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Multiple Myeloma and Related Disorders


Summary of Key Points

  • Multiple Myeloma

  • Multiple myeloma accounts for approximately 10% of hematologic malignancies.

  • Approximately 30,000 new cases are estimated to occur each year in the United States.

  • In almost all patients, multiple myeloma is thought to evolve from an asymptomatic premalignant stage termed monoclonal gammopathy of undetermined significance (MGUS).

  • The most common presenting symptoms are fatigue and bone pain.

  • Osteolytic bone lesions are the hallmark of the disease.

  • Hypercalcemia is found in one-fourth of patients; the serum creatinine is elevated in almost one-half.

  • The diagnostic criteria for multiple myeloma have been revised. Diagnosis requires 10% or more clonal plasma cells in the bone marrow and/or a biopsy-proven plasmacytoma plus one or more of the following multiple myeloma defining events: evidence of end-organ damage (hypercalcemia, renal insufficiency, anemia, or bone lesions) attributable to the underlying plasma cell disorder, 60% or more clonal plasma cells in the bone marrow, serum involved or uninvolved free light chain (FLC) ratio of 100 or higher (provided involved FLC level is ≥100 mg/L), or more than one focal lesion (5 mm or more in size) at magnetic resonance imaging (MRI).

  • Monoclonal proteins can be detected with serum protein electrophoresis (SPEP) and immunofixation in 93% of patients. Addition of urine protein electrophoresis (UPEP) and urine immunofixation or the serum FLC assay will increase sensitivity to 97% or higher.

  • The Revised International Staging System (RISS) divides patients into three distinct stages and prognostic groups based on β2-microglobulin, albumin, and lactate dehydrogenase levels in the serum, and certain cytogenetic abnormalities (deletion 17p, t[4;14], t[14;16]).

  • High-risk multiple myeloma is defined as any one or more of the following: deletion 17p, gain 1q, immunoglobulin heavy chain (IgH) translocations t(4;14), t(14;16) or t(14;20), plasma cell leukemia, increased lactate dehydrogenase, or high-risk signature on gene expression profiling studies. All others are considered others standard risk.

  • Newly diagnosed patients are categorized into standard- and high-risk multiple myeloma groups based on specific prognostic factors.

  • Initial therapy typically consists of bortezomib, lenalidomide, and dexamethasone (VRd). Alternatives include bortezomib, cyclophosphamide, and dexamethasone (VCd) or bortezomib, thalidomide, and dexamethasone (VTd).

  • After 3 to 4 months of initial therapy, standard-risk patients eligible for transplantation can pursue early or delayed autologous stem cell transplantation (ASCT). If delayed ASCT is used, the initial induction is continued until plateau or progression occurs at reduced doses. In high-risk patients, early ASCT after 4 months of induction therapy is preferred in patients who are candidates for transplantation.

  • After ASCT, lenalidomide maintenance is recommended for standard-risk patients, whereas bortezomib-based maintenance is preferred for high-risk patients.

  • Options for relapsed disease include carfilzomib, pomalidomide, daratumumab, elotuzumab, and panobinostat.

  • Monoclonal Gammopathy of Undetermined Significance (MGUS)

  • MGUS is an asymptomatic, premalignant, clonal plasma cell proliferative disorder. There are three main types of MGUS based on the monoclonal (M) protein: IgM MGUS, non-IgM MGUS, and light chain MGUS.

  • By definition, the bone marrow (if tested) should contain less than 10% clonal cells, and there should be no evidence of multiple myeloma–defining events or any end-organ damage suggestive of Waldenström macroglobulinemia.

  • MGUS is prevalent in approximately 3% of the general population 50 years of age and older.

  • Patients with three adverse risk factors, namely an abnormal serum FLC ratio, non-IgG MGUS, and a high serum M protein level (≥15 g/L), have a risk of progression at 20 years of 58% (high-risk MGUS) compared with 37% in patients with any two of these risk factors (high- or intermediate-risk MGUS), 21% with one risk factor (low- or intermediate-risk MGUS), and 5% with none of the risk factors (low-risk MGUS).

  • The current standard of care for MGUS is observation alone, without therapy.

  • Smoldering Multiple Myeloma (SMM)

  • SMM is defined by the presence of a serum IgG or IgA M protein level of 3 g/dL or higher and/or bone marrow plasma cells 10% to 60%, and absence of multiple myeloma–defining events.

  • The risk of progression to multiple myeloma or related malignancy is much higher in SMM compared with MGUS: 10% per year versus 1% per year, respectively.

  • The standard of care is observation alone until evidence of progression to multiple myeloma occurs; however, high-risk patients may benefit from early therapy, and clinical trials are ongoing.

  • Waldenström Macroglobulinemia

  • Waldenström macroglobulinemia is a clonal IgM monoclonal protein–secreting lymphoid and plasma cell disorder, which currently also includes the entity referred to previously as lymphoplasmacytic lymphoma.

  • Median survival is approximately 5 years.

  • There are three main options for initial therapy: bendamustine plus rituximab (BR), dexamethasone, rituximab, and cyclophosphamide (DRC), and ibrutinib.

  • Options listed for initial therapy can also be tried at the time of relapse. The same initial therapy can be tried again at relapse, if there was an adequate interval between cessation of therapy and relapse. Other options for relapsed, refractory disease include purine nucleoside analogues, stem cell transplantation, interferon-α, lenalidomide, and bortezomib.

  • Plasmapheresis is indicated for the treatment of hyperviscosity syndrome.

  • Systemic AL (Immunoglobulin Light Chain) Amyloidosis

  • Amyloid is a fibrillar proteinaceous material detected with Congo red staining based on a characteristic apple-green birefringence under polarized light.

  • It consists of rigid, linear, nonbranching fibrils, 7.5 to 10 nm in width, aggregated in a β-pleated sheet conformation. There are several distinct types of amyloidosis, classified based on the protein composition of the amyloid material.

  • AL (immunoglobulin light chain) amyloidosis refers to the type of amyloidosis derived from the variable portion of a monoclonal light chain. It should be suspected when patients with the appropriate clinical syndrome—for example, nephrotic syndrome, axonal neuropathy, or restrictive cardiomyopathy—display evidence of a plasma cell proliferative disorder such as a serum or urine monoclonal protein.

  • Patients are offered ASCT if eligible. Patients not eligible for stem cell transplantation (poor performance status, major comorbidities, three or more organs involved, and advanced cardiac amyloidosis) are treated with either bortezomib, melphalan, and dexamethasone (BMd) or VCd.

  • Immunomodulatory drugs such as lenalidomide and pomalidomide are second-line treatment options for patients with systemic AL amyloidosis.

  • Solitary Plasmacytoma

  • Solitary plasmacytomas may be confined to bone (solitary bone plasmacytoma) or may occur in extramedullary sites (extramedullary plasmacytoma). The bone marrow in patients with solitary plasmacytoma should not have any evidence of clonal plasma cells.

  • Patients who have a solitary lesion but have evidence of clonal bone marrow involvement (up to 10%) are considered to have solitary plasmacytoma with minimal marrow involvement; Patients who have a solitary lesion and 10% or more clonal bone marrow plasma cells are considered to have multiple myeloma.

  • Patients with solitary plasmacytoma and solitary plasmacytoma with minimal marrow involvement are at risk for progression to multiple myeloma. The risk of recurrence or progression to multiple myeloma within 3 years is approximately 10% in patients with true solitary plasmacytoma versus 20% to 60% in patients with solitary plasmacytoma and minimal marrow involvement.

