Chapter 11: Multiple Myeloma and Other Plasma Cell Dyscrasias

Plasma cell dyscrasias are heterogeneous disorders arising from the proliferation of a monoclonal population of plasma cells. Some of these disorders can present serendipitously as benign processes that can be observed; others are highly aggressive and require immediate intervention. The most common plasma cell dyscrasia is monoclonal gammopathy of undetermined significance (MGUS), a benign condition that can be observed. Related disorders include smoldering multiple myeloma (SMM), multiple myeloma (MM), solitary plasmacytoma of the bone, extramedullary plasmacytoma, Waldenström macroglobulinemia (WM), primary amyloid light-chain (AL) amyloidosis, heavy-chain disease, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, and the recently recognized TEMPI (telangiectasias, elevated erythropoietin and erythrocytosis, monoclonal gammopathy, perinephric fluid collection, and intrapulmonary shunting) syndrome. The spectrum of MGUS, SMM, and MM represents a natural progression of the same disease. This chapter focuses on the etiology, genetics, biology, diagnosis, clinical features, and current therapy of MM and other plasma cell disorders.

Major recent discoveries have changed the way we understand, diagnose, and treat plasma cell dyscrasias. The initial sequencing of the myeloma genome and single-cell genetic analysis paved the way for the concept of intraclonal heterogeneity and Darwinian selection of clones. Increasingly sensitive diagnostic and monitoring techniques allow for more accurate diagnosis, minimal residual disease monitoring, and detection of early relapse. New diagnostic criteria for MM have been implemented, and the introduction of novel classes of agents such as immunomodulatory drugs and proteasome inhibitors has led to improved overall survival. Additionally, immunotherapy using monoclonal antibodies against different myeloma targets has shown promising activity in clinical trials. Major advances have also occurred in WM as a highly recurrent single point mutation of the MYD88 gene has been identified, and new treatments that abrogate this highly active pathway are already in use. Finally, a new paraneoplastic syndrome, the TEMPI syndrome, has been identified and described.

Multiple myeloma is a malignant proliferation of plasma cells. In virtually all cases, myeloma cells (as well as their precursors MGUS and SMM) secrete immunoglobulins. Usually, myeloma cells secrete immunoglobulin (Ig) G (60%); other types are less common (IgA 20%, IgD 2%, IgE <0.1%, biclonal <1%). Light chain–only secretion is noted in 18%; <5% of patients do not secrete a heavy- or light-chain immunoglobulin (nonsecretory MM).

Epidemiology and Risk Factors

In 2014, approximately 24,000 people were diagnosed with MM in the United States, and 11,090 died from the disease. The median age at diagnosis is 69 years. The incidence is highest in the age range of 65 to 74 years (27.7%), followed by the 75- to 84 year-old range (24.7%). The annual age-adjusted incidence of the disease per 100,000 population is 7.2 among white men and 4.3 among white women. Among African Americans, the frequency doubles to 14.8 in men and 10.5 in women. There is also a difference in mortality by racial group. The annual age-adjusted mortality rate per 100,000 is 4.0 and 2.5 in white men and women, respectively, and 7.7 and 5.3 in African American men and women, respectively. The incidence and mortality rates are lowest among Asians and Pacific Islanders.

Risk factors that predispose to MGUS and MM point toward common shared etiologic environmental and genetic factors. Age is a risk factor for MGUS, because its prevalence is four times higher among individuals ≥80 years old than among those 50 to 59 years old. Increased risk of MGUS has also been reported in first-degree family members of patients with MGUS and MM (risk ratio between 2 and 3). In a study of black and white women of similar socioeconomic status, obesity, black race, and increasing age conferred an increased risk of MGUS. Personal and family history of autoimmune or inflammatory disorders as well as infections have been linked to an increased risk of MGUS and MM. Exposure to infections has been hypothesized to be involved in the malignant transformation of MM, or it could represent impaired immunity associated with MGUS and SMM, which often precedes a diagnosis of MM. Radiation exposure, pesticides, and cleaners are also associated with an increased risk of MGUS and MM.

Although MM is not an inherited disease, more than a hundred familial cases have been reported in the literature. The largest series described 39 unique families with 79 MM cases. Both dominant and recessive inherited traits may play a role in familial MM. Large genomic studies have identified low penetrant genetic variants that confer a modest increase in the risk of developing MM (^1,2). Based on epidemiologic and familial aggregation studies, most of the inherited risk of developing MM may result from different genetic polymorphisms, each of which has only a small effect on the predisposition to develop disease (³).

Pathophysiology and Genetics/Molecular Classification

Multiple myeloma arises from terminally differentiated B cells or even early committed B cells (germinal center B cells) that manifest clinically as more differentiated plasma cells. The major role of normal differentiated plasma cells is to produce immunoglobulins (antibodies) to fight infections. To become an effective part of the adaptive immune system, B cells must undergo immunoglobulin gene rearrangement and affinity maturation in response to antigens presented by antigen-presenting cells within the lymph node germinal center. For this to occur, hypervariable regions in the immunoglobulin heavy chain locus (IGH in chromosome 14q32) undergo programmed mutations (somatic hypermutation) through which, among others, double DNA strand breaks and chromosomal translocations are generated. The primary etiology of MM has been linked to IGH translocations and increased copies of odd-numbered chromosomes (hyperdiploidy), which result in cyclin D dysregulation. These events can be observed early in the course of monoclonal gammopathies (such as in MGUS or SMM) as well as in MM, suggesting that they are primary genetic events. Initial whole-genome and exome sequencing in 38 MM patients confirmed the complexity of genetic alterations seen in MM and uncovered secondary mechanisms of transformation to MM (⁴). Secondary events included mutations in the oncogene MYC (most commonly observed in plasma cell leukemia or aggressive forms of MM), mutations in the nuclear factor-κβ (NF-κβ) pathway, including BRAF and RAS, and chromosome copy number abnormalities such as deletions, amplifications, or additions. Changes in DNA methylation patterns are also important secondary events leading to increased tumor diversity and more aggressive forms of plasma cell dyscrasias (Table 11-1).

Different tests for gene expression profiling (GEP) are available for molecular classification of MM. Currently, molecular profiling of MM is mostly used for research purposes (eg, identification of high-risk MM for inclusion in clinical trials). These tests may become increasingly important as we develop more personalized treatment for MM.

Serial genomic analysis during the disease course of myeloma patients has identified different MM subclones within the same tumor. This has been termed intraclonal heterogeneity. In this model, different myeloma subclones compete for selection as they are exposed to the microenvironment and therapeutic pressures (⁵). Single-cell genetic analysis at diagnosis confirmed that MM is highly heterogeneous and characterized by the accumulation of a diverse range of mutations at the subclonal level (⁶). In this scenario, the acquisition of new mutations leads to new subclones with different clinical phenotypes and sensitivities to therapy. Intraclonal heterogeneity in myeloma has many potential implications for therapy, suggesting that subclonal targeting in combination therapies may be needed to eradicate the multiple subclones. Increasing genetic complexity is seen with progression from MGUS to MM and plasma cell leukemia, which may suggest that earlier treatment may result in improved clinical outcomes.

The bone marrow microenvironment also plays a role in the etiology of MM and its related disorders. Plasma cells communicate effectively with the microenvironment in a process called cell trafficking. Upregulation of cytokines that increase vascular permeability, proliferation, or cell homing (interleukin [IL]-6, vascular endothelial growth factor, and insulin-like growth factor) have been involved in the progression to MM. Gene expression profiling has revealed that modulation of certain genes can lead to a permissive microenvironment that promotes growth of myeloma subclones leading to active disease (⁷). Thus, targeting the microenvironment is an area of extensive research that, combined with therapeutic targeting of myeloma subclones, may lead to improved outcomes. New and effective antimyeloma combination therapies and well-designed clinical trials are needed to test these hypotheses.

Clinical Presentation

The clinical presentation of MM and its precursors is variable. Patients with MGUS or SMM usually do not present with specific myeloma-related symptoms. Their diagnosis is often incidental based on workup for a low albumin-to-globulin ratio, high serum protein, or other conditions such as autoimmune diseases, peripheral neuropathy, skin rashes, or hemolytic anemias.

In contrast, patients initially presenting with MM usually have at least one of the CRAB criteria (hyperCalcemia, Renal disease, Anemia, and Bone disease) classically used to define symptomatic MM. Anemia is the most common finding, occurring in 73% of patients, and is typically a normocytic, normochromic anemia. Anemia can be due to a variety of factors, including marrow replacement or cytokine production by plasma cells, which lead to decreased erythropoiesis, or decreased erythropoietin levels due to renal disease (⁸).

Bone pain is common, occurring in 60% of patients, and related to increased resorption of bone, leading to lytic bone lesions. Painful vertebral compression fractures can occur and may represent a medical emergency when associated with symptoms of cord compression. Increased bone resorption has been attributed to factors such as RANK ligand (RANKL), osteoprotegerin (OPG), macrophage inflammatory protein (MIP)-1α, IL-6, and IL-3, which stimulate osteoclast activity in areas infiltrated by plasma cells as a result of interactions between plasma cells and the microenvironment (Fig. 11-1).

