35 (100.0)^§

Thalidomide

76 (58.9)

24 (68.6)

76 (58.9)

13 (37.1)

Thalidomide or lenalidomide

119 (92.2)

27 (77.1)

Corticosteroid

125 (96.9)

34 (97.1)

Alkylating agent

105 (81.4)

31 (88.6)

Anthracycline

30 (23.3)

11 (31.4)

Stem cell transplantation

94 (72.9)

28 (80.0)

Refractory to bortezomib in any prior regimen n (%)

7 (20.0)

Refractory to last therapy, n (%)

22 (62.9)

^✫Includes 2 patient cohorts: (a) cohort 1 (n = 59) was treated with 20 mg/m² carfilzomib; (b) cohort 2 (n = 70) was treated with 20/27 mg/m² carfilzomib

^†Patients treated with 20 mg/m² carfilzomib

^‡Bortezomib exposure not considered therapeutic

^§20/35 (57.1%) had bortezomib in last regimen

Treatment Modifications

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Treatment Modifications

Carfilzomib Dose Levels

Starting dose

36 mg/m² per dose

Level –1

27 mg/m² per dose

Level –2

20 mg/m² per dose

Level –3

15 mg/m² per dose

Level –4

11 mg/m² per dose

Level –5

Discontinue

Adverse Event

Treatment Modification

Hematologic Toxicity

G3/4 neutropenia

Febrile neutropenia (ANC <1.0 × 10⁹/L with fever ≥38°C)

G4 thrombocytopenia

G3/4 thrombocytopenia associated with bleeding

Nonhematologic Toxicity

G3/4 cardiac toxicity

New onset or worsening of:

Congestive heart failure
Decreased left ventricular function
Myocardial ischemia

Pulmonary hypertension

G3/4 pulmonary complications

G3/4 elevation of transaminases, bilirubin or other liver abnormalities

Serum creatinine equal to or greater than 2× baseline

Hold carfilzomib dosing for up to 21 days to resolve toxicity to G1 or to baseline and then restart at the same dosage, or reduce the carfilzomib dosage by 1 dose level. If tolerated, the reduced dose may be escalated to the previous dose level

G2 neuropathy with pain

Hold carfilzomib dosing for up to 21 days to resolve toxicity and then restart at the same dose or reduce the carfilzomib dose by 1 level. If tolerated, the reduced dosage, or reduce the carfilzomib dosage by 1 dose may be escalated to the previous dose level

G3/4 peripheral neuropathy

Other G3/4 nonhematologic toxicities

Efficacy

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Efficacy

Response

Bortezomib-Naïve^✫ (N = 129) n (%)

Prior Bortezomib^† (N = 35) n (%)

3 (2.4)

1 (2.9)

VGPR

26 (20.6)

1 (2.9)

31 (24.6)

4 (11.4)

18 (14.3)

5 (14.3)

23 (18.3)

13 (37.1)

18 (14.3)

10 (28.6)

ORR (CR + VGPR + PR)

60 (47.6)

6 (17.1)

95% CI

38.7–56.7

CBR (ORR + MR)

78 (61.9)

11 (31.4)

95% CI

52.8–70.4

CBR, clinical benefit response; CR, complete response; MR, minimal response; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease; VGPR, very good partial response

^✫Includes 2 patient cohorts: (a) cohort 1 (n = 59) was treated with 20 mg/m² carfilzomib; (b) cohort 2 (n = 70) was treated with 20/27 mg/m² carfilzomib. Response is response rate after 6 cycles of treatment in response-evaluable population

^†Patients treated with 20 mg/m² carfilzomib. Response is best overall response in response-evaluable population

Bortezomib-Naïve^✫ (N = 129)

Prior Bortezomib^† (N = 35)

ORR % (95% CI)

Overall

126^‡

47.6 (38.7–56.7)

17.1 (6.6–33.7)

Baseline Characteristics

Age, Years

<65

58.6 (44.9–71.4)

9.5 (1.2–30.4)

≥65

38.2 (26.7–50.8)

28.6 (8.4–58.1)

ECOG Performance Status

52.9 (38.5–67.1)

26.7 (7.8–55.1)

≥1

44.0 (32.5–55.9)

10.5 (1.3–33.1)

ISS Stage

57.7 (43.2–71.3)

15.8 (3.4–39.6)

34.1 (20.1–50.6)

25.0 (3.2–65.1)

III

45.0 (23.1–68.5)

14.3 (0.4–57.9)

Baseline Neuropathy

Grade 0

39.0 (26.5–52.6)

—

Grade ≥1

56.1 (43.3–68.3)

—

Cytogenetic/FISH Prognostic Markers

Normal/favorable

100

51.0 (40.8–61.1)

16.0 (4.5–36.1)

Poor

36.8 (16.3–61.6)

11.1 (0.3–48.2)

Serum β₂-Microglobulin, mg/L

<5.5

47.3 (36.9–57.9)

—

≥5.5

45.0 (23.1–68.5)

—

Received Prior Lenalidomide

Yes

41.9 (30.5–53.9)

—

55.8 (41.3–69.5)

—

Received Prior Thalidomide

Yes

56.0 (44.1–67.5)

—

35.3 (22.4–49.9)

—

^✫Includes 2 patient cohorts: (a) cohort 1 (n = 59) was treated with 20 mg/m² carfilzomib; (b) cohort 2 (n = 67) was treated with 20/27 mg/m² carfilzomib. Response is response rate after 6 cycles of treatment in response-evaluable population

^†Patients treated with 20 mg/m² carfilzomib. Response is best overall response in response-evaluable population

^‡Reponse rate for the 2 cohorts as follows: cohort 1 (42.4%, 95% CI, 29.6–55.9); cohort 2 (52.2%, 95% CI, 39.7–64.6)

Response

Bortezomib-Naïve^✫ (N = 126)

Prior Bortezomib^† (N = 35)

Duration of Response (DOR), Months

Median, mo (95% CI)

NR (13.1–NR)

≥PR (ORR)

NE (10.6–NE)

≥MR (CBR)

10.6 (7.2–NE)

Duration of Clinical Benefit Response, Months

Median, (95% CI)

NR (11.5–NR)

Time to Progression (TTP), Months

Median (95% CI)

126

12.0 (8.2–NR)

4.6 (1.9–11.1)

Time to Response, Months

Median, (min, max)

1.7 (0.5–3.7)

≥PR (ORR)

1.4 (0.5–1.9)

≥MR (CBR)

1.0 (0.5–6.7)

Time to Clinical Benefit Response, Months

Median, (min, max)

0.5 (0.5–6.5)

CBR, clinical benefit response; DOR, duration of response; NE, not estimable; NR, not reached; ORR, overall response rate

^†Patients treated with 20 mg/m² carfilzomib. Response is best overall response in response-evaluable population

Toxicity

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Toxicity

Treatment-Emergent Adverse Event, n (%)

Bortezomib-Naïve^✫ (N = 129)

Prior Bortezomib^† (N = 35)

