Chapter 68: Myeloma

• Myeloma is a malignancy of terminally differentiated B cells (plasma cells) that produces a complete and/or partial (light chain) monoclonal immunoglobulin protein.

• Clinical and laboratory manifestations are heterogeneous but typically include:

  — A monoclonal immunoglobulin in plasma and/or monoclonal light chains in plasma and urine. In rare cases, the cells do not secrete a monoclonal protein in the plasma

  — Decreased polyclonal immunoglobulin secretion by residual normal plasma cells, which predispose to infections

  — Myeloma cell proliferation in marrow leading to impaired hematopoiesis

  — Osteolytic bone disease

  — Often hypercalcemia as a result of osteolysis

  — Renal dysfunction as a result of light chain casts or hypercalcemia

• Myeloma accounts for more than 1% of all malignancies and 10% of hematologic neoplasms.

• Most patients are diagnosed between ages 65 to 74 years of age; only 4% of cases occur before 45 years. The median age of onset is 69 years.

• Men are affected more frequently than women (1.6:1 ratio). Individuals of African descent have twice the prevalence as those of European descent.

• Myeloma is always preceded by a condition known as essential monoclonal gammopathy (MG), which may develop years before the diagnosis of myeloma. Among patients with MG, progression to myeloma is 1% per year.

• Genome-wide association studies identified six single nucleotide polymorphisms (SNPs) associated with risk for MG and myeloma, including 2p23.3, 3p22.1, 3q26.2, 6p21.33, 7p15.3, 17p11.2, and 22q13.1. The identified genes (DNMT3A, ULK4, TERC, PSORS1C1, CDCA7L/DNAH1, TNFRSF13B, and CBX7) have not been validated as myeloma-driver genes.

• Myeloma cells are derived from postgerminal-center marrow plasmablasts/plasma cells. Stages of evolution from MG to plasma cell leukemia are shown in Figure 68–1.

• Myeloma cell immunoglobulin heavy chain (IgH) variable genes present somatic mutations in the absence of intraclonal variation or ongoing somatic hypermutation.

• Myeloma is characterized by karyotypic abnormalities including translocations and copy change numbers. Common genomic aberrations are shown in Table 68–1.

• DNA hyperdiploidy is present in up to 60% of patients.

• Hyperdiploid myeloma patents, typically IgG kappa-type with bone involvement, show gains of odd-numbered chromosomes, including 15, 9, 5, 19, 3, 11, 7, and 21 (ordered by decreasing frequency).

• Nonhyperdiploid myeloma usually is associated with IgH gene translocations located at chromosome 14q32 and in some patients with translocations involving the λ light chain locus on chromosome 22. Translocations involving the κ locus on chromosome 2 are rare.

• Deletions of chromosomes 13 (resulting in RB1 gene and miRNA-15a/16-1 cluster dysregulation) and 17 (involving the TP53 locus), and amplification of chromosome 1q21 have been associated with a poor prognosis.

• The interaction of myeloma cell with the marrow microenvironment plays a key role in disease progression and drug resistance.

• Criteria for diagnosis of myeloma are shown in Table 68–2.

• The most critical criterion of symptomatic disease and, hence, initiation of therapy, is evidence of organ or tissue impairment (end-organ damage) manifested by anemia, hypercalcemia, lytic bone lesions, renal insufficiency, hyperviscosity, amyloidosis, or recurrent infections, commonly referred to as “CRAB” criteria for hypercalcemia, renal failure, anemia, and bone lesions.

Hematologic Abnormalities

• Myelomatous involvement of the marrow typically causes anemia, but when advanced may also contribute to neutropenia and thrombocytopenia.

• Overproduction of interleukin (IL)-6 by marrow stroma, normal accessory cells, and/or myeloma cells may contribute to the anemia by upregulating hepatic production of hepcidin (see Chap. 9), which blocks release of iron from macrophages and inhibits iron absorption from the intestine.

• Thrombocytopenia is uncommon in early phases of myeloma, even with extensive marrow myeloma cell replacement.