  • Treatment consists of radiation in the range of 40 to 50 Gy to the involved site.

Multiple Myeloma

Definition

The diagnosis of multiple myeloma requires 10% or more clonal plasma cells in the bone marrow and/or a biopsy-proven plasmacytoma plus one or more of the following multiple myeloma–defining events (MDEs): evidence of end-organ damage (hypercalcemia, renal insufficiency, anemia, or bone lesions) attributable to the underlying plasma cell disorder; 60% or more clonal plasma cells in the bone marrow; serum involved/uninvolved free light chain (FLC) ratio of 100 or greater (provided involved FLC level is ≥100 mg/L); or more than one focal lesion (≥5 mm) at magnetic resonance imaging (MRI) ( Table 101.1 ). These criteria, published in 2014 by the International Myeloma Working Group (IMWG), represent a major paradigm shift in disease definition. In addition, the new diagnostic criteria allow the use of computed tomography (CT) and positron emission tomography–computed tomography (PET-CT) to diagnose myeloma bone disease. These changes enable early diagnosis and allow the initiation of effective therapy to prevent the development of end-organ damage in patients who are at the highest risk.

Table 101.1
International Myeloma Working Group Diagnostic Criteria for Multiple Myeloma and Related Disorders
Modified from Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15:e538–e548.
Disorder Disease Definition References
Non-IgM monoclonal gammopathy of undetermined significance (MGUS) All three criteria must be met:

  • Serum monoclonal protein (non-IgM type) <3 g/dL

  • Clonal bone marrow plasma cells <10% a

  • Absence of end-organ damage such as hyper c alcemia, r enal insufficiency, a nemia, and b one lesions (CRAB) that can be attributed to the plasma cell proliferative disorder

Smoldering multiple myeloma Both criteria must be met:

  • Serum monoclonal protein (IgG or IgA) ≥3 g/dL, or urinary monoclonal protein ≥500 mg/24 h and/or clonal bone marrow plasma cells 10%–60%

  • Absence of myeloma-defining events or amyloidosis

Multiple myeloma Both criteria must be met:

  • Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma

  • Any one or more of the following myeloma defining events:

    • Evidence of end-organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:

      • Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL)

      • Renal insufficiency: creatinine clearance <40 m/min or serum creatinine >177 µmol/L (>2 mg/dL)

      • Anemia: hemoglobin value of >2 g/dL below the lower limit of normal, or a hemoglobin value <10 g/dL

      • Bone lesions: one or more osteolytic lesions on skeletal radiograph, CT scan, or PET-CT scan

    • Clonal bone marrow plasma cell percentage ≥60%

    • Involved/uninvolved serum FLC ratio ≥100 (involved FLC level must be ≥100 mg/L)

    • >1 focal lesion on MRI study (≥5 mm)

IgM MGUS All three criteria must be met:

  • Serum IgM monoclonal protein <3 g/dL

  • Bone marrow lymphoplasmacytic infiltration <10%

  • No evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder

Smoldering Waldenström macroglobulinemia (also referred to as indolent or asymptomatic Waldenström macroglobulinemia) Both criteria must be met:

  • Serum IgM monoclonal protein ≥3 g/dL and/or bone marrow lymphoplasmacytic infiltration ≥10%

  • No evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder

Waldenström macroglobulinemia All criteria must be met:

  • IgM monoclonal gammopathy (regardless of the size of the M protein)

  • ≥10% bone marrow lymphoplasmacytic infiltration (usually intertrabecular) by small lymphocytes that exhibit plasmacytoid or plasma cell differentiation and a typical immunophenotype (e.g., surface IgM+, CD5+/−, CD10−, CD19+, CD20+, CD23−) that satisfactorily excludes other lymphoproliferative disorders including chronic lymphocytic leukemia and mantle cell lymphoma

  • Evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder

Light chain MGUS All criteria must be met:

  • Abnormal FLC ratio (<0.26 or >1.65)

  • Increased level of the appropriate involved light chain (increased kappa [κ] FLC in patients with ratio >1.65 and increased lambda [λ] FLC in patients with ratio <0.26)

  • No immunoglobulin heavy chain expression on immunofixation

  • Absence of end-organ damage that can be attributed to the plasma cell proliferative disorder

  • Clonal bone marrow plasma cells <10%

  • Urinary monoclonal protein <500 mg/24 h

Solitary plasmacytoma All four criteria must be met:

  • Biopsy proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells

  • Normal bone marrow with no evidence of clonal plasma cells

  • Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion)

  • Absence of end-organ damage such as CRAB that can be attributed to a lymphoplasma cell proliferative disorder

Solitary plasmacytoma with minimal marrow involvement b All four criteria must be met:

  • Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells

  • Clonal bone marrow plasma cells <10%

  • Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion)

  • Absence of end-organ damage such as CRAB that can be attributed to a lymphoplasma cell proliferative disorder

Systemic AL amyloidosis All four criteria must be met:

  • Presence of an amyloid-related systemic syndrome (such as renal, liver, heart, gastrointestinal tract, or peripheral nerve involvement)

  • Positive amyloid staining by Congo red in any tissue (e.g., fat aspirate, bone marrow, or organ biopsy)

  • Evidence that amyloid is light chain related, established with direct examination of the amyloid with MS-based proteomic analysis, or immunoelectron microscopy

  • Evidence of a monoclonal plasma cell proliferative disorder (serum or urine M protein, abnormal free light chain ratio, or clonal plasma cells in the bone marrow)

Note: Approximately 2%–3% of patients with AL amyloidosis will not meet the requirement for evidence of a monoclonal plasma cell disorder listed above; the diagnosis of AL amyloidosis must be made with caution in these patients. Patients with AL amyloidosis who also meet criteria for multiple myeloma are considered to have both diseases.
POEMS syndrome All four criteria must be met:

  • Polyneuropathy

  • Monoclonal plasma cell proliferative disorder (almost always λ)

  • Any one of the following three other major criteria:

    • 1.

      Sclerotic bone lesions

    • 2.

      Castleman disease

    • 3.

      Elevated levels of VEGF c

  • Any one of the following six minor criteria:

    • 1.

      Organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy)

    • 2.

      Extravascular volume overload (edema, pleural effusion, or ascites)

    • 3.

      Endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, pancreatic) d

    • 4.

      Skin changes (hyperpigmentation, hypertrichosis, glomeruloid hemangiomata, plethora, acrocyanosis, flushing, white nails)

    • 5.

      Papilledema

    • 6.

      Thrombocytosis/polycythemia

Note: Not every patient meeting the above criteria will have POEMS syndrome; the features should have a temporal relationship to one another and no other attributable cause. Anemia and/or thrombocytopenia are distinctively unusual in this syndrome unless Castleman disease is present.
CT, Computed tomography; FLC, free light chain; MGUS, monoclonal gammopathy of undetermined significance; MRI, magnetic resonance imaging; MS, mass spectrometry; PET-CT, positron emission tomography–computed tomography; VEGF, vascular endothelial growth factor.

a Bone marrow aspiration can be deferred in patients with low-risk MGUS (IgG type, M protein <15 g/L, normal free light chain ratio) in whom there are no clinical features concerning for myeloma.

b Solitary plasmacytoma with 10% or more clonal plasma cells is considered as multiple myeloma.

c The source data do not define an optimal cutoff value for considering elevated VEGF level as a major criterion. We suggest that for VEGF level to be considered a major criteria, VEGF measured in the serum or plasma should be at least threefold or fourfold higher than the normal reference range for the laboratory that is doing the testing.

d For endocrinopathy to be considered as a minor criterion, an endocrine disorder other than diabetes or hypothyroidism is required because these two disorders are common in the general population.