All Grades^‡

G ≥3^§

All Grades^‡

G ≥3^§

Hematologic

Anemia

54 (41.9)

19 (14.7)

12 (34.3)

5 (14.3)

Neutropenia

39 (30.2)

17 (13.2)

9 (25.7)

4 (11.4)

Thrombocytopenia

39 (30.2)

17 (13.2)

11 (31.4)

7 (20.0)

Lymphopenia

33 (25.6)

21 (16.3)

6 (17.1)

2 (5.7)

Nonhematologic

Fatigue

80 (62.0)

8 (6.2)

22 (62.9)

1 (2.9)

Nausea

63 (48.8)

—

21 (60.0)

1 (2.9)

Dyspnea

50 (38.8)

7 (5.4)

13 (37.1)

2 (5.7)

Cough

44 (34.1)

—

8 (22.9)

Pyrexia

44 (34.1)

—

9 (25.7)

Headache

42 (32.6)

—

9 (25.7)

1 (2.9)

Diarrhea

40 (31.0)

—

13 (37.1)

Upper respiratory infection

40 (31.0)

—

12 (34.3)

2 (5.7)

Epiglottitis

—

2 (5.7)

Pneumonia

—

3 (8.6)

Peripheral edema

35 (27.1)

—

Congestive heart failure

—

6 (4.7)

—

Hypertension

—

8 (22.9)

1 (2.9)

Chills

29 (22.5)

—

Insomnia

29 (22.5)

—

Vomiting

29 (22.5)

—

15 (42.9)

1 (2.9)

Constipation

25 (19.4)

—

8 (22.9)

Asthenia

—

8 (22.9)

1 (2.9)

Muscle spasms

24 (18.6)

—

Arthralgia

22 (17.1)

—

Back pain

22 (17.1)

—

Pain

—

7 (20.0)

Hypoesthesia

—

9 (25.7)

Dizziness

22 (17.1)

—

7 (20.0)

Laboratory

Acute renal failure

—

6 (4.7)

—

Increased serum creatinine

24 (18.6)

—

12 (34.3)

1 (2.9)

Hypercalcemia

—

5 (14.3)

2 (5.7)

Hyperglycemia

—

6 (4.7)

—

Hypophosphatemia

—

6 (4.7)

—

Hypokalemia

—

5 (3.9)

—

Hyponatremia

—

5 (3.9)

—

Increased AST

—

3 (2.3)

7 (20.0)

Increased ALT

—

−

10 (28.6)

^✫Includes 2 patient cohorts: (a) cohort 1 (n = 59) was treated with 20 mg/m² carfilzomib; (b) cohort 2 (n = 70) was treated with 20/27 mg/m² carfilzomib

^†Patients treated with 20 mg/m² carfilzomib

^‡Treatment-emergent adverse events of all grades in ≥20% of the safety population

^§Treatment-emergent adverse events G ≥3 in ≥5% of the safety population

Therapy Monitoring

Blood counts and physical examinations on day 1 of each cycle
Serum and urinary protein electrophoresis studies on day 1 of each cycle as indicated and at the end of treatment

REGIMEN: RELAPSED/REFRACTORY MULTIPLE MYELOMA: POMALIDOMIDE + DEXAMETHASONE

Regimen: Relapsed/Refractory Multiple Myeloma: Pomalidomide + Dexamethasone

Leleu X et al. Blood 2013;121:1968–1975

Lacy MQ et al. Leukemia 2010;24:1934–1939

Pomalidomide 4 mg/day orally, continually, for 21 consecutive days, on days 1–21, every 28 days (total dose/cycle = 84 mg)

Dexamethasone 40 mg/dose; orally for 4 doses on days 1, 8, 15, and 22, every 28 days (total dose/cycle = 160 mg)

Pomalidomide 2 mg/day; orally, continually, for 28 consecutive days, on days 1–28, every 28 days (total dose/cycle = 56 mg)

Dexamethasone 40 mg daily orally on days 1, 8, 15, and 22, every 28 days (total dose/cycle = 160 mg)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL–LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis may be indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is INTERMEDIATE

Antimicrobial primary prophylaxis to be considered:

Antibacterial—consider a fluoroquinolone or no prophylaxis; Pneumocystis jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—recommended; consider use during periods of neutropenia
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

Thromboprophylaxis

Risk assessment and recommendations for VTE prophylaxis in patients with multiple myeloma with individual or myeloma-related risk factors, or risk factors related to treatment

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Individual risk factors

Obesity (BMI ≥30 kg/m²)
H/O VTE
CVAD or pacemaker
Comorbid pathologies

Cardiac disease

Chronic renal disease

Diabetes

Acute infection

Immobilization
Surgery

General surgery

Any anesthesia

Trauma
Medications

Erythropoietin (epoetin alfa, darbepoetin)

Estrogenic compounds

Bevacizumab
Clotting disorders

Thrombophilia

Myeloma-related risk factors

Diagnosis of multiple myeloma
Hyperviscosity

≤1 Individual or myeloma risk factor present:

Aspirin 81–325 mg daily

≥2 Individual or myeloma risk factors present:

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or
Warfarin, targeting an INR = 2–3

Concomitant treatment-related risk factors

Thalidomide or lenalidomide in combination with:

High-dose dexamethasone (≥480 mg/month)
Doxorubicin
Multiagent chemotherapy

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or

Warfarin, targeting an INR = 2–3

CVAD, central vascular access device; INR, international normalized ratio; LMWH, low-molecular-weight heparin; VTE, venous thromboembolic disease

Geerts WH et al. Chest 2008;133(6 Suppl):381S–453S

Multiple Myeloma, V.1.2014. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Palumbo A et al. Leukemia 2008;22:414–423

Venous Thromboembolic Disease, V.2.2013. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Bisphosphonates

All patients receiving primary therapy for symptomatic multiple myeloma should receive a bisphosphonate adjunctively; for example:

Pamidronate disodium 90 mg; administer intravenously over 2–4 hours, every month, or
Zoledronic acid 4 mg; administer intravenously over at least 15 minutes, every month

Consider baseline bone densitometry evaluation

See Chapter 43 for more information

Treatment Modifications

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Treatment Modifications

Pomalidomide Dose Levels

Starting dose

4 mg/day

Level –1

3 mg/day

Level –2

2 mg/day

Level –3

1 mg/day

Level –4

Discontinue

Dexamethasone Dose Levels

Starting dose

40 mg/dose

Level –1

20 mg/dose

Level –2

12 mg/dose

Level –3

8 mg/dose

Level –4

4 mg/dose

Level –5

Discontinue

Adverse Event

Treatment Modification

ANC <500/mm³

Interrupt pomalidomide treatment, and follow CBC weekly. When ANC ≥500/mm³ and platelet count 50,000/mm³, resume pomalidomide 1 dose level lower

Febrile neutropenia (fever ≥38.5°C + ANC <1000/mm³)

Platelets <25,000/mm³

Nonhematologic G3/4 toxicity

Interrupt pomalidomide treatment, and follow weekly or more frequently. Restart treatment 1 dose level lower than the previous dose when toxicity has resolved G ≤2