An elevated creatinine is a presenting sign in 50% of patients. Renal disease is often attributed to light-chain cast nephropathy resulting from precipitation of light chains that bind to Tamm-Horsfall mucoproteins secreted by cells in the ascending loop of Henle. These precipitated complexes obstruct the distal convoluted tubules and collecting ducts, leading to tubular atrophy and interstitial fibrosis. Other causes of renal failure include hypercalcemia, leading to nephrocalcinosis, as well as amyloidosis, heavy-chain disease, and light-chain disease.

Hypercalcemia >11 mg/dL is present in 10% of patients and represents a medical emergency requiring hydration with isotonic saline and bisphosphonate therapy with zoledronic acid or pamidronate in moderate or severe cases. Calcitonin can also be used to rapidly reduce serum calcium levels.

Other common presenting symptoms include fatigue (32%) and weight loss (20%). Due to immune dysfunction, patients are at risk for infections. About 7% to 18% of patients may present with extramedullary plasmacytomas. Less common symptoms include fever, splenomegaly, hepatomegaly, and lymphadenopathy.

Diagnostic Workup

Once a plasma cell dyscrasia is suspected, a comprehensive diagnostic workup should be initiated to demonstrate the presence or absence of a clonal plasma cell disorder, to determine if end-organ damage is present, and to evaluate laboratory markers related to prognosis. These should include the following components.

Laboratory Studies

• Complete blood count (CBC)

• Serum chemistries including creatinine, calcium, albumin, lactate dehydrogenase (LDH), β₂-microglobulin, and immunoglobulin levels (IgG, IgA, IgM)

• Serum protein electrophoresis with immunofixation to quantify monoclonal protein (M-protein) and determine immunoglobulin isotype

• Serum free light-chain assay to evaluate the ratio of serum kappa to lambda light chains

• Urinalysis with 24-hour urine collection with protein electrophoresis and immunofixation (Fig. 11-2)

Imaging Studies

• Skeletal survey with plain films of the axial and appendicular skeleton is the minimum standard of care to evaluate lytic bone lesions.

• Advanced imaging with either whole-body low-dose computed tomography (CT), positron emission tomography–computed tomography (PET-CT), or magnetic resonance imaging (MRI) can detect up to 80% more lesions compared with plain film x-rays.

  • - An advanced imaging modality is particularly recommended in the diagnosis of SMM to detect subtle bone lesions that would warrant the initiation of treatment. It is also helpful in assessing baseline disease burden as an adjunct to serum and urine markers prior to initiation of treatment in MM.

  • - A CT scan can be helpful in the characterization of soft tissue masses in the case of extramedullary plasmacytomas and can direct to an area to be biopsied.

  • - An MRI scan is useful for evaluating the axial skeleton in the presence of symptoms and assessing for spinal cord compression. It can also identify abnormal marrow uptake as T1-weighted images will show a diffuse decrease in marrow signal intensity but will enhance with the administration of contrast.

  • Positron emission tomography–computed tomography can be prone to false-positive findings but has more specificity due to increased metabolic uptake at the site of lytic lesions and is the preferred initial baseline advanced imaging modality at the University of Texas MD Anderson Cancer Center (MDACC) in combination with skeletal surveys.

• There is no role for nuclear bone imaging because bone scan isotopes are not taken up by lytic lesions.

Bone Marrow Aspiration and Biopsy

• Morphologic review and immunohistochemistry (Fig. 11-3)

• Flow cytometry for immunophenotyping of plasma cells:

  • - Plasma cells are positive for CD38 and CD138.

  • - Normal plasma cells have higher expression of CD19 and CD45; malignant plasma cells typically lack these surface antigens.

  • - Malignant plasma cells have increased expression of CD56 and CD117; normal plasma cells have weak expression of these markers.

• Conventional cytogenetic karyotyping

• Fluorescent in situ hybridization (FISH) for recurrent chromosomal deletions, amplifications, and translocations that have prognostic significance; these include:

  • - Deletion 13q14, deletion 17p13 (TP53), and deletion of 1p32

  • - Amplification of 1q21

  • - Translocations involving the immunoglobulin heavy-chain locus on chromosome 14q32 and its common partners, including 11q13 (CCND1), 4p16 (FGFR3 and MMSET), 16q23 (c-MAF), 6p21 (CCND3), and 20q12 (MAFB)

• Gene expression profiling of the CD138⁺ bone marrow aspirate plasma cells to identify high-risk MM and to facilitate inclusion in clinical trials

Other Tests

• Abdominal wall fat pad biopsy (warranted if there are signs and symptoms suggestive of amyloidosis; see separate discussion), which should be stained with Congo red stain. Amyloid fibrils show green birefringence under polarized light.

• Serum viscosity (if there are concerns for hyperviscosity usually due to elevated IgM levels in WM; see separate discussion). Hyperviscosity should be a clinical diagnosis, and therapeutic plasma exchange should not be delayed while waiting for the results of serum viscosity level.

Myeloma Diagnostic Criteria

Based on the above workup, a diagnosis of a plasma cell dyscrasia may be made, which can span the spectrum of the premalignant MGUS stage to SMM to full malignant transformation to MM. Definitions of these clinical stages according to the International Myeloma Working Group (IMWG) criteria are summarized in Table 11-2 (⁹). Historically, SMM and MM have been distinguished by the presence of end-organ damage as defined by CRAB criteria. The 2014 updated IMWG criteria were revised to reclassify some SMM patients as having MM (even in the absence of symptoms) if certain biomarkers were present that might indicate impending development of CRAB features. These include clonal bone marrow plasmacytosis ≥60%, an involved-to-uninvolved serum free light chain ratio ≥100, or more than one focal lesion on MRI studies of at least 5 mm in size. Patients with SMM and at least one of these biomarkers have a 70% to 80% chance of progression to MM at 2 years compared to 20% (10% per year) in the absence of these high-risk features. Initiating therapy in these patients may delay the onset of MM-defining end-organ damage events and associated morbidity and adverse effects on quality of life.

Staging and Risk Stratification

The course of MM is heterogeneous. Risk stratification using staging and prognostic tools may yield insights into the underlying disease biology and expected course. Prognostic studies can help stratify patients in clinical trials and may help guide therapy [eg, bortezomib in t(4;14) and del 13q].

International Staging System

The International Staging System (ISS) was established in 2005 by the IMWG after a retrospective analysis of the outcomes of >10,000 patients across 17 different centers. In this study, β₂-microglobulin and albumin were powerful correlates of median survival, and patients could be categorized into three stages based on serum levels at diagnosis (Table 11-3). Because β₂-microglobulin is renally excreted, high levels may be found in the presence of renal failure, which makes the interpretation of the ISS in this setting challenging. The ISS is the current preferred staging method and has supplanted the previously used Durie-Salmon staging system, which was confounded by observer-dependent variables, such as degree of lytic bone lesions, that added subjectivity in its assessment. It is important to note that the ISS has only been validated at the time of diagnosis in patients with MM and should not be extrapolated to patients with MGUS or SMM.

Risk Stratification

In addition to the ISS, patients can be stratified into standard-, intermediate-, and high-risk categories based on cytogenetic findings by both conventional karyotyping and FISH. Other high-risk features include elevated serum LDH, extramedullary disease, circulating plasma cells, and a high-risk GEP pattern as defined by a 70-gene panel. Risk stratification based on these criteria is summarized in Table 11-4.

Response Criteria

International Myeloma Working Group Uniform Response Criteria

The IMWG proposed new guidelines in 2006 to standardize response criteria in MM and to define disease progression to facilitate comparisons of outcomes between treatment centers and for reporting results in clinical trials. These International Uniform Response Criteria guidelines are summarized in Table 11-5. Assessment of response with M-protein measurements using serum protein electrophoresis, urine protein electrophoresis, and serum free light-chain assay is recommended prior to each cycle of therapy. Bone marrow biopsy is necessary to monitor disease in the absence of a measurable M-protein in the serum or urine or to document a complete or stringent complete response. Serial imaging assessments may be required if soft tissue plasmacytomas are present at baseline.

Minimal Residual Disease

In recent years, the fraction of patients achieving deep responses, including complete remission, after initial MM therapy has increased significantly. This correlates with improved progression-free survival (PFS) and overall survival (OS) in several studies (¹⁰). With a deepened level of remission, more sensitive methods to assess and monitor minimal residual disease (MRD) have been investigated. These include flow cytometry, allele-specific polymerase chain reaction (ASO-PCR), and next-generation sequencing (NGS)–based assays (¹¹). MRD may soon be used as a valid surrogate end point to compare treatment strategies and advise on consolidation and maintenance therapies. At present, MRD assessment by multiparameter flow cytometry is the most reproducible method in MM. It has a sensitivity of 10^–5 if at least 2 × 10⁶ cells from bone marrow aspirates are analyzed. An international effort to adopt standardized or harmonized MRD detection assay and analysis by multiparameter flow cytometry in clinical practice and in clinical trials is ongoing.