Epidemiology

Multiple myeloma accounts for approximately 10% of hematologic malignancies. The annual incidence, age adjusted to the 2000 US population, is 4.3 per 100,000. Over 30,000 new cases and 11,000 new deaths are estimated to occur each year in the United States. Multiple myeloma is twice as common in African Americans as in Caucasians, and slightly more common in males than in females. The median age at diagnosis is 66 years, and only 2% of patients are younger than 40 years. In almost all patients, multiple myeloma is believed to evolve from an asymptomatic premalignant stage termed monoclonal gammopathy of undetermined significance (MGUS). MGUS is present in over 3% of the population above the age of 50 and progresses to multiple myeloma or related malignancy a rate of 1% per year. In some patients an intermediate asymptomatic but more advanced premalignant stage referred to as smoldering multiple myeloma (SMM) can be recognized clinically.

Pathogenesis

Transition From Normal Plasma Cell to Monoclonal Gammopathy of Undetermined Significance

Antigenic stimulation and immunosuppression

MGUS is characterized by evidence of genomic instability at molecular genetic testing. The trigger for this genomic instability is not well understood, but current evidence suggests that antigenic stimulation may be a key factor ( Fig. 101.1 ). Unlike normal plasma cells, human myeloma cell lines and primary myeloma cells express a broad range of Toll-like receptors (TLRs). TLRs are normally expressed by B lymphocytes and are essential for recognition by these cells of infectious agents and pathogen-associated molecular patterns (PAMPs), which then results in initiation of the host-defense response. The aberrant expression of TLRs by plasma cells may enable them to respond to TLR-specific ligands, resulting in an abnormal and perhaps sustained response to infection. It has been shown that TLR-specific ligands cause increased myeloma cell proliferation, survival, and resistance to dexamethasone induced apoptosis. These effects are mediated in part by autocrine interleukin (IL)-6 production.

Figure 101.1, Pathogenesis of myeloma. IL-6, Interleukin-6; MGUS, monoclonal gammopathy of undetermined significance; MIP-1α, macrophage inflammatory protein-1α; OPG, osteoprotegerin; RANKL, receptor activator of nuclear factor–κB ligand; VEGF, vascular endothelial growth factor.

IL-6 is a major growth factor for plasma cells, and there is overexpression of CD126 (IL-6 receptor alpha chain) in MGUS compared with normal plasma cells. Thus abnormal TLR expression and/or overexpression of IL-6 receptors in plasma cells may be early initiating events that lead to an abnormal response to infection and act as sustained, autocrine IL-6–dependent, proliferative triggers for plasma cells. During this process plasma cells likely acquire one of the various primary cytogenetic abnormalities described later that result in a limited clonal plasma cell proliferative process, namely MGUS.

Immunosuppression either by promotion of evasion of tumor surveillance or by promotion of antigenic stimulation may also contribute to the initiation of monoclonal gammopathies. Monoclonal proteins have been reported in the context of immunosuppressive states such as bone marrow or stem cell transplantation, organ transplantation, and human immunodeficiency virus (HIV) infection. Patients undergoing renal transplantation develop monoclonal proteins dependent on the level of immunosuppression to which they are subjected.

Cytogenetic changes

The establishment of MGUS coincides and is likely causally related to the occurrence of primary cytogenetic abnormalities in clonal plasma cells: translocations involving the immunoglobulin heavy chain (IgH) locus on chromosome 14q32 or trisomies. Translocations involving chromosome 14q32 can be noted in approximately 50% of cases of MGUS (see Fig. 101.1 ). The most common partner chromosome loci and genes dysregulated in these translocations are 11q13 ( CCND1 [cyclin D1 gene]), 4p16.3 ( FGFR-3 and MMSET ), 6p21 ( CCND3 [cyclin D3 gene]), 16q23 (C-MAF), and 20q11 (MAF-B). It is likely that these translocations play an important pathogenetic role in the resultant limited clonal proliferation that clinically manifests as MGUS.

Approximately 45% of cases of MGUS are associated with trisomies, usually of the odd-numbered chromosomes with the exception of 13; and the origin of the remaining 5% or fewer of cases of MGUS is not clear. A study in multiple myeloma has shown that there is a small overlap wherein a subset of patients have both IgH translocations and trisomies; this combination is likely present at the MGUS stage, but the sequence and prevalence are not well known ( Table 101.2 ).

Table 101.2
Revised Primary Molecular Cytogenetic Classification of Myeloma
Modified from Kumar S et al. Trisomies in multiple myeloma: impact on survival in patients with high-risk cytogenetics. Blood. 2012;119:2100. © American Society of Hematology.
FISH Abnormality Genes and Chromosome (s) Affected Percentage of Myeloma Patients
Trisomy without IgH abnormality One or more trisomies of odd numbered chromosomes 42
IgH abnormality without trisomy 30

    • t(11;14)

CCND1 15

    • t(4;14)

FGFR3 and MMSET 6

    • t(14;16)

C-MAF 4

    • t(14;20)

MAF-B <1

    • Unknown partner or deletion of IgH region

CCND1 (cyclin D1 gene), 4p16.3 ( FGFR-3 and MMSET ), 6p21
CCND3 (cyclin D3 gene), 16q23 (C-MAF), and 20q11 (mafB) 		5
IgH abnormality with trisomy a 15

    • t(11;14)

CCND1 (cyclin D1) 3

    • t(4;14)

FGFR3 and MMSET 4

    • t(14;16)

C-MAF 1

    • t(6;14)

CCND3 (cyclin D3) <1

    • Unknown partner or deletion of IgH region

7
Monosomy 14 in absence of IgH translocations or trisomy 4.5
Other cytogenetic abnormalities in absence of IgH translocations or trisomy or monosomy 14 5.5
Normal 3
FISH, Fluorescence in situ hybridization; IgH, immunoglobulin heavy chain.

a In addition to the effect of the translocated gene, there is the added effect of the trisomies of odd-numbered chromosomes in this group.

Progression to Malignancy

The constant rate of progression of MGUS to multiple myeloma, macroglobulinemia, or related malignancy in an epidemiologic study over a period spanning 30 to 35 years strongly suggests a simple, random, two-hit genetic model of malignancy. The risk of progression is similar regardless of the known duration of antecedent MGUS, suggesting that the second hit responsible for progression is a random event, not cumulative damage.

The specific second hit that initiates the cascade of events associated with progression is unknown. Several abnormalities with progression in both the plasma cell and its microenvironment have been detected and likely play a role in the progression of MGUS, but little is known about the sequence of events (see Fig. 101.1 ). Ras mutations, p16 methylation, abnormalities involving the myc family of oncogenes, secondary translocations, and p53 mutations have all been identified in clonal plasma cells in association with progression to the symptomatic stage. For example, amplification of chromosome 1q21 (gain1q) been noted in over 40% of patients with SMM and multiple myeloma compared with 0% in MGUS, suggesting that such amplification (e.g., by trisomy 1) may play a role in progression. Studies have indicated that there is significant clonal heterogeneity in multiple myeloma, with a different dominant clone emerging through the course of various treatments.