G4 rash, neuropathy, hypersensitivity, or G ≥3 bradycardia or cardiac arrhythmia

Permanently discontinue pomalidomide

G3/4 adverse events occurring on or after day 15 during a single cycle

Withhold pomalidomide for the remainder of the cycle and reduce by 1 dose level beginning with the next cycle

Toxicities ascribed to dexamethasone such as severe manifestations of hypercorticism, including hyper-glycemia, irritability, insomnia, or oral candidiasis

Hold dexamethasone dosing for up to 21 days to resolve toxicity and then restart at the same dose or reduce the dexamethasone dose by 50%

Patient Population Studied

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Patient Population Studied

Patients were eligible if they had relapsed MM after at least 1 prior regimen. Patients were considered to be "nonresponders" to the last line of lenalidomide or bortezomib after having received ≥2 cycles of either drug if they did not achieve a response defined by International Myeloma Working Group (IMWG) criteria (stable disease [stable disease and minor response]) within 2 cycles of treatment

Characteristic

21/28 (N = 43)^✫

28/28 (N = 41)^✫

Median time from diagnosis to randomization, years (range)

5.1 (0.9–8.7)

6.5 (0.8–23.1)

≤3 years, n (%)

13 (30)

4 (10)

Median age, years (range)

60 (45–81)

60 (42–83)

Age ≥65 years, n (%)

11 (26)

15 (37)

ISS stage II/III [%]^†

32/24

42/17

Myeloma type, n (%)

Intact Ig

36 (84)

34 (83)

Light chain

4 (9)

5 (12)

Freelite measurable only^‡

3 (7)

2 (5)

Lytic bone lesions, n (%)

37 (86)

37 (90)

Number of lytic lesions: [3–6]

9 (25)

8 (22)

Number of lytic lesions: >6

11 (31)

17 (46)

Osseous Fracture

10 (29)

11 (32)

Medullary compression

3 (9)

Plasmacytoma

9 (21)

5 (12)

Median β₂-microglobulin, mg/L (range)

3.9 (1.0–13.2)

3.7 (1.6–12.0)

(3.5–5.5) mg/L, n (%)

19 (44)

11 (27.5)

>5.5 mg/L, n (%)

10 (23)

11 (27.5)

Median serum creatinine, (μmol/L) (range)

80.0 (0.9 mg/dL) (44.0–193.0)

87.0 (0.98 mg/dL) (42.0–196)

>115 μmol/L (1.3 mg/dL), n (%)

6 (14)

4 (10)

Median hemoglobin, g/dL (range)

10.5 (7.2–14.1)

10.5 (6.4–14.1)

<10 g/dL, n (%)

18 (42)

15 (37.5)

Median neutrophils, ×10⁹/L (range)

2.6 (0.04–10.4)

2.3 (0.9–8.3)

Median platelets, × 10⁹/L (range)

161 (51–366)

147 (33–269)

<100 × 10⁹/L, n (%)

8 (19)

10 (25)

Median number of lines (min-max)

5 (1–13)

5 (2–10)

^✫Pomalidomide was given orally either daily on days 1 to 21 of each 28-day cycle (arm 21/28 days) or continuously of each 28-day cycle (arm 28/28 days)

^†ISS classification at diagnosis

^‡Patients whose disease was considered "not measurable" based on intact serum immunoglobulin and urine light-chain excretion but had serum immunoglobulin free light chain >100 mg/L and an abnormal free light chain ratio

Leleu X et al. Blood 2013;121:1968–1975

Incidence Rate (Number and Percentage) of Patients with Various Adverse Prognostic Factors by Arm (N = 84)

Prognostic Factor

21/28 (N = 43)

28/28 (N = 41)

Total (N = 84)

Patients >6 lines of therapy, n (%)

12 (28)

7 (17)

19 (23)

Refractory^✫ to, n (%)

36 (84)

39 (95)

75 (89)

Lenalidomide last prior therapy

15 (35)

11 (27)

26 (31)

34 (79)

34 (83)

68 (81)

Both lenalidomide and bortezomib

32 (74)

32 (78)

64 (76)

Last prior therapy

36 (70)

35 (68)

71 (84.5)

FISH cytogenetics, n (%)^†

N = 33

N = 32

Deletion 17p

6 (21)

9 (33)

—

Translocation (4;14)

2 (7)

4 (17)

—

^✫Refractory by International Myeloma Working Group (IMWG) criteria

^†High-risk cytogenetics by FISH consisted of deletion 17p or t(4;14) at diagnosis and/or at entry in the trial

Leleu X et al. Blood 2013;121:1968–1975

Efficacy

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Efficacy

Response to Treatment and Survival End Points by Arm Based on Independent Review Committee Assessment

21/28

28/28

Total

ITT (N = 84)

N = 43

N = 41

N = 84

ORR (≥PR), n (%)

15 (35)

14 (34)

29 (34.5)

CR^✫, n (%)

1 (2)

2 (5)

3 (4)

VGPR, n (%)

1 (2)

2 (2)

PR, n (%)

13 (30)

11 (27)

24 (27)

Stable disease, n (%)

19 (44)

21 (51)

40 (48)

Progressive disease, n (%)

5 (12)

3 (7)

8 (9.5)

Not evaluable, n (%)

4 (9)

3 (7)

7 (8)

Median time to first response (95% CI), months

2.7 (0.8, 9.5)

1.1 (0.6, 8)

1.8 (0.6, 9.5)

Median duration of response (95% CI), months

6.4 (4, —)

8.3 (6.5, 16)

7.3 (5, 15)

1 Year free of relapse

42%

47%

44%

Efficacy-Evaluable Population (N = 66)

N = 34

N = 32

N = 66

ORR (CR + PR), n (%)

15 (44)

12 (37.5)

27 (41)

≥VGPR, n (%)

2 (6)

3 (9)

5 (7.5)

Median survival (95% CI), months

21/28 (N = 43)

28/28 (N = 41)

Total

Time to progression

5.8 (3, 10)

4.8 (3, 7)

5.4 (4, 8)

At 1 year, %

Progression-free survival

5.4 (3, 9)

3.7 (2, 7)

4.6 (4, 7)

At 1 year, %

25.5

Overall survival

14.9 (9, —)

14.8 (9, 20)

14.9 (11, 20)

At 12 months, %

At 18 months, %

CR, complete response; ORR, overall response rate; PR, partial response; VGPR, very good partial response

^✫CR confirmed by bone marrow assessment

Leleu X et al. Blood 2013;121:1968–1975

Patient Outcomes

Confirmed response rate^✫^,†

32% (95% CI: 19–53)

Confirmed response rate^✫

32% (95% CI: 17–51)

Number of responders^✫

VGPR

Best response

VGPR

3 (9%)

8 (23%)

5 (15%)

12 (35%)

6 (18%)

Median time to response^✫

2.0 months (range: 0.7–3.9)

Duration of response^✫^,‡

9.1 months (95% CI: 6.5–NA)

Overall survival^‡

13.9 months (95% CI: NA)