Treatment of Newly Diagnosed Multiple Myeloma

After the diagnostic workup and risk stratification are complete, patients who meet the criteria for MM as defined by IMWG criteria should initiate therapy. The most important initial assessment is whether a patient is a candidate for high-dose chemotherapy and autologous stem cell transplantation (SCT), largely based on existing comorbidities and age. In the transplant-eligible population, current MM standard of care involves frontline chemotherapy, followed by consolidative high-dose melphalan and autologous SCT, followed by maintenance therapy. Some chemotherapy agents (eg, melphalan) may adversely affect stem cell collection and should be avoided in the initial therapy of transplant-eligible patients. Melphalan may be included in the frontline therapy of transplant-ineligible patients.

Frontline Therapy for Transplant-Eligible Patients

A number of different regimens can be used in the frontline setting for transplant-eligible patients. These usually consist of two- or three-drug combinations, and the choice of therapy is individualized based on factors such as patient comorbidities (neuropathy, diabetes), preferred route of administration (oral, intravenous, or subcutaneous), and underlying disease biology [eg, bortezomib in t(4;14) and del 13q]. Patients are usually given two to four cycles of therapy prior to stem cell collection to reduce disease burden before proceeding to high-dose chemotherapy and autologous stem cell rescue. Given the evidence that the depth and duration of response may translate into improved long-term outcomes, we generally prefer the three-drug regimens over the two-drug regimens as initial therapy in newly diagnosed patients.

Lenalidomide and Dexamethasone

The efficacy of the second-generation immunomodulatory drug (IMiD) lenalidomide combined with dexamethasone (Len/Dex) was initially demonstrated in the relapsed and refractory setting. Subsequently, a randomized phase III study in newly diagnosed MM compared lenalidomide plus high-dose dexamethasone versus placebo plus high-dose dexamethasone (¹²). Overall response rates (ORR), defined as a partial response or greater, and very good partial response (VGPR) rates were significantly higher in the Len/Dex arm (78% and 63%, respectively) versus the placebo/Dex arm (48% and 16%, respectively). The 1-year PFS rate was also higher in the Len/Dex arm (78% vs 52%), although there was no significant difference in OS between the two groups (94% vs 88%). Grade 3 or 4 neutropenia was higher with Len/Dex (21% vs 5%), as was the rate of venous thromboembolism (VTEs) (23.5% vs 5%) despite aspirin prophylaxis.

To possibly decrease the dexamethasone dose while retaining efficacy, a randomized study was conducted with lenalidomide in combination with high-dose dexamethasone (40 mg on days 1-4, 8-11, and 17-20 every 4 weeks) versus low-dose dexamethasone (40 mg on days 1, 8, 15, and 22 every 4 weeks) (¹³). Patients receiving high-dose dexamethasone achieved a higher ORR (79% vs 68%) after four cycles of therapy. However, a second interim analysis at 1 year demonstrated a statistically significant superior OS in the low-dose dexamethasone arm compared to the high-dose arm (96% vs 87%). This was attributed to increased toxicities of high-dose dexamethasone therapy including VTEs and infections. Based on this study, lenalidomide is recommended to be given in combination with low-dose dexamethasone.

Bortezomib and Dexamethasone

The proteasome inhibitor bortezomib in combination with dexamethasone was studied as frontline therapy in a large phase III trial comparing bortezomib and dexamethasone versus vincristine, doxorubicin, and dexamethasone (VAD) therapy prior to autologous SCT (¹⁴). Postinduction ORR (78.5% vs 62.8%), ≥VGPR rates (37.7% vs 15.1%), and complete response (CR) or near complete response (nCR) rates (14.8% vs 6.4%) all favored the bortezomib and dexamethasone arm over the VAD arm. There was also a trend toward improved median PFS in the bortezomib and dexamethasone arm (36.0 vs 29.7 months) but no difference in OS. In a separate analysis, initial treatment with bortezomib and dexamethasone prior to autologous SCT was shown to overcome the adverse prognostic features of t(4;14) in relation to event-free survival (EFS) and OS compared to VAD, although del 17p remained a poor prognostic factor regardless of the treatment regimen. Herpes simplex prophylaxis with acyclovir or valacyclovir should be given with bortezomib-containing regimens. Subcutaneous administration of bortezomib is preferred because it has similar efficacy as the intravenous route with decreased peripheral neuropathy (¹⁵).

Cyclophosphamide, Bortezomib, and Dexamethasone

The addition of oral cyclophosphamide to bortezomib and dexamethasone (CyBorD) was studied in phase II trials. In the EVOLUTION phase II trial, patients were randomized to receive bortezomib, lenalidomide, and dexamethasone (VRD); bortezomib, lenalidomide, cyclophosphamide, and dexamethasone (VDCR); or CyBorD, all followed by maintenance bortezomib for four 6-week cycles (¹⁶). The study was later amended to add an additional day 15 dose of cyclophosphamide, in addition to days 1 and 8, in patients receiving CyBorD. Patients receiving the modified CyBorD regimen achieved an ORR of 82%, with a VGPR or better rate of 53% and a CR rate of 47%. The 1-year PFS rate was 100%.

In another phase II study, standard twice-weekly (days 1, 4, 8, and 11) bortezomib was compared to weekly bortezomib (days 1, 8, 15, and 22) in combination with weekly cyclophosphamide and dexamethasone (¹⁷). ORR (88% vs 93%) and VGPR rates (60% vs 61%) were similar in both the twice-weekly and weekly bortezomib groups. In addition to demonstrating the efficacy of the three-drug combination of CyBorD, this study also suggested that weekly (instead of twice-weekly) bortezomib could be used to reduce treatment-related toxicity because it resulted in fewer grade 3 and 4 adverse events compared to the twice-weekly schedule (37% and 3% vs 48% and 12%, respectively).

Bortezomib, Lenalidomide, and Dexamethasone

The efficacy of VRD has also been demonstrated in several phase II trials. A phase I/II study evaluating the safety and efficacy of VRD resulted in an impressive 100% ORR in the phase II part, with 74% of patients achieving VGPR or better (¹⁸). As mentioned, VRD was also included as one of the arms in the phase II EVOLUTION trial, which resulted in an 85% ORR, with a VGPR or better rate of 51% and a CR rate of 24% (¹⁶). Phase III studies are ongoing comparing VRD with bortezomib and dexamethasone (NCT00522392) or lenalidomide and dexamethasone (NCT00644228) in the frontline setting. In addition, the role and timing of autologous SCT are being reexamined in the era of novel agents in a large international phase III trial of frontline VRD followed by lenalidomide maintenance therapy (with the option of SCT at the time of relapse) versus VRD followed by autologous SCT as per the current standard of care (NCT01208662). Phase II studies are also evaluating the efficacy of the second-generation proteasome inhibitor carfilzomib in combination with lenalidomide and dexamethasone (CRD) in the frontline setting with delayed autologous SCT; early results show rapid and deep responses with less peripheral neuropathy (^19,20). These studies will clarify the role of novel triplet combinations in the frontline setting and provide insight as to whether deeper responses, including molecular responses, with the multiple novel agents in combination, ultimately translate into improved long-term outcomes (Table 11-6).

Frontline Therapy for Transplant-Ineligible Patients

Initial treatment regimens for transplant-eligible patients can also be used in transplant-ineligible patients. Without the need to collect autologous stem cells, the alkylating agent melphalan can be incorporated into frontline therapy in nontransplant candidates. For 40 years, melphalan and prednisone (MP) represented the standard of care for transplant-ineligible patients. However, the addition of novel agents to the MP backbone and non–melphalan-containing combinations now form the new standard of preferred regimens.

Thalidomide/Lenalidomide, Melphalan, and Prednisone

The Gruppo Italiano Malattie Ematologiche dell’Adult (GIMEMA) compared melphalan, prednisone, and thalidomide (MPT) with MP (²¹). The ORR (76% vs 47.6%) and nCR/CR rates (27.9% vs 7.2%) favored the MPT arm. The median PFS was better in the MPT arm (21.8 vs 14.5 months), although the median OS was similar (45.0 vs 47.6 months). Subsequent phase III studies also demonstrated improved ORR and PFS with MPT compared to MP, with both the Intergroupe Francophone du Myélome (IFM) 99-06 and IFM 01-01 studies also showing a higher OS rate with MPT compared to MP.

Melphalan, prednisone, and lenalidomide (MPL) was also compared with MP alone in a phase III trial comparing MPL with lenalidomide maintenance (MPL-L) versus MPL versus MP (²²). The ORR was significantly higher in patients receiving MPL-L or MPL (77% and 68%, respectively) compared to those receiving MP (50%). Although MPT and MPL are superior to MP alone in terms of ORR and PFS, increased toxicity with the addition of a third drug must be carefully balanced with enhanced efficacy, because grade 3 and 4 adverse events were more pronounced in the MPT and MPL arms compared to MP. Although not compared head-to-head, nonhematologic grade 3 and 4 adverse events were less frequent with MPL compared to MPT (^22,23).