The bone marrow microenvironment undergoes marked changes with progression, including induction of angiogenesis, suppression of cell-mediated immunity, and paracrine loops involving cytokines such as IL-6 and vascular endothelial growth factor (VEGF). As in solid tumors, the transition from MGUS to multiple myeloma may involve an angiogenic switch. In solitary plasmacytoma, which can be considered to be analogous to localized stage I solid tumor, induction of angiogenesis at the time of diagnosis has been shown to be a predictor of progression to multiple myeloma, suggesting a pathogenetic role for the process in disease progression. Furthermore, there is a gradual increase in degree of bone marrow angiogenesis along the disease spectrum from MGUS to SMM to symptomatic multiple myeloma. In one study, approximately 60% of multiple myeloma bone marrow plasma samples stimulated angiogenesis in an in vitro angiogenesis assay, compared with 0% of SMM and 7% of MGUS samples ( P < .001).

Pathogenesis of Bone Lesions

The progression of MGUS to multiple myeloma is characterized by the development of bone lesions. The pathogenetic mechanisms involved are complex and involve a combination of osteoclast activation coupled with osteoblast inhibition. Understanding these mechanisms has resulted in clinical trials with specific agents to prevent or delay the formation of bone lesions in multiple myeloma. There are several important mechanisms that mediate increased osteoclast activation. There is an increase in RANKL (receptor activator of nuclear factor–κB [NF-κB] ligand) expression by osteoblasts and possibly plasma cells. This is accompanied by decreased stromal cell secretion of the RANKL decoy receptor, osteoprotegerin (OPG). In addition, the binding of OPG to RANKL is also inhibited by syndecan 1 (CD138) secreted and/or shed by myeloma cells. The net result of these facts is an increase in RANKL/OPG ratio. This causes increased osteoclast activation mediated through the NF-κB pathway. A second factor governing the activation of osteoclasts is the release of macrophage inflammatory protein 1α (MIP-1α) and MIP-1β by myeloma cells. Both these cytokines cause osteoclast activation primarily by increasing RANKL expression in stromal cells. Finally, there is increased expression of stromal cell–derived factor 1α (SDF-1α) by stromal cells and myeloma cells. SDF-1α causes osteoclast activation by binding to CXCR4 on osteoclast precursors. In addition to these three factors, several other cytokines such as IL-1β and IL-6 are also thought to play a role in osteoclast activation and bone resorption.

Osteoblast inhibition in multiple myeloma is felt to be primarily related to increased Dickkopf 1 (DKK-1) expression by myeloma cells. DKK-1 binds to Wnt receptors and inhibits the Wnt signaling pathway by preventing the normal binding of Wnt glycoproteins to Wnt receptors. The inhibition of Wnt signaling prevents the intracellular stabilization of β-catenin, leading to the phosphorylation and degradation of β-catenin through the proteasome pathway. Normally, β-catenin plays an important role in osteoblast activation and its absence reduces the activity of osteoblasts. In addition to its key role in causing osteoblast inhibition, increased levels of DKK-1 may also contribute in some measure to osteoclast activation. In addition to DKK-1, there are other factors such as IL-3 and IL-7 that may contribute to osteoblast inhibition. The combination of osteoclast activation and inhibition of osteoblast differentiation is felt to be the mechanism behind the development of osteolytic lesions in multiple myeloma.

Clinical Features

The most common presenting symptoms of multiple myeloma are fatigue and bone pain. Osteolytic bone lesions and/or compression fractures are the hallmark of the disease and can be detected on routine radiographs, MRI images, CT scans, or fluorodeoxyglucose–positron emission tomography (FDG-PET) scans ( Figs. 101.2–101.4 ). Bone pain may be present as an area of persistent pain or migratory bone pain, often in the lower back and pelvis. Pain may be sudden in onset when associated with a pathologic fracture and is often precipitated by movement. Extramedullary expansion of bone lesions may cause nerve root or spinal cord compression. Anemia occurs in 70% of patients at diagnosis and is the primary cause of fatigue. Hypercalcemia is found in one-fourth of patients, and the serum creatinine is elevated in almost one-half.

Figure 101.2, Osteolytic lesions in the skull on plain radiograph in a patient with myeloma.

Figure 101.3, Magnetic resonance images of the spine in a patient with myeloma showing marrow edema of T11 and L1–L3 vertebral bodies. Marrow signal intensity is diffusely heterogeneous, consistent with patient's known clinical diagnosis of multiple myeloma.

Figure 101.4, Computed tomographic scan of a vertebral body showing osteolytic bone lesions in a patient with myeloma.

Investigation

A complete blood count, urinalysis, and serum creatinine, calcium, β2-microglobulin, albumin, C-reactive protein, and lactate dehydrogenase levels are needed for diagnosis, prognosis, and staging. If available, peripheral blood flow cytometry to detect and quantify circulating plasma cells should be done. In addition, patients require tests to identify and quantitate monoclonal proteins, bone disease, and bone marrow involvement. Specialized tests are also performed on the bone marrow for risk stratification.

Identification of Monoclonal Proteins

Myeloma is characterized by the presence of monoclonal immunoglobulins in the serum and/or urine. Monoclonal immunoglobulins are commonly referred to as monoclonal proteins, M proteins, or paraproteins. The presence of M proteins is indicative of a clonal plasma cell proliferative disorder such as multiple myeloma, MGUS, or Waldenström macroglobulinemia; additional tests are required to distinguish among the various plasma cell disorders.

M proteins can be detected with serum protein electrophoresis (SPEP) in 82% of patients with multiple myeloma, and with serum immunofixation electrophoresis (IFE) in 93%. Up to 20% of patients with multiple myeloma lack heavy chain expression in the M protein and are considered to have light chain multiple myeloma. The M protein in these patients is always detected in the urine but can be absent in the serum even with immunofixation, making it imperative that protein electrophoresis and immunofixation always be done on both the serum and the urine in all patients in whom multiple myeloma is suspected. Addition of urine protein electrophoresis (UPEP) and urine IFE will increase the sensitivity of detection of monoclonal proteins in patients with multiple myeloma to 97%. Most (60%) of the remaining patients who are negative for monoclonal protein on serum and urine electrophoresis and immunofixation studies will have evidence of clonal paraproteins on the serum FLC assay. Currently only 1% to 2% of patients with multiple myeloma will have no detectable M on any of these tests; these patients have true nonsecretory multiple myeloma.

Serum protein electrophoresis and immunofixation

Agarose gel SPEP and IFE are the preferred methods of detection of serum monoclonal (M) proteins ( Fig. 101.5 ). M proteins appear as a localized band on SPEP. After recognition of a localized band suggestive of an M protein at SPEP, IFE is necessary for confirmation and to determine the heavy and light chain class of the M protein. In addition, IFE is more sensitive than SPEP and allows detection of smaller amounts of M protein and should therefore be performed whenever multiple myeloma, amyloidosis, macroglobulinemia, or a related disorder is suspected. The size of the M protein is measured with SPEP. For purposes of clinical trials and monitoring, the M protein is considered to be “measurable” if the level is 1 g/dL or more in the serum and/or 200 mg/day or more in the urine.