• Most patients have an inappropriate erythropoietin response for the level of their anemia.

• Bleeding occurs in 15% of patients with IgG myeloma and in 30% of patients with IgA myeloma.

• Thrombocytosis should alert one to the possibility of hyposplenism because of amyloid deposition in the spleen.

• Hypercoagulable states may result from defective fibrin structure and fibrinolysis because of increased immunoglobulin levels; increased acquired protein C resistance; and increased synthesis of proinflammatory cytokines, such as IL-6.

• Lupus anticoagulants have been reported in association with myeloma.

Immunoglobulin Abnormalities

• Virtually all patients with myeloma secrete a monoclonal immunoglobulin (M-protein or M-spike) that can be detected by immunofixation analysis of the serum and/or urine.

  — Approximately 60% of myeloma patients have detectable monoclonal IgG (usually > 3.5 g/dL), 20% have monoclonal IgA (typically > 2 g/dL), and 20% have only monoclonal immunoglobulin light chains. Excess light-chain proteinuria, however, can accompany IgG, IgA, and, especially, IgD myeloma.

• As a result of the advent of highly sensitive assays to detect serum free light chains (FLCs), an extremely small proportion of patients may have nonsecretory myeloma (no apparent extracellular monoclonal protein).

• Myelomas producing monoclonal IgD, IgE, IgM, or more than one immunoglobulin class are rare.

• The presence of a low concentration of serum monoclonal immunoglobulin by zonal electrophoresis should alert to the possibility of IgD myeloma, especially when associated with excess λ light chains in the serum and light-chain proteinuria, as 80% of IgD myeloma are of the λ light-chain variety.

  — Even patients with light-chain type myeloma, nonsecretory myeloma, or IgD or IgE myeloma often have depressed levels of normal, polyclonal serum IgG, IgA, and IgM.

• The half-life of FLCs is 2 to 4 hours, providing a means to assess the effects of therapy on the myeloma cell mass more quickly than by following serum immunoglobulin.

• Intact immunoglobulins have a half-life of 17 to 21 days, and responses in immunoglobulin levels to therapy are much slower to become apparent.

Marrow Findings

• The marrow can be diffusely infiltrated but commonly displays considerable site-to-site variation in myeloma cell density in a given patient (focal or nodular involvement).

• Cytologically, myeloma cells resemble plasma cells, exhibiting varying degrees of maturity (Figure 68–2).

• Myeloma cells produce either κ or λ light chains, which are present in the cytoplasm but not on the membrane surface (Figure 68–3).

• Myeloma cells are normally CD138+, CD45-, CD38+, and CD19-, and are CD56+ in 70% of patients.

• Secondary myelodysplasia (dysmorphic red cells, granulocytes, and megakaryocytes) can rarely develop after prolonged treatment in myeloma patients, particularly with alkylating agents (see Chap. 44).

• Metaphase cytogenetic studies and interphase fluorescent in situ hybridization (FISH) analysis should be performed routinely at diagnosis.

• Plasma cell labeling index, as determined by tritiated thymidine or bromodeoxyuridine techniques, that exceeds 0.5% is associated with a relatively short survival.

Renal Disease

• Some form of renal impairment occurs in 30% to 50% of myeloma patients at diagnosis, with up to 10% of patients requiring hemodialysis.

• Myeloma cast nephropathy is the most common cause of renal impairment and is also referred to as myeloma kidney.

  — Myeloma kidney is most commonly caused by the formation of tubular casts in the distal nephron formed by the binding of light chains to uromodulin (Tamm-Horsfall protein).

  — There is considerable variation in the nephrotoxic proclivity of light chains (eg, λ light chains are more nephrotoxic than the κ type).

• The second most common cause of renal impairment is hypercalcemia, which is present in 15% of patients at diagnosis. Hypercalcemia creates volume depletion, natriuresis, and renal vasoconstriction.

• AL amyloidosis associated with light-chain immunoglobulin proteinuria usually presents as the nephrotic syndrome, with very little light-chain secretion in the urine, but can lead, over time, to renal failure (see Chap. 71).