Bortezomib, Melphalan, and Prednisone

Bortezomib plus MP (VMP) was also compared with MP alone in a large randomized phase III trial. The ORR and CR rates were 71% and 30%, respectively, in patients receiving VMP versus 35% and 4%, respectively, in the MP arm. Median PFS was better with VMP (24.0 vs 16.6 months). An OS benefit for VMP versus MP (median, 56.4 vs 43.1 months) was also reported in the final analysis (²⁴). Again, the benefits of efficacy must be weighed carefully against toxicity, as grade 3 and 4 adverse events, particularly peripheral neuropathy, were greater in the VMP arm (13%).

Non–Melphalan-Based Regimens

The role of melphalan-containing regimens in transplant-ineligible patients has been challenged. Lenalidomide and low-dose dexamethasone (Rd) in four-week cycles until disease progression versus the same regimen for a fixed duration of 72 weeks versus MPT in 6-week cycles for 72 weeks were compared in a randomized phase III study in over 1,500 transplant-ineligible patients (²⁵). Although the ORRs were similar between the three arms, median PFS favored continuous Rd (25.5 months) versus 18 cycles of Rd (20.7 months) and MPT (21.2 months). There was a trend toward improved 3-year OS with continuous Rd (59%) versus fixed-duration Rd (56%) and MPT (51%). There was also a trend toward fewer grade 3 and 4 adverse events in the continuous Rd arm (70%) compared to the MPT arm (78%), in particular grade 3 and 4 neutropenia and neuropathy. However, there was a higher incidence of grade 3 and 4 infections with continuous Rd (29%), likely related to the longer duration of glucocorticoid use.

A community-based phase IIIB trial compared bortezomib and dexamethasone (BD) versus bortezomib, thalidomide, and dexamethasone (BTD) versus melphalan, prednisone, and bortezomib (MPB) followed by maintenance bortezomib (²⁶). The ORR, PFS, and OS were similar across all three arms. Discontinuation due to adverse events was highest in the BTD arm (35%) compared to BD (24%) and MPB (30%). This demonstrates the safety and efficacy of the use of BD in the elderly population. In general, the incorporation of novel agents to combination therapy has improved ORR and long-term outcomes in elderly, transplant-ineligible patients. However, treatment must be individualized based on comorbidities and disease characteristics as well as the patient’s own goals of care (Table 11-7).

Stem Cell Transplantation

Autologous Stem Cell Transplantation

High-dose melphalan without autologous SCT was first reported in 1983 by McElwain and colleagues from the Royal Marsden Hospital. Compared with chemotherapy alone, intensified chemotherapy followed by autologous SCT appears to prolong OS in previously untreated patients with MM. One comparative study and two randomized trials showed that autologous SCT provided survival benefits of approximately 12 months.

In the French IFM 90 trial, high-dose chemotherapy supported by autologous SCT was compared with conventional chemotherapy in 200 previously untreated patients with MM <65 years of age (²⁷). The results showed a higher CR rate (22% vs 5%) and higher rates of 5-year EFS (28% vs 10%) and OS (52% vs 12%) in the autologous SCT group. The median OS in patients assigned to the SCT arm was 13 months longer (57 vs 44 months).

The Medical Research Council Myeloma VII trial compared conventional-dose chemotherapy with high-dose therapy and autologous SCT in 401 previously untreated patients with MM <65 years old (²⁸). The rates of CR were significantly higher in the autologous SCT group (44% vs 8%). Intent-to-treat analysis showed a significant higher rate of OS and PFS with SCT. Compared with standard therapy, autologous SCT increased median OS by almost 12 months (54.1 vs 42.3 months). There was a trend toward a greater survival benefit in patients with poor prognosis (defined by β₂-microglobulin level >8 mg/L).

In three other randomized studies, however, there has been no survival benefit with autologous SCT (^29,30,31). Comparison among these trials is difficult due to the variability in patient eligibility including age, induction chemotherapy, conditioning regimen for SCT, and definitions of response. Subsequent trials have confirmed that autologous SCT deepens the response obtained with primary therapy. Thus, autologous SCT has become standard of care for eligible patients based on performance status and organ function. Most recently, a retrospective analysis of 1,038 patients with MM treated at the Mayo Clinic (2001-2010) reported a superior OS after autologous SCT. The median OS was 4.9 years without autologous SCT and not reached with autologous SCT (³²).

Many different preparative regimens have been assessed over the last 20 years, but only one prospective randomized trial by the IFM has directly compared two different preparative regimens (³³). In 282 newly diagnosed patients <65 years old, high-dose melphalan at 200 mg/m² was shown to be superior to a combination of melphalan 140 mg/m² plus 8 Gy of total-body irradiation (TBI), mainly due to reduced toxicity including mucositis and transplant-related mortality. Melphalan remains the standard of care, but the addition of novel agents to conditioning is being investigated.

Transplantation can be performed either early after induction therapy or later at disease progression. Fermand et al compared early and late autologous SCT and reported a similar OS (³¹). However, the average time without symptoms, treatment, and treatment toxicity were significantly better with early autologous SCT. A retrospective study of 167 patients who received induction therapy containing at least one of three novel agents (lenalidomide, thalidomide, or bortezomib) followed by autologous SCT either within 12 months of diagnosis or later found a higher CR rate in the early autologous SCT arm but no difference in PFS or OS. The potential benefit of early versus late autologous SCT was assessed in a trial randomizing patients between 55 and 65 years of age to either conventional chemotherapy alone or chemotherapy followed by autologous SCT. With a median follow-up of 120 months, a trend toward better EFS, but no OS benefit, was observed in patients undergoing early transplantation (³¹). Finally, the US Intergroup Trial S9321 found no PFS or OS benefit with early SCT (²⁹). A recent cost analysis study by Pandya et al suggests that early autologous SCT is cost-effective compared to delayed autologous SCT (³⁴).

At MDACC, we offer autologous SCT to all eligible patients after induction therapy regardless of age. We use a preparative regimen of melphalan 200 mg/m² (unless the patient is treated on a clinical trial with a novel preparative regimen). In selected patients (>70 years old or dialysis dependent), we lower the melphalan dose to 140 mg/m². We offer tandem autologous SCT only in the setting of a clinical trial or if there is significant residual disease after first autologous SCT. A second salvage transplant is an option for patients with relapsed disease; we offer this mainly to patients whose benefit from transplant was >1 year and whose disease burden can be significantly reduced by salvage chemotherapy. We offer maintenance therapy after transplantation (discussed later).

Allogeneic Stem Cell Transplantation

The curative potential of allogeneic SCT results from a graft-versus-tumor effect and dose-intense therapy rescued with a tumor-free graft. The existence of a graft-versus-myeloma effect was first documented by Tricot and colleagues and later confirmed in large single- and multi-institutional series of donor lymphocyte infusions. High-dose therapy is toxic but potentially curative. To overcome toxicity from high-dose regimens and to extend applicability to older patients with significant comorbidities, allogeneic SCT with reduced-intensity conditioning regimens has been attempted.

Two prospective trials investigated a tandem autologous plus reduced-intensity allogeneic SCT approach as part of the initial therapy for MM, with conflicting results. The IFM group reported on the outcomes of patients with high-risk disease (defined at the time as high levels of β₂-microglobulin and deletion of chromosome 13 by FISH) who received initial autologous SCT with melphalan 200 mg/m² (³⁵). Sixty-five patients had an human leukocyte antigen (HLA)-identical sibling donor, of whom 46 received a reduced-intensity conditioning regimen consisting of fludarabine, busulfan, and antithymocyte globulin (ATG). Patients without an HLA sibling donor received a second autologous SCT prepared with melphalan 220 mg/m². On an intent-to-treat basis, the OS and the EFS did not differ significantly between the two groups (median OS and EFS, 35 and 25 months with allogeneic SCT vs 41 and 30 months with autologous SCT, respectively). There was a trend toward better OS with tandem autologous SCT (median, 47.2 vs 35 months) for patients who actually received a reduced-intensity allogeneic SCT.