Progression free survival^‡

4.8 months (95% CI: 2.7–10.1)

CI, confidence interval; MR, best response; NA, not attained; PD, progressive disease; PR, partial response; SD, stable disease; VGPR, very good partial response

^✫Does not include MR per study design

^†Study design uses the first 32 patients

^‡Kaplan–Meier method

Lacy MQ et al. Leukemia 2010;24:1934–1939

Toxicity

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Toxicity

Summary of G3/4 (NCI-CTC^✫) Adverse Events that Occurred in >5% of Cases

Adverse Events, n (%)

21/28 (N = 43)

28/28 (N = 41)

Total (N = 84)

SAEs

32 (74)

33 (80)

65 (77)

Study drug-related SAEs

14 (33)

18 (44)

32 (38)

Any G3 or G4 AE

40 (93)

35 (85)

75 (89)

Hematologic

Blood and lymphatic system

32 (74)

30 (73)

62 (74)

Anemia

16 (37)

14 (34)

30 (36)

Neutropenia

28 (65)

24 (58.5)

52 (62)

Thrombocytopenia

12 (28)

11 (27)

23 (27)

Nonhematologic

General disorders

10 (23)

10 (24)

20 (24)

Asthenia

6 (14)

2 (5)

8 (9.5)

Infections and infestations

8 (19)

11 (27)

19 (23)

Pneumonia

3 (7)

8 (19.5)

11 (13)

Musculoskeletal/connective tissue

9 (21)

8 (19.5)

17 (20)

Bone pain

6 (14)

3 (7)

9 (11)

Renal and urinary disorders

7 (16)

2 (5)

9 (11)

Renal failure

7 (16)

2 (5)

9 (11)

Respiratory disorders

8 (19)

2 (5)

10 (12)

Dyspnea

5 (12)

5 (6)

^✫National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0

Leleu X et al. Blood 2013;121:1968–1975

Maximum Severity of Toxicities^✫ (N = 34)

Toxicity^†

All Grades

Hematologic

Anemia

Lymphocyte count decreased

Neutrophil count decreased

Platelet count decreased

Leukopenia

Nonhematologic

Edema limbs

Musculoskeletal

Muscle weakness lower limb

Agitation

Anxiety

Confusion

Peripheral sensory neuropathy

Tremor

Myalgia

Dyspnea

Pneumonitis

Edema

Fatigue

Dermatology

Anorexia

Constipation

Diarrhea

Gastritis

Nausea

Metabolic/Laboratory

Hyperglycemia

Infection/Febrile Neutropenia

Infection—no ANC

Upper airway infection

Bladder infection

Pneumonia G0 to G2 ANC

Respiratory tract infection

Skin infection

^✫Possibly, probably, or definitely related

^†National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0

Lacy MQ et al. Leukemia 2010;24:1934–1939

Therapy Monitoring

Blood counts and physical examinations on day 1 of each cycle
Serum and urinary protein electrophoresis studies on day 1 of each cycle as indicated and at the end of treatment

REGIMEN: RELAPSED/REFRACTORY MULTIPLE MYELOMA: POMALIDOMIDE + CYCLOPHOSPHAMIDE + PREDNISONE

Regimen: Relapsed/Refractory Multiple Myeloma: Pomalidomide + Cyclophosphamide + Prednisone

Larocca A et al. Blood 2013;122:2799–2806

Induction:

Cyclophosphamide 50 mg/dose orally, every other day (eg, days 1, 3, 5…, etc. or days 2, 4, 6…, etc.) continually, for 14 doses every 28 days (total dose/cycle = 700 mg)

Prednisone 50 mg/dose orally, every other day (eg, days 1, 3, 5…, etc. or days 2, 4, 6…, etc.) continually, for 14 doses every 28 days (total dose/cycle = 700 mg)

plus

Pomalidomide 2–3 mg/day orally, continually, for 28 consecutive days, on days 1–28, every 28 days (total dose/cycle = 56–84 mg), or

Pomalidomide 4 mg/day orally, continually, for 21 consecutive days, on days 1–21, every 28 days (total dose/cycle = 84 mg)

Maintenance:

Pomalidomide 1 mg/day orally, continually, until disease relapse or progression (total dose/week = 7 mg)

Prednisone 25 mg/dose orally, every other day (eg, days 1, 3, 5…, etc. or days 2, 4, 6…, etc.) continually, until disease relapse or progression

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL–LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis may be indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is INTERMEDIATE

Antimicrobial primary prophylaxis to be considered:

Antibacterial—consider a fluoroquinolone or no prophylaxis; Pneumocystis jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—recommended; consider use during periods of neutropenia, and in anticipation of mucositis
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

Thromboprophylaxis

Risk assessment and recommendations for VTE prophylaxis in patients with multiple myeloma with individual or myeloma-related risk factors, or risk factors related to treatment

| Download (.pdf) | Print

Individual risk factors

Obesity (BMI ≥30 kg/m²)
H/O VTE
CVAD or pacemaker
Comorbid pathologies

Cardiac disease

Chronic renal disease

Diabetes

Acute infection

Immobilization
Surgery

General surgery

Any anesthesia

Trauma
Medications

Erythropoietin (epoetin alfa, darbepoetin)

Estrogenic compounds

Bevacizumab
Clotting disorders

Thrombophilia

Myeloma-related risk factors

Diagnosis of multiple myeloma
Hyperviscosity

≤1 Individual or myeloma risk factor present:

Aspirin 81–325 mg daily

≥2 Individual or myeloma risk factors present:

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or
Warfarin, targeting an INR = 2–3

Concomitant treatment-related risk factors

Thalidomide or lenalidomide in combination with:

High-dose dexamethasone (≥480 mg/month)
Doxorubicin
Multiagent chemotherapy

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or

Warfarin, targeting an INR = 2–3

CVAD, central vascular access device; INR, international normalized ratio; LMWH, low-molecular-weight heparin; VTE, venous thromboembolic disease

Geerts WH et al. Chest 2008;133(6 Suppl):381S–453S

Multiple Myeloma, V.1.2014. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Palumbo A et al. Leukemia 2008;22:414–423

Venous Thromboembolic Disease, V.2.2013. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Bisphosphonates

All patients receiving primary therapy for symptomatic multiple myeloma should receive a bisphosphonate adjunctively; for example:

Pamidronate disodium 90 mg; administer intravenously over 2–4 hours, every month, or
Zoledronic acid 4 mg; administer intravenously over at least 15 minutes, every month

Consider baseline bone densitometry evaluation

See Chapter 43 for more information

Treatment Modifications

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Treatment Modifications

Pomalidomide Dose Levels

Starting dose

2.5 mg/day

Level –1

2 mg/day

Level –2

1.5 mg/day

Level –3

1 mg/day

Level –4

0.5 mg/day

Level –5

Discontinue

Prednisone Dose Levels

Starting dose

50 mg/dose

Level –1

25 mg/dose

Level –2

20 mg/dose

Level –3

10 mg/dose

Level –4

5 mg/dose

Level –5

Discontinue

Adverse Event

Treatment Modification

ANC <500/mm³

Interrupt pomalidomide and cyclophosphamide treatment, and follow CBC weekly. When ANC ≥500/mm³ and platelet count ≥50,000/mm³, resume pomalidomide 1 dose level lower and cyclophos-phamide at a dose of 25 mg every other day