Figure 101.5, (A) Serum protein electrophoresis (PEL) and immunofixation (IFE) showing a normal pattern with no evidence of monoclonal protein. (B) Serum PEL showing a monoclonal (M) protein in the gamma region, which is IgG lambda on immunofixation (IFE).

Quantitative immunoglobulin studies

Quantitation of serum immunoglobulins is performed with a rate nephelometer in patients in whom M proteins are detected. It is an added parameter that can be followed particularly in patients with multiple myeloma and macroglobulinemia in whom at times the M protein size estimated with SPEP may be unreliable (e.g., small beta migrating proteins; IgA and IgM proteins, which tend to polymerize).

Urine protein electrophoresis and immunofixation

Typically, screening for suspected monoclonal gammopathies has included UPEP and immunofixation in addition to the serum studies discussed earlier because a subset of patients with multiple myeloma and amyloidosis may have an M protein restricted to the urine and absent on serum studies. In such patients the diagnosis of plasma cell dyscrasia would be missed if urine studies were not performed. A 24-hour urine specimen is required for UPEP and immunofixation. Urine M protein levels are measured with UPEP and used in monitoring disease progression and response to therapy.

Serum free light chain assay

The serum FLC assay provides an important tool to quantify monoclonal light chains secreted by myeloma cells, especially in patients who secrete small amounts of intact monoclonal immunoglobulin. This automated nephelometric assay allows quantitation of free kappa (κ) and lambda (λ) chains (i.e., light chains that are not bound to intact immunoglobulin) secreted by plasma cells. The normal reference range in the FLC assay reflects a higher serum level of free λ light chains than would be expected given the usual κ/λ ratio of 2 for intact immunoglobulins. This occurs because the renal excretion of free κ (which exists usually in a monomeric state) is much faster than free λ (which is usually in a dimeric state). Patients with a κ/λ FLC ratio below the normal range are typically defined as having monoclonal λ FLC, and those with ratios above the normal range are defined as having a monoclonal κ FLC. If the FLC ratio is elevated, κ is considered to be the “involved” FLC and λ the “uninvolved” FLC, and vice versa if the ratio is less than the normal range.

A study of 428 patients at the Mayo Clinic demonstrated that through use of the serum FLC assay in combination with the SPEP and immunofixation, urine studies can be eliminated from screening for the presence of monoclonal plasma cell disorders. If a monoclonal plasma cell disorder is identified at screening, urine studies should be performed to aid in monitoring of disease progression and response to therapy over time. Besides its role as a substitute for urine studies in the screening of plasma cell disorders, the FLC assay is used to predict prognosis in MGUS, SMM, and solitary plasmacytoma. In addition, it is also used to monitor patients with oligosecretory or nonsecretory multiple myeloma, primary amyloidosis, and the light chain–only form of multiple myeloma. For the FLC assay to be used to monitor disease progression, the baseline FLC ratio must be abnormal and the involved FLC level must be 100 mg/L or higher.

Identification of Bone Disease

Examination of all bones with plain radiography or preferably whole-body low-dose CT is required for detection of lytic bone lesions. These studies show skeletal abnormalities in more than 80% to 90% of patients with multiple myeloma. The bone lesions in multiple myeloma have a characteristic punched-out appearance. Osteoporosis and/or fractures can also be present. Occasionally, osteosclerotic lesions can occur. Whole-body low-dose CT and FDG-PET CT scans are more sensitive than conventional radiography in detecting bone disease and are useful in the initial assessment of bone disease, in staging, and in assessment of response to therapy in multiple myeloma ( Fig. 101.6 ). They are also of value in monitoring response to therapy in patients with oligosecretory multiple myeloma, in assessing extramedullary disease, and whenever there is a concern that disease assessment may be inadequate with plain radiographs and M protein assessments alone. The use of MRI and/or PET-CT or whole-body low-dose CT is also required for differentiation of SMM and solitary plasmacytoma from multiple myeloma. MRI scans are also of value in patients with suspected cord compression. The role of bone mineral density studies in multiple myeloma and the use of these studies in identifying patients at risk for pathologic fractures and prophylactic bisphosphonate therapy remain unresolved. However, if these studies have been done, they can be used to guide frequency of bisphosphonate administration.

Figure 101.6, Fluorodeoxyglucose–positron emission tomography (FDG-PET) images of bone lesions in a patient with myeloma showing lesions in the sternum, right rib, right ilium, left hip, and left ischium.

Bone Marrow Studies

Unilateral bone marrow aspiration and biopsy are indicated in all patients with multiple myeloma. Almost all patients with multiple myeloma will have 10% or more clonal bone marrow plasma cells. If a lower extent of involvement is detected, either one is dealing with an erroneous diagnosis, or there is a sampling error due to patchy marrow involvement, in which case a repeat marrow biopsy is indicated. The monoclonal (or more accurately monotypic) nature of bone marrow plasma cells is established by the demonstration of an abnormal κ/λ ratio with multiparametric flow cytometry. With flow cytometry, plasma cells in multiple myeloma typically stain positive for CD38, CD56, and CD138 and are usually negative for surface immunoglobulin and CD19. Up to 20% stain positively for CD20. Morphologically, the presence of immature “blast”-like plasma cells (plasmablastic morphology) carries an adverse prognosis. Given their impact on prognosis (see Prognosis , later) bone marrow sample fluorescence in situ hybridization (FISH) studies or other molecular methods must be performed to detect specific abnormalities such as t(4;14), t(14;16), and deletion 17p (del17p). The bone marrow plasma cell proliferative rate should be estimated with multiparametric flow cytometry, if available. Gene expression profiling studies, if done, can provide additional prognostic information.

Differential Diagnosis

In patients with evidence of monoclonal proteins, the main differential diagnosis is among multiple myeloma, MGUS, SMM, macroglobulinemia, and immunoglobulin light chain (AL) amyloidosis. These disorders are distinguished from one another with the criteria listed in Table 101.1 . In patients with marrow plasmacytosis, monoclonal plasma cell disorders are differentiated from polyclonal reactive plasmacytosis that occurs in conditions such as autoimmune diseases, metastatic carcinoma, chronic liver disease, acquired immunodeficiency syndrome (AIDS), or chronic infection based on κ/λ expression on immunostaining or multiparametric flow cytometry.

Prognosis

Survival in multiple myeloma has improved significantly in the last 10 years with the emergence of newer therapeutic options. However, survival varies greatly among patients, depending on several independent prognostic factors ( Table 101.3 ). As with any cancer, prognosis in multiple myeloma is broadly determined by four factors: the general condition of the patient including his or her ability to tolerate antimyeloma therapy (host factors), the tumor burden (stage), the aggressiveness of the disease (biology), and the susceptibility of the neoplastic plasma cells to the administered antimyeloma drugs (response to therapy). Of these, only host factors, stage, and disease biology can be assessed at the time of diagnosis, before initiation of therapy. Response to therapy does influence outcome, but it is unclear whether the depth of the response is primarily serving as a surrogate for disease biology or is an independent factor that should be pursued as a therapeutic goal.