The Italian Cooperative Group performed a similar study (³⁶). After a median follow-up of 3 years, nonrelapse mortality was 11% for the autologous-plus-allogeneic group versus 4% for the tandem autologous group (P = 0.09). The CR rates were significantly higher in the autologous-plus-allogeneic group than the tandem autologous group (46% vs 16%), as was OS (84% vs 62%) and EFS (75% vs 41%). A follow-up analysis at 7 years further suggests a long-term survival and disease-free survival advantage with allogeneic SCT over standard autologous SCT (median OS, not reached vs 5.3 years; median EFS, 39 vs 33 months) (³⁷). The Bone Marrow Transplant Clinical Trials Network (BMT CTN) enrolled 710 patients, of whom 625 had standard-risk disease; 156 patients received autologous SCT followed by allogeneic SCT, whereas 366 patients underwent tandem autologous SCT. The 3-year PFS was 43% with autologous-allogeneic SCT and 46% with autologous-autologous SCT. No OS difference was seen (³⁸). A long-term follow-up analysis of the NMAM2000 study by the European Society for Blood and Marrow Transplantation demonstrated that PFS and OS with autologous SCT followed by reduced-intensity allogeneic SCT were improved at 96 months compared to autologous SCT alone (PFS and OS: 22% and 49% vs 12% and 36%, respectively) (³⁹). Specifically, autologous SCT followed by reduced-intensity conditioning allogeneic SCT seemed to overcome the poor prognostic impact of del 13q.

At MDACC, we only perform reduced-intensity allogeneic SCT. We use the tandem autologous plus allogeneic SCT approach only in the setting of a clinical trial. Allogeneic SCTs are offered to patients with relapsed, chemotherapy-sensitive disease who are <70 years old, have an HLA-identical sibling or unrelated donor, and are in good general physical condition. Our preparative regimen is a combination of fludarabine and melphalan (100 or 140 mg/m²), with ATG added for unrelated donor SCT.

To improve outcomes of autologous transplantation by adding a graft-versus-myeloma component, current laboratory research and clinical trials at MDACC are focused on eradicating MRD after autologous SCT using cellular therapy and vaccines.

Maintenance Therapy

The curability of MM has long been a matter of discussion. A small proportion of patient may achieve long-term survival and possibly a cure, but most patients relapse even after initial complete remission is achieved (⁴⁰). To delay the time to disease recurrence, maintenance therapy following autologous SCT has been explored to limit growth of residual malignant plasma cells. Initial maintenance strategies included interferon-α, although treatment-related toxicities such as flu-like symptoms and malaise made it challenging to administer. The approval of thalidomide in the late 1990s renewed interest in maintenance therapy. Multiple trials showed improvements in PFS and sometimes OS with thalidomide maintenance after autologous SCT. Toxicities related to long-term therapy, notably peripheral neuropathy, made it difficult to tolerate.

Given its more favorable side effect profile, lenalidomide maintenance therapy after autologous SCT was next explored. The Cancer and Leukemia Group B (CALGB) study randomized patients to lenalidomide or placebo maintenance starting 100 days following autologous SCT (⁴¹). PFS was significantly greater in the lenalidomide arm (46 vs 27 months); OS was also significantly better. The IFM reported a similar trial in which patients received two 4-week cycles of consolidation with lenalidomide 25 mg after autologous SCT before being randomized to lenalidomide maintenance versus placebo (⁴²). PFS also favored lenalidomide maintenance (median PFS, 41 vs 23 months), but there was no difference in OS. Both studies reported an increase in second primary malignancies with lenalidomide maintenance (8% in the CALGB and IFM studies) versus placebo (3% in CALGB and 4% in IFM). However, when all competing factors for death are considered (including death from relapsed MM), patients have a much higher risk of mortality from other causes rather than secondary malignancies (^43,44). Potential risks and benefits of lenalidomide maintenance should be discussed with patients to make informed decisions. Lenalidomide maintenance can also be considered in nontransplant patients after initial therapy based on the phase III MPL-L versus MPL versus MP study described earlier (²²).

Bortezomib maintenance therapy was investigated in the phase III Hemato-Oncologie voor Volwassenen Nederland (HOVON)-65/German Multicenter Myeloma Group (GMMG)-HD4 trial, where patients were randomized to receive either VAD or bortezomib, doxorubicin, and dexamethasone (PAD) induction, followed by high-dose melphalan and autologous SCT (⁴⁵). Patients were then randomized again to receive either thalidomide or bortezomib maintenance therapy for 2 years. The CR rates, PFS, and OS all favored bortezomib-containing induction and maintenance regimens, and benefit was also noted in high-risk patients with del 17p. In general, we offer patients lenalidomide maintenance therapy following autologous SCT at MDACC. In the setting of high-risk cytogenetic features, bortezomib consolidation/maintenance should be considered based on the HOVON data.

Treatment of Relapsed/Refractory Multiple Myeloma

We recommend enrollment in clinical trials when possible for all patients with relapsed/refractory MM. Alternatively, there are a number of therapeutic options that have gained regulatory approval that may be considered in this setting.

Immunomodulatory Drugs

Many patients may already be on maintenance lenalidomide at the time of disease recurrence. Increasing to standard-dose lenalidomide (25 mg daily for 21 out of 28 days) with or without dexamethasone is an option. Two large phase III trials demonstrated the efficacy of lenalidomide and dexamethasone compared to dexamethasone alone, with ORR, PFS, and OS favoring the combination. Although high-dose dexamethasone was used in these trials, low-dose dexamethasone is typically given in combination with lenalidomide in this setting, extrapolating from data comparing these approaches in frontline therapy.

Pomalidomide is a third-generation IMiD with greater in vivo potency than thalidomide and lenalidomide. In a phase III study in relapsed/refractory MM, patients were randomized to receive either pomalidomide plus low-dose dexamethasone (Pd) versus only high-dose dexamethasone (⁴⁶). Around 75% patients were double refractory to both lenalidomide and bortezomib. The ORR was 35% with Pd versus 10% with high-dose dexamethasone. The median PFS was 4.0 months with Pd versus 1.9 months with high-dose dexamethasone. Based on these results, pomalidomide gained US Food and Drug Administration (FDA) approval in 2013 for MM refractory to last therapy and prior bortezomib and lenalidomide exposure.

Proteasome Inhibitors

Bortezomib has shown efficacy in relapsed MM in two large randomized phase III trials. The APEX phase III trial compared intravenous bortezomib to high-dose dexamethasone; ORR, PFS, and OS were all superior in the bortezomib arm. As mentioned, subcutaneous bortezomib is favored over the intravenous route due to similar efficacy and less peripheral neuropathy (¹⁵).

Bortezomib has also been studied in combination with other agents. The addition of pegylated liposomal doxorubicin in combination with bortezomib gained regulatory approval after demonstrating superior PFS compared to bortezomib monotherapy in relapsed/refractory bortezomib-naïve MM patients, although the ORRs were not statistically different between the two groups (⁴⁷). Phase II data of VRD in relapsed/refractory MM resulted in an ORR of 64%. Median PFS was 8.5 months, and median OS was 30 months (⁴⁸). The CyBorD regimen may also be considered in relapsed MM based on phase II data.

The second-generation proteasome inhibitor carfilzomib recently gained regulatory approval for patients exposed to bortezomib and an IMiD and whose disease was refractory to last therapy. Like bortezomib, carfilzomib inhibits the chymotrypsin-like activity of the 20S proteasome, but its unique structural properties allow for greater specificity and irreversible binding to its target. The efficacy of carfilzomib in relapsed/refractory MM was established in a single-arm phase II trial of 266 patients, all of whom received prior IMiD therapy, and all but one patient received prior bortezomib (⁴⁹). The ORR was 24%. Among 169 patients refractory to both bortezomib and lenalidomide, the ORR was 15%. Only 12% of patients reported any grade of treatment-emergent peripheral neuropathy.

The role of carfilzomib in relapsed and/or refractory MM continues to evolve, as it is being tested in combination with other novel agents. Interim results of a phase III study comparing carfilzomib, lenalidomide, and dexamethasone (CRd) with lenalidomide and dexamethasone (Rd) were recently reported (⁵⁰). In this study, 66% of patients received prior bortezomib and 20% received prior lenalidomide. The median PFS was significantly longer with CRd compared with Rd (26.3 vs 17.6 months). The combination of carfilzomib, pomalidomide, and dexamethasone has also shown promising results (⁵¹). However, the impact of carfilzomib on OS is uncertain. An interim analysis of a phase III study that randomized relapsed/refractory patients to carfilzomib versus glucocorticoid therapy did not meet its primary end point of OS benefit (⁵²). Finally, although earlier studies established the maximum-tolerated dose of carfilzomib at 20 mg/m² for cycle 1 and 27 mg/m² for subsequent cycles, phase I and II data have emerged demonstrating the safety and efficacy of higher doses of carfilzomib up to 56 mg/m² administered over 30 minutes compared to a 2- to 10-minute intravenous bolus given in earlier studies (⁵³). An ongoing Southwest Oncology Group randomized phase II study is comparing high-dose versus low-dose carfilzomib (with dexamethasone in both arms).