  — Amyloid deposits can be detected by Congo red staining.

  — AL amyloidosis is more common in patients with λ light-chain myeloma proteins than in patients with κ light-chain myeloma, especially those with λ light-chain proteins that have immunoglobulin variable regions belonging to the λ VI light-chain subgroup.

• The differential diagnosis of nephrotic syndrome in the myeloma patient should include renal vein thrombosis.

• Therapy of myeloma renal impairment, in addition to supportive care, includes (1) correction of hypercalcemia with aggressive hydration and calcitonin and (2) slow infusion of a single dose of a bisphosphonate. Cytoreductive therapy should be started as soon as possible. High cutoff hemodialysis using filters that remove light chains with great efficiency have resulted in improved patient outcomes.

• In general, myeloma renal impairment is reversible in approximately 50% of patients.

Pain

• Back or chest bone pain from factures or lytic bone lesions is present in 60% of patients at diagnosis.

• Localized pain can derive from focal plasmacytomas or amyloid deposits into nerve sheaths.

Infections

• Infection is a leading cause of morbidity and mortality in myeloma patients.

• Hypogammaglobulinemia, reflecting suppression of CD19+ B lymphocytes, results in susceptibility to encapsulated organisms such as Streptococcus pneumoniae and Haemophilus influenzae.

• Deficiencies in cellular immune function account for the recurrent infections commonly seen.

• Abnormalities in T-cell function include reversed CD4+/CD8+ T-cell ratios, severe disruptions in the T-cell repertoire, and abnormal intracellular signal transduction impairing T-cell activation.

• In patients with persistently low CD4+ counts, Pneumocystis jiroveci prophylaxis should be considered.

• Yearly influenza vaccination and a single pneumococcal vaccination is recommended at diagnosis.

Neuropathy

• Neurologic abnormalities generally are caused by regional myeloma cell growth compressing the spinal cord or cranial nerves.

• Polyneuropathies are observed with perineuronal or perivascular (vasa nervorum) amyloid deposition.

Hyperviscosity

• Hyperviscosity occurs in less than 10% of patients with myeloma.

  — Symptoms of hyperviscosity result from circulatory problems, leading to cerebral, pulmonary, renal, and other organ dysfunction.

  — Patients with IgA myeloma have hyperviscosity more frequently than do patients with IgG myeloma.

  — Among patients with IgG myeloma, those with tumors expressing immunoglobulins of the IgG₃ subclass are the most susceptible.

Extramedullary Disease

• Plasma cell leukemia is diagnosed when more than 2.0 × 10⁹/L myeloma cells are present in the blood or plasmacytosis accounts for more than 20% of the differential white cell count. It is rare at presentation but can develop in approximately 5% of patients as a terminal disease manifestation.

• Visceral organ involvement of liver, lymph nodes, spleen, kidneys, breasts, pleura, meninges, and cutaneous sites should be suspected in the presence of elevated serum levels of lactic acid dehydrogenase (LDH).

Spinal Cord Compression

• Spinal cord compression can result from an extramedullary plasmacytoma or vertebral fracture. It should be considered a medical emergency, evaluated with magnetic resonance imaging (MRI), and promptly treated.

• In the presence of a solitary plasmacytoma, local radiotherapy using less than 30 Gy can be curative.

• In patients with systemic disease, chemotherapy that includes high-dose dexamethasone pulsing, as part of the combination oral dexamethasone, daily thalidomide, and 4 days of continuous-infusion cisplatin, doxorubicin, cyclophosphamide, and etoposide (DT PACE) is effective.

  — In the absence of symptom relief and lack of tumor shrinkage on MRI within 1 week, local radiation should be added.

  — If cord compression results from vertebral collapse without identifiable plasmacytoma on MRI, radiation may not be beneficial, and decompressive laminectomy may be the treatment of choice.

• Minimal evaluation requirements include evaluation of the complete blood count with white cell differential count, myeloma protein studies, examination of the blood film for the presence of pathological rouleaux or circulating myeloma cells, a comprehensive serum metabolic panel for the detection of hypercalcemia and azotemia, serum β₂-microglobulin, C-reactive protein, and LDH (Table 68–3).