Febrile neutropenia (fever ≥38.5°C + ANC <1000/mm³)

Platelets <25,000/mm³

Nonhematologic G3/4 toxicity

Interrupt pomalidomide treatment, and follow weekly or more frequently. Restart treatment 1 dose level lower than the previous dose when toxicity has resolved G ≤2

ANC <1000/mm³, platelet count <50,000/mm³, hemoglobin <8 g/dL, and/or nonhematologic adverse events G ≥3

Delay the start of a new cycle. If delayed by ≥2 weeks, reduce the dose of pomalidomide by 1 dose level

G4 rash, neuropathy or hypersensitivity, or G ≥3 bradycardia or cardiac arrhythmia

Permanently discontinue pomalidomide

G3/4 adverse events occurring on or after day 15 during a single cycle

Withhold pomalidomide for the remainder of the cycle, and reduce pomalidomide dose by 1 dose level beginning with the next cycle

Toxicities ascribed to prednisone such as severe manifestations of hypercorticism, including: hyperglycemia, irritability, insomnia, or oral candidiasis

Hold prednisone doses for up to 21 days to resolve toxicity and then restart at the same dose level or reduce the prednisone dose by 50%

Efficacy

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Efficacy

Best Responses to Pomalidomide + Cyclophosphamide + Prednisone

Relapsed

Refractory to

>LEN

LEN

LEN/BOR

POL Dose

1 mg (N = 4)

1.5 mg (N = 4)

2 mg (N = 4)

2.5 mg (N = 55)

2.5 mg (N = 18)

2.5 mg (N = 37)

2.5 mg (N = 16)

Response

CR/PR

1 (25%)

2 (50%)

28 (51%)

11 (61%)

17 (46%)

8 (50%)

—

VGPR

—

BOR, bortezomib; CR, complete response; LEN, lenalidomide; MR, minimal response; PD, progressive disease; POL, pomalidomide; PR, partial response; SD, stable disease; VGPR, very good partial response

Time to Event Analysis

Median Follow-Up

Median PFS

Median OS

12-Month OS

Months (Range)

Months (95% CI)

All patients

15.0 (3.7–26.4)

8.6 (7.5–13.9)

65% (51–76%)

LEN 1–2 mg

24.1 (3.7–26.4)

4.6 (3.3–8.0)

9 (5.2–NR)

44% (15–70%)

LEN 2.5 mg

14.8 (6.1–21.4)

10.4 (7.8–15.8)

69% (54–81%)

Relapsed > LEN

12.7 (7.2–21.4)

15.7 (12.8–20.7)

88% (60–97%)

Refractory to LEN

15.3 (6.1–21.4)

8.6 (7.5–13.9)

60% (41–75%)

Refractory to

LEN/BOR

15.8 (6.6–21.4)

8.6 (4.8–NR)

67% (37–85%)

BOR, bortezomib; LEN, lenalidomide; NR, not reached; OS, overall survival; PFS, progression-free survival

Toxicity

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Toxicity

Treatment—Related Adverse Events During Salvage Therapy Phase 2 (N = 55)

Event

All Grades

Hematologic

Neutropenia

—

Thrombocytopenia

—

Anemia

—

Nonhematologic

Ischemia

—

Arrhythmia

—

Sensory neuropathy

—

Neuralgia

—

Motor neuropathy

—

Tremor

—

Confusion

—

Mood depression

—

Other neurologic

—

Upper respiratory

—

Pneumonia

—

Sepsis

—

Other infective

—

Diarrhea

—

Constipation

—

Nausea/vomiting

—

Other gastrointestinal

—

Increased transaminase

—

Liver failure

—

Pancreatitis

—

Deep vein thrombosis

—

Phlebitis

—

Nonhematologic

Fatigue

—

Fever

—

Drowsiness

—

Weight gain

—

Rash

—

Other dermatologic

—

Other

—

Patient Population Studied

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Patient Population Studied

Patients with MM who had received 1–3 prior lines of therapy and whose disease had relapsed after lenalidomide or was refractory. Relapse was defined as reoccurrence of disease requiring the initiation of a salvage therapy. Refractory disease was defined as relapse while on salvage therapy or progression within 60 days after the most recent therapy. Patients were required to have Karnofsky performance status ≥60%, platelet count ≥50,000/mm³, neutrophil count ≥1000/mm³, corrected serum calcium ≤3.5 mmol/L (≤14 mg/dL), and serum creatinine ≤2 mg/dL (≤177 μmol/L)

Baseline Patients Characteristics (N = 66)

Median age, years (range)

69 (41–84)

Gender (F/M)

33 (48%)/36 (52%)

International Staging System stage I/II/III

34 (49%)/27 (39%)/8 (12%)

Myeloma protein class

IgG

42 (61%)

IgA 4

16 (23%)

Bence-Jones protein

10 (15%)

Non-secretory

1 (1%)

Karnofsky performance status 60–70/80/90–100

10 (14%)/13 (19%)/46 (67%)

Serum β₂-microglobulin level: median (mg/L)

3 (1.6–12)

Months from diagnosis to on study: median (range)

53 (11–203)

Prior lines of therapy: median (range)

3 (1–3)

Prior therapies

69 (100%)

58 (84%)

Thalidomide

14 (20%)

Autologous transplant

23 (33%)

Allogeneic transplant

10 (15%)

Previous lenalidomide

Relapsed

23 (33%)

Refractory

46 (67%)

Previous bortezomib [data not available for 14 (20%)]

Relapsed

17 (25%)

Refractory

27 (39%)

FISH^✫

High risk

18 (26%)

Standard risk

35 (51%)

Not available

16 (23%)

Chromosome abnormalities

Del 13

24 (35%)

(4;14)

8 (12%)

t(11;14)

12 (17%)

t(14;16)

3 (4%)

Del17

8 (12%)

^✫High risk FISH = presence of at least 1 of the following: t(4;14), t(14;16), or del17

Therapy Monitoring

Blood counts and physical examinations on day 1 of each cycle
Serum and urinary protein electrophoresis studies on day 1 of each cycle as indicated and at the end of treatment

REGIMEN: RELAPSED/REFRACTORY MULTIPLE MYELOMA: LIPOSOMAL DOXORUBICIN + BORTEZOMIB

Regimen: Relapsed/Refractory Multiple Myeloma: Liposomal Doxorubicin + Bortezomib

Orlowski RZ et al. J Clin Oncol 2007;25:3892–3901

Bortezomib 1.3 mg/m² per dose; administer by intravenous injection over 3–5 seconds for 4 doses on days 1, 4, 8, and 11, every 3 weeks (total dosage/cycle = 5.2 mg/m²)