Investigational Agents

Although IMiDs and proteasome inhibitors now form the backbone of most MM regimens, both in the upfront and relapsed settings, several promising new classes of investigational agents have shown both safety and promising efficacy in phase I and II clinical trials. These include novel immunotherapeutic approaches with the anti-CD38 antibody daratumumab (⁵⁴) and the anti-SLAMF7 antibody elotuzumab in combination with lenalidomide and low-dose dexamethasone (⁵⁵), both of which have garnered “breakthrough therapy” designations from the FDA based on early efficacy data. Phase III studies are comparing lenalidomide and low-dose dexamethasone with or without elotuzumab in both relapsed/refractory (NCT01239797) and newly diagnosed MM (NCT01891643). These same combinations with lenalidomide and low-dose dexamethasone are also being tested in phase III trials with daratumumab in both relapsed/refractory (NCT02076009) and frontline MM (NCT02252172).

Histone deacetylase (HDAC) inhibitors have also shown promising activity. Although they only have modest activity as single agents, the potential of HDAC inhibitors has been most pronounced in combination with other anti-MM drugs, namely bortezomib. Disruption of aggresome formation by HDAC inhibition may provide potent synergy with proteasome inhibition by interfering with protein turnover and inducing the unfolded protein response. Based on this rationale, the pan-deacetylase inhibitor panobinostat was studied in combination with bortezomib and dexamethasone and compared to placebo, bortezomib, and dexamethasone in a large phase III trial (⁵⁶). At interim analysis, PFS was significantly higher with panobinostat compared to placebo (11.99 vs 8.08 months); OS was similar. The ORR did not differ between the arms, although the depth of response (CR or nCR) was significantly higher in the panobinostat arm. Concerns have been raised about drug efficacy (measured only by PFS) in the setting of significant toxicities, particularly grade 3 and 4 thrombocytopenia, diarrhea, and fatigue. In the future, more selective HDAC inhibitors with fewer off-target effects may need to be developed and tested for the full potential of this therapeutic approach to be realized.

ARRY-520, a novel antimitotic, inhibits the kinesin-spindle protein (KSP). In a phase II study, ARRY-520 was given with or without low-dose dexamethasone in relapsed/refractory MM (⁵⁷). Patients in the cohort with low-dose dexamethasone were all refractory to lenalidomide and bortezomib; the ORR was 22%. A phase II trial with ARRY-520 in combination with carfilzomib or bortezomib is ongoing (Table 11-8).

Monoclonal Gammopathy of Undetermined Significance

The 2014 IMWG guidelines define MGUS as a serum M-protein <3 g/dL, <10% clonal marrow plasma cells, and absence of end-organ damage (CRAB criteria and myeloma-defining events; see Table 11-2) attributed to an underlying plasma cell proliferative disorder. The 2014 standard of care for MGUS is surveillance every 6 to 12 months with a physical exam and typical MM serum and urine studies. Patients with MGUS can also be risk stratified for progression to MM according to established models (Table 11-9).

Smoldering Multiple Myeloma

Smoldering MM is defined as having a serum M-protein of ≥3.0 g/dL and/or ≥10% more marrow plasma cells without evidence of end-organ damage as defined by CRAB criteria and MM-defining events (see Table 11-2). Compared with MGUS, this premalignant clonal plasma cell proliferation carries a higher risk of progression to overt MM. In a large retrospective study of 276 patients with SMM followed over 26 years, the risk of progression to MM was 10% per year for the first 5 years, 3% per year for the next 5 years, and 1% per year for the last 10 years.

There is great heterogeneity in the SMM disease course. Some patients may remain asymptomatic for the rest of their lives, whereas others may rapidly develop disease that meets MM criteria. Efforts have been made to risk stratify SMM to help predict the clinical course, guide surveillance strategies, and design trials for early intervention. One prognostic model found that patients with both clonal bone marrow plasmacytosis ≥10% and serum M-protein ≥3 g/dL had an 87% chance of MM progression at 15 years compared to 70% with only ≥10% marrow plasma cells (but monoclonal protein of <3 g/dL) and 39% with only monoclonal protein ≥3 g/dL (but <10% bone marrow plasma cells) (⁵⁸). Later, a serum free light-chain ratio of <0.125 or >8 was suggested as an independent prognostic factor for disease progression and incorporated into the prognostic score for SMM. A number of other factors have been shown to increase the risk of progression such as high-risk cytogenetics [del 17p, t(4;14), amplification of 1q], ≥95% aberrant marrow plasma cells by flow cytometry, IgA M-protein, immunoparesis of uninvolved immunoglobulins, circulating plasma cells by slide-based immunofluorescence, and proteinuria (⁵⁹).

Through these studies, a very-high-risk group was identified, with a 2-year progression risk of 70% to 80%, when there is at least one of the following risk factors: ≥60% bone marrow plasmacytosis, an involved-to-uninvolved serum free light-chain ratio ≥100, or more than one focal lesion on MRI that is at least 5 mm in size. This prompted revisiting the classical definition of SMM and led the IMWG in 2014 to recategorize asymptomatic patients with SMM who meet these criteria as having active MM requiring therapy (⁹).

The benefits of preemptive treatment of high-risk SMM are still unclear. Until this is further clarified, treatment of high-risk SMM should be undertaken preferentially through clinical trials. A phase III trial comparing lenalidomide and dexamethasone versus observation in high-risk patients found an improvement in median PFS in the treatment arm (median PFS, not reached vs 26 months) and a significant 3-year OS benefit (94% vs 80%, P = 0.03) (⁶⁰). However, results have not yet been replicated in other studies, and an excessive mortality rate in the observation arm for SMM patients has raised concerns about the interpretation of these results.

At MDACC, we recommend that patients with high-risk SMM be enrolled in a clinical trial. In the absence of clear data, we would otherwise recommend observation and close surveillance in these patients, although this practice may change soon as we gather data from relevant trials focused on high-risk SMM.

Solitary Plasmacytoma of Bone

A solitary plasmacytoma of bone is defined by the presence of a plasmacytoma without bone marrow evidence of monoclonal plasma cells, lytic bony lesions, or other clinically significant sequelae of MM. About 24% to 72% of patients with a solitary plasmacytoma have a monoclonal protein in the serum or urine. Initial workup should include all of the aforementioned serum and urine laboratory studies used in evaluation of MM, as well as advanced imaging with PET-CT or MRI to rule out multifocal disease that would upstage the disease to MM. Biopsy of the solitary plasmacytoma to demonstrate clonal plasma cells and a unilateral bone marrow biopsy to rule out systemic disease are necessary. Treatment should include radiation therapy of at least 40 Gy, although one may consider a dose of up to 50 Gy for lesions greater than 5 cm. After radiation therapy, surveillance should be performed with serial measurements of serum and urine M-protein levels and imaging studies, initially every 3 months and then less frequently. Patients who progress to overt MM during surveillance should follow the treatment guidelines for MM.

Patients with solitary plasmacytoma of bone often progress to MM within 2 to 4 years, with a median OS of 7.5 to 12 years. In one study, persistence of a serum M-protein 1 year after radiation therapy was an adverse prognostic factor predicting a 10-year myeloma-free survival of 29% compared to 91% with undetectable M-protein. Another study found that an abnormal free light-chain ratio and a serum M-protein >0.5 g/dL were significant adverse factors for disease progression at 5 years.

Waldenström Macroglobulinemia

Background

Waldenström macroglobulinemia is an uncommon, low-grade malignancy characterized by the presence of lymphoplasmacytic cells together with the presence of a monoclonal IgM paraprotein. The median age at diagnosis is between 63 and 68 years. Men are more commonly affected, and the disease is more common among whites than other populations. Recent data show that 67% to 100% of WM cases are associated with a mutation of the myeloid differentiation primary response 88 (MYD88) gene located on chromosome 3p22 (⁶¹).

Clinical Presentation and Diagnostic Workup

Many patients are asymptomatic at diagnosis. When symptoms develop, they are caused by tumor infiltration (cytopenias, hepatomegaly, splenomegaly), circulating IgM (hyperviscosity, cryoglobulinemia, and/or cold agglutinin anemia), and/or tissue deposition of IgM (neuropathy, glomerular disease, and/or amyloidosis). Symptomatic hyperviscosity syndrome may be associated with visual disturbances, dizziness, cardiopulmonary symptoms, decreased consciousness, and a bleeding diathesis. Polyneuropathies are common. Some are associated with antigenic targets of the monoclonal serum IgM, including myelin-associated glycoprotein (MAG) and sulphatide. Others are caused by direct tumor infiltration, tissue deposition of IgM, the amount and properties of the circulating monoclonal IgM, or binding of unidentified antigens. Patients may also present with cold or warm autoimmune hemolytic anemia, iron deficiency anemia, or dilutional anemia.