• Myeloma protein studies should include:

  — Serum protein electrophoresis

  — Serum free light-chain assay, as well as a 24-hour urine collection to quantify 24-hour total urinary protein and measure quantity of light chains

  — Immunofixation of serum and urine, which is needed for the immunoglobulin heavy- and light-chain isotype determination

• Marrow aspiration and biopsy should include genetic studies (eg, FISH and cytogenetics) and flow cytometry.

• Bone imaging should include a complete skeletal survey. MRI and fluoro-2-deoxyglucose (FDG) positron emission tomography–computed tomography (PET-CT) are more sensitive and better capture early bone disease, the extent of bone disease, and extramedullary disease.

• Assessment of the heart in the proper clinical context by echocardiogram and electrocardiogram is useful to detect cardiac amyloidosis.

• Measurement of brain natriuretic peptide and N-terminal prohormone B-type natriuretic peptide are useful screening tests to detect cardiac dysfunction caused by amyloidosis or light chain deposition disease, or LCDD.

Staging

• The Salmon-Durie staging system has been in use for more than 30 years but is being replaced by newer staging systems (see Table 68–4).

• The international staging system (ISS) is based on two widely available parameters, serum β₂-microglobulin and albumin, and recognizes three stages (see Table 68–5). Shortcomings of the ISS include lack of accounting for cytogenetics and bone disease.

Imaging Studies

• Standard of care in initial staging is a complete skeletal survey that includes posteroanterior view of the chest; anterior-posterior and lateral views of the skull, spine, and pelvis; rib series; and long bone images.

• Roentgenographically detectable osteolytic lesions require at least 50% to 70% loss of bone mass and represent advanced bone destruction; thus conventional x-rays have limited sensitivity.

• MRI detects focal intramedullary disease in two-thirds of patients at time of diagnosis, even before the onset of bone destruction. MRI is more sensitive than the skeletal survey and is now widely used in both newly diagnosed and relapsed myeloma, as well as in event of suspected cord compression.

• PET-CT scans are able to detect lesions at least 1 cm in diameter; active disease may be identified before bony destruction.

Management of Newly Diagnosed Myeloma

• Every newly diagnosed myeloma patient should be assessed for fitness to undergo an autologous hematopoietic stem cell transplant. Performance status, organ function, and comorbidities, rather than age alone, should be considered.

• Autologous transplantation achieves a complete response rate of 40%, but a median duration of response of only 2 to 3 years. Whether tandem autologous transplantation can improve on these results is being addressed in a Blood and Marrow Transplant Clinical Trials Network (BMT CTN) phase III, multicenter trial.

• Table 68–6 lists novel agents and combinations used for induction in newly diagnosed transplant-eligible patients. Regimens that include alkylating agents should be avoided, because these drugs damage normal hematopoietic stem cells and make stem cell harvesting more difficult.

• Table 68–7 lists induction regimens for newly diagnosed transplant-ineligible patients.

Maintenance Therapy

• Maintenance regimens, particularly with lenalidomide, have been proposed to extend the duration of complete remission following autologous transplantation.

• A significant concern with maintenance therapy with lenalidomide is the risk of secondary malignancy, which has been reported to nearly double the risk of second primary cancers, including hematologic malignancies and solid tumors.

• Table 68–8 summarizes maintenance trials.

Approach to Patients with Relapsed or Refractory Disease

• Table 68–9 summarizes trials of novel therapies for relapsed or refractory disease.

Monitoring Disease Markers for Documentation of Response and Relapse

• The criteria for evaluating response, the International Uniform Response Criteria, proposed by the International Myeloma Working Group (IMWG), are shown in Table 68–10.

• Survival end points include progression-free survival, event-free survival, and disease-free survival.

• Sequencing-based platforms, quantitative polymerase chain reaction, and multiparametric flow cytometry are being used to detect minimal residual disease and may be of prognostic value.