Doxorubicin HCl Liposome Injection ([pegylated] liposomal doxorubicin) 30 mg/m²; administer intravenously in 250 mL (doses ≤90 mg) or 500 mL (doses ≤90 mg) 5% dextrose injection over 60 minutes after bortezomib on day 4, every 3 weeks (total dosage/cycle = 30 mg/m²)

Notes:

Liposomal doxorubicin doses >60 mg are administered at an initial rate of 1 mg/min to minimize the risk of infusion reactions. If no infusion-related adverse reactions are observed within 15 minutes after starting administration, the infusion rate may be increased to complete administration over 1 hour
Treatment on study continued until disease progression, unacceptable treatment-related toxicities, or for 8 cycles. Patients still responding after 8 cycles were permitted to continue, provided treatment was well tolerated

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days with bortezomib alone is MINIMAL–LOW

Emetogenic potential on days with liposomal doxorubicin is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis may be indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is HIGH

Antimicrobial primary prophylaxis is recommended:

Antibacterial—consider fluoroquinolone prophylaxis; P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—recommended
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

Acyclovir and famciclovir elimination is inversely related to renal function
Acyclovir, famciclovir, and valacyclovir utilization is modified in renally impaired individuals (consult product labeling or Summary of Product Characteristics for guidance about dose/dosage and administration frequency modifications, and, when relevant, recommendations for drug dilution, administration rate, concurrent fluid administration, and fluid supplementation as a function of urine output)
Impaired acyclovir elimination is associated with neurologic adverse effects, including agitation, ataxia, coma, confusion, dizziness, dysarthria, encephalopathy, hallucinations, paresthesia, seizure, somnolence, and tremors

See Chapter 47 for more information

Thromboprophylaxis

Risk assessment and recommendations for VTE prophylaxis in patients with multiple myeloma with individual or myeloma-related risk factors, or risk factors related to treatment

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Individual risk factors

Obesity (BMI ≥30 kg/m²)
H/O VTE
CVC or pacemaker
Comorbid pathologies

Cardiac disease

Chronic renal disease

Diabetes

Acute infection

Immobilization
Surgery

General surgery

Any anesthesia

Trauma
Medications

Erythropoietin (epoetin alfa, darbepoetin)

Estrogenic compounds

Bevacizumab
Clotting disorders

Thrombophilia

Myeloma-related risk factors

Diagnosis of multiple myeloma
Hyperviscosity

≤1 Individual or myeloma risk factor present:

Aspirin 81–325 mg daily

≥2 Individual or myeloma risk factors present:

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or
Warfarin, targeting an INR = 2–3

Concomitant treatment-related risk factors

Thalidomide or lenalidomide in combination with:

High-dose dexamethasone (≥480 mg/month)
Doxorubicin
Multiagent chemotherapy

LMWH^✫, equivalent to enoxaparin sodium 40 mg/day or dalteparin sodium 5000 IU/day; administer subcutaneously, or

Warfarin, targeting an INR = 2–3

CVC, central venous catheter; INR, international normalized ratio; LMWH, low-molecular-weight heparin; VTE, venous thromboembolic disease

Geerts WH et al. Chest 2008;133(6 Suppl):381S–453S

Multiple Myeloma, V.1.2014. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Palumbo A et al. Leukemia 2008;22:414–423

Venous Thromboembolic Disease, V.2.2013. National Comprehensive Cancer Network, Inc., 2013. (Accessed October 8, 2013, at http://www.nccn.org)

Hand-foot reaction (palmar-plantar erythrodysesthesia)

For patients who develop a hand-foot reaction, use topical emollients (eg, Aquaphor), topical or orally administered steroids, antihistamine agents (H₁-receptor antagonists), or pyridoxine

Pyridoxine may provide relief for discomfort/pain associated with PPE, although the mechanism through which this occurs remains unclear

The suggested pyridoxine starting dose is 50 mg/day, which may be increased to a maximum of 200 mg/day

Patients who have developed G1/2 PPE while receiving doxorubicin HCl liposome injection may receive a fixed daily dose of pyridoxine 200 mg. This may allow for treatment to be completed without dosage reduction, treatment delay, or recurrence of PPE

Diarrhea management

Latent or delayed-onset diarrhea^✫:

Loperamide 4 mg; administer orally initially after the first loose or liquid stool, then
Loperamide 2 mg; administer orally every 2 hours during waking hours, plus
Loperamide 4 mg; administer orally every 4 hours during hours of sleep
- Continue for at least 12 hours after diarrhea resolves
- Recurrent diarrhea after a 12-hour diarrhea-free interval is treated as a new episode
- Rehydrate orally with fluids and electrolytes during a diarrheal episode
- If a patient develops blood or mucus in stool, dehydration, or hemodynamic instability, or if diarrhea persists >48 hours despite loperamide, stop loperamide and hospitalize the patient for IV hydration
  
  Alternatively, a trial of Diphenoxylate hydrochloride 2.5 mg with Atropine sulfate 0.025 mg (eg, Lomotil)
- Initial adult dose is two tablets four times daily until control has been achieved, after which the dose may be reduced to meet individual requirements. Control may often be maintained with as little as two tablets daily
- Clinical improvement of acute diarrhea is usually observed within 48 hours. If improvement of chronic diarrhea after treatment with a maximum daily dose of 8 tablets is not observed within 10 days, control is unlikely with further administration

Oral care

Prophylaxis and treatment for mucositis/stomatitis

General advice:

Encourage patients to maintain intake of non-alcoholic fluids
Evaluate patients for oral pain and provide analgesic medications
Consider histamine H₂-receptor antagonists (eg, ranitidine, famotidine), or a proton pump inhibitor for epigastric pain
Lactobacillus sp.-containing probiotics may be beneficial in preventing diarrhea

Patients with intact oral mucosa:

Clean the mouth, tongue, and gums by brushing after every meal and at bedtime with an ultra-soft toothbrush with fluoride toothpaste
Floss teeth gently every day unless contraindicated. If gums bleed and hurt, avoid bleeding or sore areas, but floss other teeth
Patients may use saline or commercial bland, non-alcoholic rinses
- Do not use mouthwashes that contain alcohols

If mucositis or stomatitis is present:

Keep the mouth moist utilizing water, ice chips, sugarless gum, sugar-free hard candies, or a saliva substitute
Rinse mouth several times a day to remove debris
- Use a solution of ¼ teaspoon (1.25 g) each of baking soda and table salt (sodium chloride) in one quart (~950 mL) of warm water. Follow with a plain water rinse
- Do not use mouthwashes that contain alcohols
Foam-tipped swabs (eg, Toothettes) are useful in moisturizing oral mucosa, but ineffective for cleansing teeth and removing plaque
Advise patients who develop mucositis to:
- Choose foods that are easy to chew and swallow
- Take small bites of food, chew slowly, and sip liquids with meals
- Encourage soft, moist foods such as cooked cereals, mashed potatoes, and scrambled eggs
- For trouble swallowing, soften food with gravies, sauces, broths, yogurt, or other bland liquids
- Avoid sharp, crunchy foods; hot, spicy or highly acidic foods (eg, citrus fruits and juices); sugary foods; toothpicks; tobacco products; alcoholic drinks