Initial evaluation (Table 11-10) in suspected WM should include a CBC, serum chemistries, liver function tests, viral hepatitis serologies, serum protein electrophoresis (SPEP) and immunofixation, quantitative immunoglobulin levels, and a β₂-microglobulin. In patients suspected of having a cryoglobulinemia, a cryocrit should be drawn and, together with SPEP and quantitative immunoglobulin specimens, should immediately be placed in a 37°C water bath to facilitate accurate assessment. A serum viscosity level and cold agglutinin titer/Coombs test should be drawn if hyperviscosity or a hemolytic anemia, respectively, is suspected. Iron studies should be considered for patients having a microcytic anemia. Bone marrow biopsy should be performed to demonstrate infiltration by lymphoplasmacytic cells and can help determine the cause of an existing anemia. Flow cytometry will typically show a pattern of sIgM⁺, CD19⁺, CD20⁺, CD22⁺, and CD79⁺. Testing for the MYD88 L265 gene mutation in the marrow or peripheral blood can help distinguish WM from marginal zone lymphoma and MM, where the incidence of this mutation is low (⁶¹). Patients should have baseline CT scans (chest, abdomen, and pelvis) to evaluate for extramedullary disease. An ophthalmologic examination should be performed to look for retinal changes (hemorrhages or “sausage vessels”) in patients with suspected hyperviscosity syndrome.

Asymptomatic patients can be followed every 3 months during the first year, with longer follow-up intervals thereafter, in the setting of disease stability (⁶²). In such patients, the risk of developing symptomatic disease is about 6% in the first year, 39% at 3 years, and 55% at 5 years, so lifelong follow-up is necessary (⁶²). Higher M-protein and marrow infiltration have been associated with increased risk of progression to symptomatic disease (⁶²).

At MDACC, therapy is initiated for symptomatic hyperviscosity, hemoglobin <10 g/dL, platelet count ≤100,000/μL, bulky adenopathy, symptomatic organomegaly, symptomatic cryoglobulinemia, or significant peripheral neuropathy (Table 11-11) (⁶³). Therapy for hyperviscosity consists of prompt initiation of plasma exchange followed by chemotherapy. Because of the risk of precipitating symptomatic hyperviscosity in patients with high levels of circulating IgM, packed red cell transfusions should be used conservatively and should preferably be administered after plasma exchange in high-risk patients.

Frontline Therapy

When autologous SCT may be considered at relapse, nucleoside analogs should be avoided prior to stem cell harvest, and primary therapy with a proteasome inhibitor or alkylator, together with rituximab with or without dexamethasone, should be considered (^64,65). Combinations of bortezomib-rituximab with or without dexamethasone result in an ORR of 57% to 83%. Carfilzomib-rituximab-dexamethasone showed an ORR of 68% (^65,66). Comparable ORRs (77%-96%) have been seen with alkylating agent–based regimens (rituximab plus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP]; rituximab-cyclophosphamide-vincristine-prednisone; rituximab-cyclophosphamide-dexamethasone; and rituximab-bendamustine) (⁶⁷). The use of single-agent rituximab should be reserved for patients unable to tolerate combination chemotherapy, because ORRs are low (20%-50%).

When future autologous SCT is not a consideration, nucleoside analog–based combinations may be considered. In a trial by the Waldenström Macroglobulinemia Clinical Trials Group, fludarabine-rituximab demonstrated an ORR of 96% and median PFS of 51.2 months (⁶⁸). In a phase II trial of 18 patients, two cycles of cladribine, cyclophosphamide, and rituximab yielded an ORR of 94%, and at a median follow-up of 8 years, median OS was not reached (⁶⁹).

Rituximab is integral to the treatment of WM but must be used with caution in patients with highly elevated IgM levels due to the potential for an associated IgM flare. In these cases, it is prudent to delay administration of rituximab until after the patient has received some cytoreductive therapy. Because this phenomenon can confound interpretation of results, disease response should be assessed after two cycles of induction therapy unless there is clear progression of extramedullary disease.

Treatment at Disease Relapse

At relapse, patients may be re-treated with a previously successful regimen if their initial remission lasted at least 1 year. When the initial disease-free-interval is shorter, use of one of the other frontline regimens (detailed above) should be considered.

Another effective option is the Bruton tyrosine kinase (BTK) inhibitor ibrutinib. In a phase II trial of 63 patients, ibrutinib showed an ORR of 57% and was well tolerated (⁷⁰). Immunomodulatory agents with or without rituximab have shown efficacy. Thalidomide-rituximab and lenalidomide-rituximab resulted in a major response rate of 64% and 25%, respectively. Pomalidomide monotherapy is associated with a ≥ minor response rate of 33%.

For patients intolerant to rituximab, the fully humanized monoclonal anti-CD20 antibody ofatumumab may be useful. In patients who have previously received rituximab, two cycles of ofatumumab were associated with an ORR of 52% (⁷¹).

Alemtuzumab can also be considered because WM cells express CD52. In a phase II study of 28 previously treated patients with either lymphoplasmacytic lymphoma or WM, alemtuzumab-rituximab yielded an ORR of 76% (⁷²). However, this regimen is rarely used due to the associated high risk of CMV reactivation.

The role of SCT in WM is still being defined. In a retrospective review of 158 patients (32% had at least three prior lines of therapy), the 5-year PFS and OS rates with autologous SCT were 39.7% and 68.5%, respectively (⁷³). Several groups have also studied allogeneic SCT in WM. The 5-year PFS was between 49% and 56% but with notable treatment-related mortality (⁷⁴).

Future Directions

Next-generation proteasome inhibitors (eg, ixazomib, oprozomib), new anti-CD20 monoclonal antibodies (eg, GA-101), the HDAC inhibitor panobinostat, the toll-like receptor antagonist IMO-8400, and second-generation BTK inhibitors are under study in WM. Emerging knowledge about the MYD88 gene and CXCR4 mutations may allow more rational disease-targeted therapies.

Systemic Light-Chain Amyloidosis

Background

Systemic light-chain (AL) amyloidosis is a rare plasma cell proliferative disorder. It results from organ deposition of amyloid fibrils that consist of the NH₂-terminal amino acid residues of the variable portion of the light-chain immunoglobulin molecule. The estimated age-adjusted incidence is 5.1 to 12.8 cases per million person-years. About 75% of cases are derived from lambda light chain. AL amyloidosis may result primarily from a small plasma cell clone in the bone marrow or may be associated with an underlying plasma cell dyscrasia or other B-cell malignancies. Coexisting AL amyloid deposits are identified in 10% to 15% of patients with MM.

The commonly affected organs include the heart, kidneys, liver, gastrointestinal tract, and peripheral nervous system. This leads to clinical symptomatology of nephrotic syndrome, cardiomyopathy, hepatomegaly, neuropathy, macroglossia, anemia, carpal tunnel syndrome, and periorbital purpura. The exact pathophysiology of organ or tissue damage in AL amyloidosis is not completely understood, but the reduction of serum free light-chain concentration after chemotherapy treatment results in improved cardiac function and suggests that free light chain plays an important role in organ dysfunction.

Clinical Presentation and Diagnostic Workup

The clinical presentation of AL amyloidosis depends on the spectrum and severity of organ involvement. The common clinical features at diagnosis include nephrotic syndrome with or without renal insufficiency, cardiomyopathy, autonomic neuropathy, and hepatosplenomegaly. Many patients have multisystem involvement at diagnosis (Table 11-12). The diagnosis requires histologic evidence of amyloid deposition in tissues either by aspiration of abdominal subcutaneous fat and/or biopsy of the organs involved, with the demonstration of clonal plasma cell disorder and abnormal free light chain in serum or urine. The pathognomic diagnostic feature of AL amyloidosis a positive tissue stain with Congo red to demonstrate apple-green birefringence under polarized light. Mass spectrometry–based proteomic analysis of amyloid tissue should be pursued when available. This helps confirm the type of amyloid protein, because more than 10 forms of systemic amyloidosis are currently known, and correct typing is imperative for appropriate treatment (Table 11-13).

Prognosis and Staging

Even though patients commonly have a low burden of clonal plasma cells, long-term survival outcome is dismal due to organ impairment from amyloid deposition. The presence of cardiac involvement is a detrimental factor for survival. The median survival time is 4 months in patients presenting with congestive heart failure versus 16 months in those without it (⁷⁵). Cardiac dysfunction is best assessed by the elevation of cardiac biomarkers: brain natriuretic peptide (BNP), N-terminal pro-brain natriuretic peptide (NT-proBNP), and cardiac troponin T (cTnT) and troponin I (cTnI). Many studies have confirmed the prognostic significance of markers of cardiac injury and dysfunction in AL amyloidosis, and they been incorporated in the staging system for AL amyloidosis (⁷⁶). According to the Revised Prognostic Scoring System from the Mayo Clinic group, patients are assigned a score of 1 for each of the following: difference between involved and uninvolved light chain ≥18 mg/dL, cTnT ≥0.025 ng/mL, and NT-proBNP ≥1,800 pg/mL. The median OS times of patients with Mayo stage I, II, III, and IV (score of 0, 1, 2, and 3, respectively) are 94, 40, 14, and 5.8 months, respectively (⁷⁶).

Treatment

Treatment for AL amyloidosis is similar to that for MM, comprising mainly of various chemotherapy combinations or high-dose therapy with autologous SCT (HDT-ASCT), aimed at eliminating clonal plasma cells. The choice of treatment should be based on risk stratification. Patients with good performance status and normal cardiac markers should be considered for HDT-ASCT.