• Disease features can change over the course of the disease. Clonal evolution occurs, resulting in loss of previously secreted complete immunoglobulin and switch to only light-chain secretion (“Bence Jones escape”). or entire loss of immunoglobulin-secretory capacity, often associated with extramedullary spread, best signified by increased LDH levels and lesions found on PET-CT examination.

  — Occasionally, unexplained anemia or pancytopenia accompanies disappearing myeloma protein markers, necessitating prompt marrow examination to detect fulminant relapse.

• Monthly determinations of myeloma protein should be performed during induction therapy.

• After two to four induction cycles and prior to high-dose melphalan-based autologous transplantation, the disease should be restaged, including marrow examination with cytogenetics and MRI and/or PET-CT of indicator lesions.

• Disease monitoring should be performed at least every month for the first year and at a minimum of every other month thereafter.

Prognosis

• The prognosis of myeloma is determined by three factors:

  — Patient factors (eg, age, comorbid conditions)

  — Tumor biology and disease burden (eg, intrinsic cell drug sensitivity)

  — Type of therapy applied (eg, newer thalidomide derivatives and proteasome inhibitors)

• Cytogenetic findings associated with poor outcome include:

  — Hypodiploidy and deletions 13q and 17p13

  — Mutations at locus of the tumor-suppressor gene TP53

  — Gains and translocations of chromosome 1, which are associated with more aggressive and more advanced myeloma

  — Gain of the 1q21 region (amp1q21), which increases from approximately 40% at diagnosis to 70% at relapse

  — Both the proportion of cells with 1q21 and the copy number increases at relapse, suggesting the existence of a gene-dosage effect involved in drug resistance.

  — The gene CKS1B located at 1q21 controls the G1 to S transition of the cell cycle and has been linked to shorter progression-free survival after autologous transplantation.

• Hyperdiploidy, which accounts for almost half of the patients with abnormal cytogenetics and involves nonrandom gains of chromosomes 3, 5, 7, 9, 11, 15, 19, and 21, is associated with chemosensitive disease and better overall survival.

• Translocation t(11;14) also confers a better outcome.

• Interphase FISH does not depend on cycling cells and can detect abnormal cells in as many as 80% to 90% of cases.

  — FISH can also detect cytogenetically silent translocations.

• Gene-expression profiling has the potential to define disease pathogenesis as well as novel prognostic factors and potential therapeutic targets; profiling will have an important impact on the interpretation of future clinical trials.

IgM Myeloma

• IgM myeloma is distinct from Waldenström macroglobulinemia (see Chap. 69).

• Plasma cells, rather than the lymphoplasmacytic infiltrate, dominate the marrow of myeloma.

• DNA-aneuploidy and the presence of lytic bone lesions support a diagnosis of myeloma.

Solitary Plasmacytoma

• Solitary plasmacytoma of bone (solitary osseous plasmacytoma [SOP]) or soft tissue (extramedullary plasmacytoma [EMP]) requires the absence of indicators of systemic disease, such as marrow plasmacytosis, anemia, or other lytic or soft-tissue lesions.

• Median age of diagnosis of SOP or EMP is approximately 50 years, nearly 10 years less than for myeloma.

• The majority of patients with SOP progress to myeloma; only 50% of patients with EMP do so.

• Local therapy, primarily radiotherapy, with surgery as needed for structural anatomic support is standard treatment of SOP and EMP.

• Rising monoclonal Ig levels in a patient with a history of either SOP or EMP should trigger a workup for either recurrent plasmacytoma or myeloma.

AL Amyloidosis

• When clinical features of congestive heart failure, nephrotic syndrome, malabsorption, coagulopathy, skin rash (oral mucosal rash, “raccoon’s eyes”) or neuropathy are present, a careful search for primary amyloidosis should be carried out (see Chap. 71).

Smoldering Myeloma

• Smoldering myeloma is a form of myeloma in which there is no evidence of end-organ damage at diagnosis.

• There is no role for treating these patients; however, the IMWG has advised that patients with greater than 60% marrow plasma cells, a κ:λ free light chain ratio greater than 100, and two lesions on MRI or PET-CT imaging may benefit from therapy.