Bisphosphonates

All patients receiving primary therapy for symptomatic multiple myeloma should receive a bisphosphonate adjunctively; for example:

Pamidronate disodium 90 mg; administer intravenously over 2–4 hours, every month, or
Zoledronic acid 4 mg; administer intravenously over 15 minutes, every month

Consider baseline bone densitometry evaluation

See Chapter 43 for more information

Toxicity (N = 318)

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Toxicity (N = 318)

Overview of Treatment-Emergent Adverse Events

Percent of Patients

Any adverse event

Drug-related adverse events

Serious adverse events

Drug-related serious adverse events

G3/4 adverse events

Drug-related G3/4 adverse events

Adverse event leading to bortezomib discontinuation

Adverse event leading to liposomal doxorubicin discontinuation

Adverse event with fatal outcome

Drug-related adverse event with fatal outcome

Adverse Events During Treatment Reported by at Least 15% of Patients

% Total

% G3/4

Hematologic Events

Thrombocytopenia

Anemia

Neutropenia

Febrile neutropenia

Gastrointestinal Events

Nausea

Diarrhea

Constipation

Vomiting

Constitutional Symptoms

Fatigue

Pyrexia

Asthenia

Anorexia

Other

Thromboembolic event

Bleeding/hemorrhage

Cough

Stomatitis

Hand-foot syndrome

Cardiac events

Neuralgia

Headache

Peripheral neuropathy

Alopecia

N/A

Efficacy (N = 324)

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Efficacy (N = 324)

Total response (CR + PR)

44%

40%

nCR

CR + VGPR

27%

Median time to first response

43 days

Median number of cycles administered

5 cycles

Median treatment duration

105 days

Median duration of response

10.2 months

Median time to progression

9.3 months

Median progression-free survival

9 months

Median duration of overall survival

311 days

15-month survival rate

76%

CR, complete response; nCR, near-complete response; PR, partial response; VGPR, very good partial response

Patient Population Studied

A randomized phase III study of 646 patients with relapsed refractory multiple myeloma. Eligible subjects had an Eastern Cooperative Oncology Group performance status ≤1, must have experienced disease progression after a response to 1 or more lines of therapy or were refractory to initial treatment, but were bortezomib naïve. Subjects were excluded if their disease progressed while receiving anthracycline-containing therapy, and if they had already received >240 mg/m² doxorubicin, clinically significant cardiac disease, a left ventricular ejection fraction less than institutional normal limits, or peripheral neuropathy G ≥2

Therapy Monitoring

Blood counts with differential leukocyte count and physical examinations on day 1 of each cycle
Serum and urinary protein electrophoresis studies on day 1 of each cycle and at the end of treatment

Treatment Modifications

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Treatment Modifications

Bortezomib Dosage Levels

Dosage Level 1

1.3 mg/m²

Dosage Level −1

1 mg/m²

Dosage Level −2

0.7 mg/m²

Modification Guidelines for Hematologic Toxicity on Day 1 of Planned Therapy

Toxicity

Treatment Modification

ANC 1000–1500/mm³ or platelets 75,000–100,000/mm³

Resume treatment with no dosage reduction

ANC 500–999/mm³ or platelets 50,000–75,000/mm³

Hold treatment until toxicity resolves to G ≤1 or 75% of the counts measured at the start of the previous cycle, then resume without dosage reduction

ANC <500/mm³ or platelets <25,000/mm³

First episode: Hold treatment until toxicity resolves to G ≤1, then resume with a 25% dosage reduction of both liposomal doxorubicin and bortezomib or continue full dose with hematopoietic growth factor support (filgrastim, sargramostim)

Reduce dose by 25% if neutropenia occurs despite growth factor use

Febrile neutropenia

Withhold therapy until fever abates then resume therapy

Treatment Modification for Bortezomib-Induced Peripheral Neuropathy^✫

Severity of Peripheral Neuropathy

Modification of Dose and Schedule

G1 (paresthesias or loss of reflexes) without pain or loss of function

No action

G1 with pain or G2 (interferes with function but not with activities of daily living)

Reduce bortezomib dosage to 1 mg/m² per dose

G2 with pain or G3 (interferes with activities of daily living)

Withhold bortezomib treatment until toxicity resolves, then reinitiate at a dosage of 0.7 mg/m² per dose once weekly

G4 (permanent sensory loss that interferes with function)

Discontinue treatment

^✫Richardson PG et al. J Clin Oncol 2006;24:3113–3120

Liposomal Doxorubicin: Treatment Modification Guidelines for Cardiac Toxicity

Toxicity

Treatment Modification

LVEF decreases by ≥15% from baseline, or to <45%

Discontinue liposomal doxorubicin

LVEF, left ventricular ejection fraction

Treatment Modification Guidelines for Palmar-Plantar Erythrodysesthesia (PPE, Hand-Foot Syndrome)

Grade of Toxicity

Liposomal Doxorubicin Dosing Interval

4 Weeks

5 Weeks

6 Weeks

G1: Mild erythema, swelling, or desquamation not interfering with daily activities

Resume unless patient has previous G3/4 skin toxicity. If so, delay an additional week

Resume liposomal doxorubicin at a 25% dose reduction; return to a 4-week dosing interval or discontinue therapy

G2: Erythema, desquamation, or swelling interfering with, but not precluding, normal physical activities; small blisters or ulcerations <2 cm in diameter

Delay treatment 1 week

Resume liposomal doxorubicin at a 25% dose reduction; return to 4-week dosing interval or discontinue therapy

G3: Blistering, ulceration, or swelling interfering with walking or normal daily activities; cannot wear regular clothing

Delay treatment 1 week

Discontinue therapy

G4: Diffuse or local process causing infectious complications, or a bedridden state, or hospitalization

Delay treatment 1 week

Discontinue therapy

REGIMEN: RELAPSED/REFRACTORY MULTIPLE MYELOMA: CONDITIONING REGIMEN BEFORE AUTOLOGOUS PERIPHERAL BLOOD STEM CELL TRANSPLANTATION: HIGH-DOSE MELPHALAN

Regimen: Relapsed/Refractory Multiple Myeloma: Conditioning Regimen Before Autologous Peripheral Blood Stem Cell Transplantation: High-Dose Melphalan

Moreau P et al. Blood 2002;99:731–735

Conditioning for autologous PBSC transplant:

Melphalan 200 mg/m²; administer intravenously, diluted in sufficient 0.9% sodium chloride injection (0.9% NS) to produce a concentration ≤0.45 mg/mL over 30 minutes, 2 days before PBSC reinfusion (on day −2) (total dosage = 200 mg/m²). PBSC reinfusion on day 0 (zero), or

Melphalan 100 mg/m² per day; administer intravenously, diluted in sufficient 0.9% NS to produce a concentration ≤0.45 mg/mL over 30 minutes, for 2 consecutive days, starting 3 days before PBSC reinfusion (on days −3 and −2) (total dosage = 200 mg/m²). PBSC reinfusion on day 0 (zero)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is HIGH on days melphalan is administered. Potential for delayed symptoms