High-Dose Therapy With Autologous Stem Cell Transplantation

High-dose therapy with autologous SCT has been used since the early 1990s, and it is the only effective treatment modality associated with hematologic and organ responses as well as long-term survival (^77,78). It is associated with high treatment-related mortality, ranging from 13% to 43%, especially in patients with cardiac involvement. Careful patient selection based on comorbidity index and cardiac staging is the key to successful outcome of high-dose therapy in AL amyloidosis. A randomized trial comparing HDT-ASCT with standard-dose melphalan plus high-dose dexamethasone showed no differences in hematologic or organ response. Landmark analysis examining only patients surviving more than 6 months after transplantation also showed no survival benefit for HDT-ASCT (⁷⁹). However, almost 25% of the patients in this study received reduced-dose melphalan conditioning, which has been associated with poor transplantation outcomes. A meta-analysis of 12 studies of HDT-ASCT showed no superiority of HDT-ASCT over conventional chemotherapy (⁸⁰). However, in the MDACC experience, improved 10-year survival outcomes were reported in patients undergoing HDT-ASCT compared to conventional chemotherapy (⁷⁸). At centers with extensive experience in treating AL amyloidosis, HDT-ASCT provides promising outcomes with careful patient selection (^79,81). Involvement of two or fewer organs and AL amyloidosis with renal involvement show best overall outcome with HDT-ASCT (⁷⁸).

Induction Therapy Before High-Dose Therapy With Autologous Stem Cell Transplantation

With the inclusion of novel agents in induction therapy, improvement in performance status can lead to transplantation eligibility for newly diagnosed patients (⁸²). A randomized trial evaluating the role of induction therapy containing bortezomib and dexamethasone followed by HDT-ASCT versus HDT-ASCT in newly diagnosed AL amyloidosis showed better responses and survival outcomes with induction therapy (⁸³). In our experience, incorporation of novel-agent induction therapy prior to transplantation is associated with improved survival (⁷⁸). There are no data to support maintenance treatment in AL amyloidosis.

Conventional Chemotherapy

The combination of melphalan and high-dose dexamethasone remains the gold standard for first-line treatment of transplant-ineligible patients and is associated with a good hematologic response (67%) and low toxicity (4%) (⁸⁴). Today, several novel therapeutic combination choices are available for transplant-ineligible patients. Immunomodulatory drugs such as thalidomide and lenalidomide have been investigated in the upfront and relapsed settings with hematologic response rates of 40% to 74% and organ response rates of 20% to 40% (^85,86). However, they have also been associated with serious adverse events including bradycardia, fatigue, sedation, and cytopenia (^85,87). Bortezomib in combination with conventional chemotherapy such as cyclophosphamide and/or dexamethasone is also effective (^82,88,89,90). Bortezomib has successfully been used as consolidation in patients who did not achieve a CR after HDT-ASCT to improve the quality of response (⁹¹).

POEMS Syndrome

POEMS syndrome, also known as osteosclerotic myeloma, is a paraneoplastic syndrome related to an underlying clonal plasma cell disorder. The major diagnostic criteria are polyneuropathy, monoclonal gammopathy, sclerotic bone lesions, elevated vascular endothelial growth factor (VEGF), and Castleman disease. Minor features include organomegaly, endocrinopathy, characteristic skin changes, papilledema, extravascular volume overload, and thrombocytosis. The diagnosis of POEMS syndrome is made with three of the major criteria, two of which must include polyneuropathy and a clonal plasma cell neoplasm, and at least one of the minor criteria (Table 11-14) (⁹²). Patients may have delays in diagnosis because it is rare and resembles other neurologic diseases, most commonly chronic inflammatory demyelinating polyradiculoneuropathy. The natural history of POEMS syndrome is defined by progressive polyneuropathy and sclerotic bone disease, which leads to significant morbidity, along with mortality if respiratory compromise occurs. POEMS syndrome should be distinguished from the Castleman disease variant of POEMS syndrome, which has no clonal plasma cell association and usually no peripheral neuropathy.

The pathogenesis of this syndrome is not known. Risk stratification is solely based on the clinical phenotype. The extent of plasma cell clonal disease correlates with prognosis in POEMS, but the number of clinical criteria does not. Treatment is aimed at eradicating the underlying plasma cell clone and control of symptoms. With one to three sclerotic plasmacytomas (usually <1 cm in diameter each) without marrow infiltration, localized radiation therapy may suffice. For patients with a dominant sclerotic bone lesion, frontline radiation therapy may be appropriate. Patients with diffuse sclerotic lesions, disseminated marrow involvement, or relapsed disease within 6 months of completing radiation therapy should receive systemic therapy adapted largely from therapy for MM. Alkylators such as melphalan are the mainstay of treatment; lenalidomide has shown promise with manageable toxicity (⁹³). Therapies based on CHOP also show responses. Thalidomide and bortezomib have activity but could exacerbate disease-related peripheral neuropathy. Benefit from anti-VEGF antibodies is unproven (⁹⁴).

High-dose melphalan and autologous SCT can lead to prolonged remissions and significant improvement in clinical symptoms. Seven patients with POEMS syndrome underwent autologous SCT at MDACC (⁹⁵); all had significant or complete resolution of clinical symptoms, and PFS and OS at 5 years were 86% and 100%, respectively. Prompt recognition and institution of supportive care measures and therapy directed against the plasma cell clone result in the best outcomes.

TEMPI Syndrome

In 2011, six patients from the literature were recognized as having common clinical features defining a new multisystem disease characterized by telangiectasias, erythrocytosis with elevated erythropoietin levels, monoclonal gammopathy, perinephric fluid collections, and intrapulmonary shunting. This was termed the TEMPI syndrome (⁹⁶). Bortezomib therapy improved disease-related clinical features, suggesting a pathogenic role of the monoclonal gammopathy (^97,98). Bone marrow examination of three patients showed marked erythroid hyperplasia (⁹⁹). Elevated erythropoietin level and a normal VEGF level distinguish TEMPI from POEMS. Due to the disease rarity, patients suspected of having TEMPI syndrome should be referred to academic centers for management.

Immunoglobulin Heavy-Chain Disease

Heavy-chain diseases are plasma cell dyscrasias characterized by the production of heavy-chain immunoglobulin molecules (gamma, alpha, mu) that lack light chains. Alpha-chain disease is the most common variant and can be thought of as an extranodal marginal zone lymphoma of mucosa-associated lymph node tissue. The disease results from lymphocyte and plasma cell infiltration of the mesenteric nodes and small bowel and has features of malabsorption, such as diarrhea, weight loss, abdominal pain, edema, and clubbing. The heavy-chain molecule may be detected in serum, jejunal secretions, and urine (¹⁰⁰). These patients may be treated with antibiotics or occasionally with surgery. If symptoms persist or if a lymphoma is suspected, chemotherapy may be used.

Gamma heavy-chain disease is similar to lymphoplasmacytoid non-Hodgkin lymphoma (¹⁰¹). Patients may present with fever, weakness, lymphadenopathy, hepatosplenomegaly, and Waldeyer ring involvement. Eosinophilia, leukopenia, and thrombocytopenia are common. Treatment with regimens similar to those used for non-Hodgkin lymphoma may be effective (¹⁰⁰).

Mu heavy-chain disease is extremely rare and often seen in patients with chronic lymphocytic leukemia, although it has been described with underlying WM or MM (¹⁰²). Vacuolated plasma cells are common in the marrow, and many patients have lambda light chains in urine. Therapy choice should follow existing recommendations for the underlying primary disease.

The last decade has seen unprecedented advances in the treatment of plasma cell dyscrasias. The advent of novel agents, notably proteasome inhibitors and IMiDs, has resulted in a doubling of the life expectancy in MM. These treatments have been incorporated in standard regimens for primary AL amyloidosis with improved outcomes. Proteasome inhibitors, anti-CD20 monoclonal antibodies, and drugs targeting the B-cell receptor pathway (eg, ibrutinib) have also represented important advances in WM therapy.

Many challenges remain. For example, MM is still considered mostly an incurable disease, and a subgroup of patients with high-risk MM have not benefited substantially from recent therapeutic advances. Promising investigational agents including immunotherapeutic approaches with monoclonal antibodies and rational combinations to overcome resistance are being tested.

Future work involves identifying predictive biomarkers to help individualize therapy in MM and related plasma cell dyscrasias to help maximize efficacy while balancing treatment toxicity. In high-risk SMM, the role of early preemptive therapy needs to be clarified. Improving our understanding of the molecular pathogenesis of MM and its genetic drivers through molecular profiling and refining current risk stratification models remain are key priorities. Another important question is the role and timing of autologous SCT in the era of novel agents. Finally, as new drug combinations induce deeper responses in the frontline setting, significance of achieving molecular remissions is an area of intense research focus. Bridging these knowledge gaps will improve on the advances achieved over the last decade and offer greater individualized treatment approaches, leading to possible cure of MM and its related disorders.