Table 101.3
Revised International Staging System (RISS) for Multiple Myeloma
Stage Frequency
(% of patients)		 Five-Year Survival Rate (%)
Stage 1

  • ISS stage I (serum albumin >3.5, serum β2-microglobulin <3.5) and

  • No high-risk cytogenetics

  • Normal lactate dehydrogenase (LDH)

28 82
Stage II

  • Neither stage I nor stage III

62 62
Stage III

  • ISS stage III (serum β2-microglobulin >5.5) and

  • High-risk cytogenetics (t[4;14], t[14;16], or del[17p]) or elevated LDH

10 40
Derived from Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised International Staging System for Multiple Myeloma: a report from International Myeloma Working Group. J Clin Oncol. 2015;33:2863–2869.

Host Factors

Age, performance status, and extent of comorbidities are important prognostic factors. In addition, they affect choice of therapy. In most countries, only patients younger than age 65 are considered candidates for autologous stem cell transplantation (ASCT). Performance status is of critical importance but is not reflected in results of clinical trials, which systematically exclude patients with poor performance status from trial entry. Renal function is another host factor that plays a role in outcome; it also plays a role in choice of initial therapy.

Stage

The Durie-Salmon staging system (DSS) and the International Staging System (ISS) have now been replaced by the Revised International Staging System (RISS) ( Table 101.3 ). The RISS incorporates important markers of disease biology including cytogenetics in order to provide a more accurate estimation of prognosis than prior staging systems. The RISS is not a true staging system that measure tumor burden, but rather a prognostic index that incorporates elements of host characteristics, tumor burden, renal function, and disease aggressiveness.

Molecular Classification and Risk Stratification

Myeloma is a cytogenetically heterogeneous condition. A revised molecular cytogenetic classification that takes into account overlapping categories is provided in Table 101.2 . Most patients can be subdivided into at least three distinct primary cytogenetic categories: presence of IgH translocations, trisomies of odd-numbered chromosomes, or both. These abnormalities originate at the MGUS stage and are readily recognized on bone marrow FISH studies. In addition, other cytogenetic abnormalities occur during disease progression, including del17p and secondary MYC translocations. Newly diagnosed multiple myeloma can be stratified into standard- and high-risk disease using the Mayo Stratification for Myeloma and Risk-Adapted Therapy (mSMART) classification ( Table 101.4 ). The presence of concomitant trisomies may ameliorate the adverse prognosis associated with high-risk multiple myeloma. Patients with standard-risk multiple myeloma have a median overall survival (OS) in excess of 7 to 10 years, whereas those with high-risk disease have a median OS of less than 3 years despite best available therapy. Some patients with high-risk disease can achieve survival similar to that in patients with standard-risk multiple myeloma when treated with bortezomib-containing regimens and ASCT. Other biomarkers that assist in risk stratification include gain1q, 1p deletion (del1p), MYC translocations, plasma cell immunophenotyping, detection of minimal residual disease (MRD), and identification of circulating plasma cells with multiparametric flow cytometry.

Table 101.4
Mayo Stratification for Myeloma and Risk-Adapted Therapy (mSMART) Classification
Modified from Rajkumar SV. Multiple myeloma: 2016 update on diagnosis, risk-stratification, and management. Am J Hematol. 2016;91;720–734.
  • A.

    Standard risk

    • Hyperdiploidy

    • t(11;14)

    • t(6;14)

  • B.

    High risk a

    • 17p deletion

    • t(4;14)

    • t(14;16)

    • t(14;20)

    • 1q gain

    • p53 mutation

    • High-risk gene expression profiling signature

a High lactate hydrogenase and plasma cell leukemia are also considered high-risk myeloma.

Management

There are at least several active classes of systemic agents that can be used for the treatment of multiple myeloma: alkylators (e.g., melphalan, cyclophosphamide), corticosteroids (e.g., prednisone, dexamethasone), proteasome inhibitors (bortezomib, carfilzomib, ixazomib), immunomodulatory drugs (thalidomide, lenalidomide, pomalidomide), monoclonal antibodies (daratumumab, elotuzumab), deacetylase inhibitors (panobinostat), and anthracyclines (e.g., doxorubicin, liposomal doxorubicin). Although thalidomide, lenalidomide, and pomalidomide are termed immunomodulatory agents (immunomodulatory imide drugs [IMiDs]), their exact mechanism of action is still unclear. IMiDs bind to cereblon and activate cereblon E3 ligase activity, resulting in the rapid ubiquitination and degradation of two specific B-cell transcription factors, Ikaros family zinc finger proteins Ikaros (IKZF 1) and Aiolos (IKZF3). They may cause direct cytotoxicity by inducing free radical–mediated DNA damage. They also have anti-angiogenic, immunomodulatory, and tumor necrosis factor–α inhibitory properties. Elotuzumab and daratumumab are monoclonal antibodies targeting SLAMF7 and CD38, respectively. Radiation therapy is used primarily for palliation in settings where systemic therapy is not effective. In addition, it may be needed in the treatment of urgent complications such as spinal cord compression.

The treatment of multiple myeloma depends on risk stratification and eligibility for stem cell transplantation. Eligibility for stem cell transplantation is determined according to age, performance status, and coexisting comorbidities. There is an ongoing “cure versus control” debate on whether treatment for multiple myeloma should target complete response (CR) (or MRD-negative state) with multiagent combinations or whether a sequential approach designed to maximize disease control and quality of life should be used.

Table 101.5 lists the most common regimens used in the treatment of newly diagnosed multiple myeloma. After initiation of therapy, patients should be monitored with complete blood count (CBC), serum creatinine, serum calcium, SPEP, and serum FLC levels to assess treatment response and monitor for relapse. These tests are typically done monthly during active therapy and once every 3 to 4 months thereafter. In patients with nonsecretory multiple myeloma, monitoring is more difficult and requires periodic radiographic studies and bone marrow examinations. Radiographic tests are done every 6 to 12 months depending on response to treatment and when symptoms indicate their need. Bone marrow studies are repeated if needed to confirm CR or when clinically indicated to assess relapse. In patients with CR, estimation of MRD through next-generation flow cytometry (NGF) or next-generation sequencing (NGS) provides added prognostic information and is recommended. Response to therapy is assessed with the IMWG Response Criteria ( Table 101.6 ). Table 101.7 provides the results of recent randomized trials with the most commonly used regimens in the treatment of newly diagnosed and relapsed multiple myeloma.