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Filgrastim (G-CSF), 5–10 mcg/kg per day; administer by subcutaneous injection starting on day +7 after PBSC reinfusion, and continue until granulocyte counts recover, or

Sargramostim (GM-CSF) 5–10 mcg/kg per day; administer by subcutaneous injection starting on day +7 after PBSC reinfusion, and continue until granulocyte counts recover

Antimicrobial prophylaxis

Antibacterial prophylaxis (P. jirovecii pneumonia prophylaxis):

Trimethoprim + Sulfamethoxazole (TMP + SMZ) 160 mg/800 mg; administer orally, daily, continually for 3 months, or

TMP + SMZ 80 mg/400 mg; administer orally daily, continually for 3 months, or

TMP + SMZ 160 mg/800 mg; administer orally 3 days per week, continually for 3 months

Antifungal prophylaxis

Fluconazole 200–400 mg/day; administer orally or intravenously daily for 30 days after PBSC reinfusion or until neutrophil engraftment occurs (ANC >500/mm³)

Antiviral prophylaxis for HSV-seropositive recipients to prevent reactivation of HSV during the early posttransplant period

Acyclovir 200 mg; administer orally every 8 hours for 30 days, or

Acyclovir 250 mg/m² per dose; administer intravenously every 12 hours for 30 days, or

Valacyclovir 500 mg; administer orally daily for 30 days

Note: Routine acyclovir prophylaxis for >30 days after HSCT is not recommended

Acyclovir and famciclovir elimination is inversely related to renal function
Acyclovir, famciclovir, and valacyclovir utilization is modified in renally impaired individuals (consult product labeling or Summary of Product Characteristics for guidance about dose/dosage and administration frequency modifications, and, when relevant, recommendations for drug dilution, administration rate, concurrent fluid administration, and fluid supplementation as a function of urine output)
Impaired acyclovir elimination is associated with neurologic adverse effects, including agitation, ataxia, coma, confusion, dizziness, dysarthria, encephalopathy, hallucinations, paresthesia, seizure, somnolence, and tremors

See Chapter 47 for more information

Oral care

Prophylaxis and treatment for mucositis/stomatitis

General advice:

Encourage patients to maintain intake of non-alcoholic fluids
Evaluate patients for oral pain and provide analgesic medications
Consider histamine H₂-receptor antagonists (eg, ranitidine, famotidine), or a proton pump inhibitor for epigastric pain
Lactobacillus sp.-containing probiotics may be beneficial in preventing diarrhea

Patients with intact oral mucosa:

Clean the mouth, tongue, and gums by brushing after every meal and at bedtime with an ultra-soft toothbrush with fluoride toothpaste
Floss teeth gently every day unless contraindicated. If gums bleed and hurt, avoid bleeding or sore areas, but floss other teeth
Patients may use saline or commercial bland, non-alcoholic rinses
- Do not use mouthwashes that contain alcohols

If mucositis or stomatitis is present:

Keep the mouth moist utilizing water, ice chips, sugarless gum, sugar-free hard candies, or a saliva substitute
Rinse mouth several times a day to remove debris
- Use a solution of ¼ teaspoon (1.25 g) each of baking soda and table salt (sodium chloride) in one quart (~950 mL) of warm water. Follow with a plain water rinse
- Do not use mouthwashes that contain alcohols
Foam-tipped swabs (eg, Toothettes) are useful in moisturizing oral mucosa, but ineffective for cleansing teeth and removing plaque
Advise patients who develop mucositis to:
- Choose foods that are easy to chew and swallow
- Take small bites of food, chew slowly, and sip liquids with meals
- Encourage soft, moist foods such as cooked cereals, mashed potatoes, and scrambled eggs
- For trouble swallowing, soften food with gravies, sauces, broths, yogurt, or other bland liquids
- Avoid sharp, crunchy foods; hot, spicy or highly acidic foods (eg, citrus fruits and juices); sugary foods; toothpicks; tobacco products; alcoholic drinks

Notes:

This conditioning regimen was part of a more comprehensive therapy for multiple myeloma that included the following:

Before PBSC harvest, patients received 3 cycles of vincristine + doxorubicin + dexamethasone (VAD)
In the absence of tumor progression (>25% increase in tumor mass), and if cardiopulmonary, hepatic, and renal function (serum creatinine <1.7 mg/dL [<150 μmol/L]) remained adequate after a third course of VAD, peripheral blood stem cells (PBSCs) were collected
After PBSC collection, patients received a fourth course of VAD

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Response to VAD Regimen and Stem Cell Collection

Complete response

Very good partial response^✫

12%

Partial response

61%

Stable disease

22%

Stem Cell Collection

G-CSF priming

75%

Stem cell factor + G-CSF

Cyclophosphamide + G-CSF

21%

Median number of CD34 infused

5 (range: 1.2–132) × 10⁶/kg

G-CSF, granulocyte-colony stimulating factor

^✫Ninety percent decrease in serum paraprotein level

4. After completion of high-dose chemotherapy (HDT) and PBSCT, treatment with recombinant interferon alfa 3 million International Units was given by subcutaneous injection 3 times weekly after granulocytes exceeded 1500/mm³ and platelets exceeded 100,000/mm³ during the first year after transplantation. Interferon was continued at participating physicians' discretion in case of disease progression or when it induced severe and persistent adverse effects. The value of maintenance interferon in this or any setting is uncertain

Patient Population Studied

A study of 142 patients ≤65 years of age with symptomatic multiple myeloma responding to primary chemotherapy with VAD

Exclusions:

Stable stage 1 MM deemed not to require therapy (Durie-Salmon classification)
Previous cytotoxic chemotherapy other than VAD in preparation for transplantation^✫
Previous radiation therapy
Severe abnormalities of cardiac, pulmonary, and hepatic function (not characterized)
Serum creatinine concentration >5.7 mg/dL (>504 μmol/L)

Efficacy (N = 142)

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Efficacy (N = 142)

Response to HDT

Complete response

35%

Very good partial response^✫

20%

Partial response

39%

Stable or progressive disease

Toxic death

Median event-free survival

20.5 months

^✫Ninety percent decrease in serum paraprotein level

Adverse Events (N = 142)

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Adverse Events (N = 142)

Event

Duration in Days Median (Range)

Hematopoietic growth factor

7 (0–23)

Neutropenia

8 (4–34)

Thrombocytopenia

7 (0–30)

Intravenous antibiotics

8 (0–30)

Length of hospital stay

19 (11–47)

Supportive Measure

Number Median (Range)

Platelet transfusions

1 (0–18)

RBC transfusions

2 (0–9)

G3/4 Toxicity

WHO Criteria

Cardiac

0.7%

Mucositis

30%

Pulmonary

1.4%

Renal

2.1%

Liver

0.7%

Toxic death

Therapy Monitoring

CBC with differential, daily to every third day as hematological recovery occurs

REGIMEN: MAINTENANCE THERAPY—MULTIPLE MYELOMA: BORTEZOMIB