Venous Thromboembolism

• Patients with myeloma are at an increased risk for deep venous thrombosis and pulmonary embolism, particularly when known risk factors are present. These risk factors are:

  — History of prior venous thromboembolism (VTE), immobilization, and/or dehydration

• Genetic predispositions include high levels of homocysteine; deficiencies of antithrombin, protein C, and protein S; and factor V Leiden or prothrombin gene mutations.

• The incidence of VTE is highest during the first 3 to 4 months following diagnosis and occurs in approximately 3% to 4% of patients receiving either dexamethasone alone or melphalan and prednisone (MP) but is much higher when newer agents are combined with dexamethasone and melphalan.

  — A number of procoagulant abnormalities have been described in myeloma, including endothelial damage, paraprotein interference with fibrin structure, elevated von Willebrand multimers, elevated factor VIII, decreased protein S, and acquired activated protein C resistance.

• The incidence of VTE with single-agent thalidomide is approximately 2% to 4% in newly diagnosed and in relapsed patients, comparable to that observed with dexamethasone alone or MP, implying that thalidomide alone does not increase the risk of VTE.

  — However, the risk of VTE increases significantly when thalidomide is combined with either dexamethasone, melphalan, doxorubicin, or cyclophosphamide, or with other multiagent chemotherapy.

  — Most VTEs occur within the first 60 days of therapy.

• Single-agent lenalidomide does not appear to increase VTE, at least not in the setting of myeloma relapse, but it is associated with a marked increased in VTE risk when lenalidomide is combined with dexamethasone.

• Bortezomib did not seem to increase the risk of VTE.

• Prevention of VTE is based on the assessment for known risk factors for VTE:

  — Myeloma-related (hyperviscosity, newly diagnosed status)

  — Therapy-related (high-dose dexamethasone [≥ 480 mg/month], doxorubicin, multiagent chemotherapy)

  — Individual factors (age, history of VTE, inherited thrombophilia, obesity, immobilization, central venous line, infections, surgery, administration of erythropoietin)

  — Factors related to comorbidities (acute infection, diabetes mellitus, cardiac or renal dysfunction)

• Therapy-related risks factor most in the risk-equation of VTE.

• The following thromboprophylaxis is recommended:

  — Acetylsalicylic acid (aspirin) in either a standard oral dose of 325 mg/day or in a low-dose of 81 mg/day for patients with one or no risk factor

  — Low-molecular-weight heparin, or LMWH, once a day, or full-dose warfarin for patients if two or more risk factors or therapy-related risks are present

• The recommended duration of prophylaxis in general is 6 to 12 months.

• Long-term prophylaxis may be indicated in some patients.

Peripheral Neuropathy

• Bortezomib and thalidomide-induced peripheral neuropathy should be distinguished from other causes, such as paraneoplastic neuropathies, antecedent chemotherapy with neurotoxic agents (vincristine or cisplatinum), diabetes mellitus, or AL amyloidosis.

• If significant weakness or asymmetry of signs is present, a neurologic consultation must be obtained along with electromyography and nerve conduction studies.

• Subcutaneous administration of bortezomib is now the preferred route of administration due to a decreased incidence of peripheral neuropathy compared with intravenous administration.

• Second-generation, more selective proteasome inhibitors such as carfilzomib have reduced neurotoxicity.

• Symptomatic treatment for thalidomide- and bortezomib-induced neuropathy includes gabapentin, pregabalin, or tricyclic antidepressants.

Osteonecrosis of the Jaw

• Osteonecrosis of the jaw is characterized by the presence of exposed bone in the maxillofacial region that does not heal within 8 weeks.

• The exact cause is not known and is likely multifactorial. Bisphosphonates and invasive dental procedures are predisposing factors.

• The risk increases with duration of bisphosphonate exposure (5%–15% at 4 years). Risk is associated with a polymorphism in the cytochrome P450-2C polypeptide; the mechanism is unknown.

• Patents should be referred for dental evaluation prior to beginning bisphosphonates.