Table 101.5
Selected Regimens for the Treatment of Multiple Myeloma
Modified from Rajkumar SV. Multiple myeloma: 2016 update on diagnosis, risk-stratification, and management. Am J Hematol. 2016;91;720–734.
Regimen Usual Schedule a
Lenalidomide-dexamethasone (Rd) Lenalidomide 25 mg orally days 1–21 every 28 days
Dexamethasone 40 mg orally days 1, 8, 15, 22 every 28 days
Repeated every 4 wk
Pomalidomide-dexamethasone (Pom-Dex) Pomalidomide 4 mg days 1–21
Dexamethasone 40 mg orally on days on days 1, 8, 15, 22
Repeated every 4 wk
Bortezomib-thalidomide-dexamethasone (VTd) b , Bortezomib 1.3 mg/m 2 intravenously days 1, 8, 15, 22
Thalidomide 100–200 mg orally days 1–21
Dexamethasone 20 mg on day of and day after bortezomib (or 40 mg days 1, 8, 15, 22)
Repeated every 4 wk × 4 cycles as pretransplant induction therapy
Bortezomib- cyclophosphamide-dexamethasone (VCd or CyBord) b , Cyclophosphamide 300 mg/m 2 orally on days 1, 8, 15 and 22
Bortezomib 1.3 mg/m 2 intravenously on days 1, 8, 15, 22
Dexamethasone 40 mg orally on days on days 1, 8, 15, 22
Repeated every 4 wk c
Bortezomib-lenalidomide-dexamethasone (VRd) b , Bortezomib 1.3 mg/m 2 intravenously days 1, 8, 15
Lenalidomide 25 mg orally days 1–14
Dexamethasone 20 mg on day of and day after bortezomib (or 40 mg days 1, 8, 15, 22)
Repeated every 3 wk d
Carfilzomib- cyclophosphamide-dexamethasone (CCyd) e , Carfilzomib 20 mg/m 2 (cycle 1) and 36 mg/m 2 (subsequent cycles) intravenously on days 1, 2, 8, 9, 15, 16
Cyclophosphamide 300 mg/m 2 orally on days 1, 8, 15
Dexamethasone 40 mg orally on days on days 1, 8, 15
Repeated every 4 wk
Carfilzomib-lenalidomide-dexamethasone (KRd) Carfilzomib 20 mg/m 2 (cycle 1) and 27 mg/m 2 (subsequent cycles) intravenously on days 1, 2, 8, 9, 15, 16
Lenalidomide 25 mg orally days 1–21
Dexamethasone 20 mg on day of and day after bortezomib (or 40 mg days 1, 8, 15, 22)
Repeated every 4 wk
Daratumumab-lenalidomide-dexamethasone (DRd) Daratumumab 16 mg/kg intravenously weekly × 8 wk, and then every 2 wk for 4 mo, and then once monthly
Lenalidomide 25 mg orally days 1–21
Dexamethasone 40 mg days 1, 8, 15, 22
Lenalidomide-dexamethasone repeated in usual schedule every 4 wk
Elotuzumab-lenalidomide-dexamethasone (ERd) Elotuzumab 10 mg/kg intravenously weekly × 8 wk, and then every 2 wk
Lenalidomide 25 mg orally days 1–21
Dexamethasone 40 mg days 1, 8, 15, 22
Lenalidomide-dexamethasone repeated in usual schedule every 4 wk
Ixazomib-lenalidomide-dexamethasone (IRd) Ixazomib 4 mg orally days 1, 8, 15
Lenalidomide 25 mg orally days 1–21
Dexamethasone 40 mg days 1, 8, 15, 22
Repeated every 4 wk
Daratumumab-bortezomib-dexamethasone (DVd) b , Daratumumab 16 mg/kg intravenously weekly × 8 wk, and then every 2 wk for 4 mo, and then once monthly
Bortezomib 1.3 mg/m 2 subcutaneously on days 1, 8, 15, 22
Dexamethasone 20 mg on day of and day after bortezomib (or 40 mg days 1, 8, 15, 22
Bortezomib-dexamethasone repeated in usual schedule every 4 wk
Panobinostat-bortezomib b , Panobinostat 20 mg orally three times a week × 2 wk
Bortezomib 1.3 mg/m 2 intravenous days 1, 8, 15
Repeated every 3 wk

a All doses need to be adjusted for performance status, renal function, blood counts, and other toxicities.

b Doses of dexamethasone and/or bortezomib reduced based on subsequent data showing lower toxicity and similar efficacy with reduced doses.

c The day 22 dose of all three drugs is omitted if counts are low, or after initial response to improve tolerability, or when the regimen is used as maintenance therapy. When used as maintenance therapy for high-risk patients, further delays can be instituted between cycles.

d Omit day 15 dose if counts are low or when the regimen is used as maintenance therapy. When used as maintenance therapy for high-risk patients, lenalidomide dose may be decreased to 10–15 mg per day, and delays can be instituted between cycles as done in total therapy protocols.

e Dosage based on trial in newly diagnosed patients; in relapsed patients cycle 2 carfilzomib dose is 27 mg/m 2 , consistent with approval summary

Table 101.6
International Myeloma Working Group (IMWG) Criteria for Response Assessment Including Criteria for Minimal Residual Disease (MRD) in Multiple Myeloma
Modified from Kumar S, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17;e328–e346.
Flow MRD negative Absence of phenotypically aberrant clonal plasma cells by next-generation flow cytometry on bone marrow aspirates using the EuroFlow standard operation procedure for MRD detection in multiple myeloma (or validated equivalent method) with a minimum sensitivity of 1 in 10 5 nucleated cells or higher
Sequencing MRD negative Absence of clonal plasma cells by next-generation sequencing on bone marrow aspirates in which presence of a clone is defined as less than two identical sequencing reads obtained after DNA sequencing of bone marrow aspirates using the Lymphosight platform (or validated equivalent method) with a minimum sensitivity of 1 in 10 5 nucleated cells or higher
CR (complete response) Negative immunofixation on the serum and urine and
Disappearance of any soft tissue plasmacytomas and
<5% plasma cells in bone marrow aspirates
VGPR (very good partial response) Serum and urine M protein detectable with immunofixation but not with electrophoresis or
≥90% reduction in serum M protein plus
urine M protein level <100 mg/24 h
PR (partial response) ≥50% reduction of serum M protein plus reduction in 24-h urinary M protein by ≥90% or to <200 mg/24 h
If the serum and urine M protein are unmeasurable, a ≥50% decrease in the difference between involved and uninvolved free light chain (FLC) levels is required in place of the M protein criteria
If serum and urine M protein are unmeasurable and serum free light assay is also unmeasurable, ≥50% reduction in plasma cells is required in place of M protein, provided baseline bone marrow plasma cell percentage was ≥30%
In addition to the aforementioned criteria, if present at baseline, a ≥50% reduction in the size (SPD) of soft tissue plasmacytomas is also required
MR (minimal response) ≥25% but ≤49% reduction of serum M protein and reduction in 24-h urine M protein by 50%–89%
In addition to the aforementioned criteria, if present at baseline, a ≥50% reduction in the size (SPD) of soft tissue plasmacytomas is also required
SD (stable disease) (Not recommended for use as an indicator of response; stability of disease is best described by providing the time to progression estimates)
Not meeting criteria for CR, VGPR, PR, MR, or progressive disease (PD)
PD (progressive disease) Any one or more of the following:

  • Increase of 25% from lowest confirmed response value in one or more of the following:

    • Serum M protein (absolute increase must be ≥0.5 g/dL)

    • Serum M protein increase ≥1 g/dL, if the lowest M component was ≥5 g/dL

    • Urine M protein (absolute increase must be ≥200 mg/24 h)

    • In patients without measurable serum and urine M protein levels, the difference between involved and uninvolved FLC levels (absolute increase must be >10 mg/dL)

    • In patients without measurable serum and urine M protein levels and without measurable involved FLC levels, bone marrow plasma cell percentage irrespective of baseline status (absolute % increase must be ≥10%)

  • Appearance of a new lesion(s), ≥50% increase from nadir in SPD of more than one lesion, or ≥50% increase in the longest diameter of a previous lesion >1 cm in short axis

  • ≥50% increase in circulating plasma cells (minimum of 200/µL) if this is the only measure of disease

All response categories except MRD require two consecutive assessments made at anytime before the institution of any new therapy.
SPD, Sum of the products of diameters.

Table 101.7
Results of Selected Randomized Trials in Multiple Myeloma
Modified from Rajkumar SV. Multiple myeloma: 2016 update on diagnosis, risk-stratification, and management. Am J Hematol. 2016;91;720–734.
Trial Regimen No. of Patients Overall Response Rate (%) CR Plus VGPR (%) Progression-Free Survival (Median, mo) P Value for Progression- Free Survival Overall Survival a P Value for Overall Survival
NEWLY DIAGNOSED MYELOMA
Rajkumar et al RD 223 81 50 19.1 75% at 3 yr
Rd 222 70 40 25.3 .026 74% at 3 yr .47
Durie et al Rd 261 72 32 31.0 .002 75 (median in mo) .025
VRd 264 82 43 43.0 64 (median in mo)
Moreau et al VCd 170 84 66 N/A N/A N/A
VTd 170 92 77 N/A N/A N/A
Attal et al VRd 350 N/A 46% CR NR; 48% at 3 yr 88% at 3 yr .25
VRd-ASCT 350 N/A 58% CR NR; 61% at 3 yr < .001 88% at 3 yr
RELAPSED MYELOMA
Lonial et al Rd 325 66 28 14.9 N/A N/A
Elo-Rd 321 79 33 19.4 < .001 N/A
Stewart et al Rd 396 67 14 17.6 65% at 2 yr 0.04
KRd 396 87 32 26.3 .0001 73% at 2 yr
Moreau et al Rd 362 72 7 14.7 N/A N/A
IRd 360 78 12 20.6 .01 N/A
Dimopoulos et al Rd 283 76 44 18.4 < .001 87% at 1 yr NS
DRd 286 93 76 NR 92% at 1 yr
San Miguel et al Vd 381 55 6 8.1 30.4 (median in mo) 0.26
Pano-Vd 387 61 11 12.0 < .0001 33.7 (median in mo)
Palumbo et al Vd 247 63 29 7.2 < .001 70% at 1 yr 0.30
DVd 251 83 59 NR 80% at 1 yr
CR, Complete response; DRd, daratumumab, lenalidomide, dexamethasone; DVd, daratumumab, bortezomib, dexamethasone; Elo-Rd, elotuzumab, lenalidomide, dexamethasone; IRd, ixazomib, lenalidomide, dexamethasone; KRd, carfilzomib, lenalidomide, dexamethasone; N/A, not available; NR, not reached; NS, not significant; Pano-Vd, panobinostat, bortezomib, dexamethasone; RD, lenalidomide, high-dose dexamethasone; Rd, lenalidomide, low-dose dexamethasone; VCd, bortezomib, cyclophosphamide, dexamethasone; Vd, bortezomib, dexamethasone; VGPR, very good partial response; VRd, bortezomib, lenalidomide plus dexamethasone; VTd, bortezomib, thalidomide, dexamethasone.

a Estimated from survival curves when not reported.

Initial Therapy

The approach to treatment of symptomatic newly diagnosed multiple myeloma is outlined in Fig. 101.7 . It is important to avoid protracted melphalan-based therapy in patients with newly diagnosed multiple myeloma who are considered eligible for ASCT, because such therapy can interfere with adequate stem cell mobilization, regardless of whether an early or delayed transplant is contemplated. Patients who are candidates for stem cell transplantation are first treated with three or four cycles of induction therapy before stem cell harvest. This includes patients who are transplant candidates but who wish to reserve ASCT as a delayed option for relapsed refractory disease. Such patients can resume induction therapy after stem cell collection until progression or a plateau phase is reached, reserving ASCT for relapse. Patients who are not candidates for stem cell transplantation are typically treated with a triplet regimen such as bortezomib, lenalidomide, and dexamethasone (VRd) for approximately 12 to 18 months, followed by maintenance or observation. The main choices for initial therapy currently are VRd; bortezomib, cyclophosphamide, and dexamethasone (VCd); and bortezomib, thalidomide, and dexamethasone (VTd). Frail patients may be initially treated with lenalidomide plus low-dose dexamethasone (Rd) until progression. The lowercase “d’ is used as the abbreviation for dexamethasone in this chapter to highlight the fact that low-dose once weekly dexamethasone is the preferred dosing schedule in clinical practice. Although some clinical trials, used high dose pulsed dexamethasone, for the sake of consistency and to match clinical practice the lower case d is used as the abbreviation for dexamethasone regardless of the dosing schedule used.

Figure 101.7, (A) Algorithm for approach to the treatment of newly diagnosed myeloma in patients eligible for stem cell transplantation. (B) Approach to the treatment of newly diagnosed myeloma in patients not eligible for stem cell transplantation. ASCT, Autologous stem cell transplantation; KRd, carfilzomib, lenalidomide, and dexamethasone; VRd, bortezomib, lenalidomide, dexamethasone.

Bortezomib-lenalidomide-dexamethasone

VRd produces remarkably high overall response and CR rates in newly diagnosed multiple myeloma. In a randomized trial led by the Southwest Oncology Group, VRd was associated with a higher response rate and a greater depth of response compared with Rd. More important, progression-free survival (PFS) and OS were superior with VRd compared with Rd (median PFS, 43 months versus 30 months, respectively [ P = .0018]; median OS, 75 months versus 64 months, respectively [ P = .025]). Given the results of this trial, VRd is now considered the standard regimen for initial therapy in the United States except in frail patients, in whom Rd remains an option. Although this trial was performed in the non-transplant setting, the data are interpreted to also apply to pretransplant induction. VCd and VTd are alternatives to VRd in patients who lack access to lenalidomide and in patients with acute renal failure due to light chain cast nephropathy.

The risk of bortezomib-induced neuropathy with VRd and other bortezomib-containing regimens can be greatly decreased with use of a once-weekly schedule of bortezomib and the subcutaneous route of administration. Similarly, the toxicity of dexamethasone can be minimized with use of a lower dose schedule. A randomized trial by the Eastern Cooperative Oncology Group (ECOG) found that lenalidomide plus low-dose dexamethasone (40 mg of dexamethasone once a week) was superior to lenalidomide plus high-dose dexamethasone (40 mg of dexamethasone on days 1–4, 9–12, and 17–20) in terms of OS. Based on this trial, the use of high-dose dexamethasone is no longer recommended in newly diagnosed multiple myeloma, and almost all regimens in multiple myeloma use the once-weekly schedule of dexamethasone.

All patients treated with VRd (and other IMiD-containing regimens) require antithrombosis prophylaxis. Aspirin is adequate for most patients, but in patients who are at higher risk of thrombosis, either low-molecular-weight heparin or warfarin is needed. Stem cell collection with granulocyte colony-stimulating factor (G-CSF) alone may be impaired when lenalidomide is used as induction therapy. Therefore in patients older than 65 and those who have received more than four to six cycles of lenalidomide-based therapy, stem cells must be mobilized either with cyclophosphamide plus G-CSF or with plerixafor. Lenalidomide is an analogue of thalidomide and is considered a teratogen; all patients treated with lenalidomide need to follow strict precautions to prevent pregnancy.

Bortezomib-cyclophosphamide-dexamethasone

VCd (also commonly known as CyBord) has significant activity in newly diagnosed multiple myeloma. The randomized phase II EVOLUTION trial in newly diagnosed multiple myeloma showed that VCd is well tolerated and has similar activity compared with VRd. CR was achieved in 22% and 47% of patients treated with two different schedules of VCd, versus 24% of patients treated with VRd. Based on efficacy, ease of use, safety, and cost, VCd is an excellent choice in countries where lenalidomide is not available for frontline therapy, or in the presence of acute renal failure.

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