Bethesda Handbook of Clinical Oncology, 2nd Edition

Hematologic Malignancies

27

Multiple Myeloma

Sattva S. Neelapu*

Cynthia E. Dunbar†

*Department of Lymphoma and Myeloma, M.D. Anderson Cancer Center, University of Texas, Houston, Texas

†Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland

EPIDEMIOLOGY

  • In 2004, 15,270 new cases and 11,070 deaths from multiple myeloma (MM) were estimated in the United States.
  • The incidence rate of myeloma is 5.5 per 100,000 population per year in the United States. Incidence among African Americans is twice that in whites and three times that in Asians and Pacific Islanders.
  • The median age at diagnosis is 71 years.
  • An increased incidence of myeloma in atomic bomb survivors implicates excessive radiation as a risk factor, but there is little evidence to implicate other environmental causes. Familial clustering has been reported in some cases.

PATHOPHYSIOLOGY

MM is characterized by the proliferation and accumulation of clonal plasma cells. The involvement of B cells is somewhat controversial, but the extent of somatic mutation in the complementarity-determining regions (the antigen-binding portions) of the variable gene segment suggests that the proliferation of the clone is antigen driven at some point, although the identity of the antigen or antigens is unknown (seeFig. 27.1). Five recurrent translocations involving the heavy chain locus on chromosome 14 have been identified and are present in approximately 40% of all myeloma tumors. Deletion of chromosome 13q is also common and portends a very poor prognosis. The clinical features of MM are a result of bone marrow infiltration by the malignant clone; damage from high levels of immunoglobulins or free light chains in the circulation or glomeruli; the secretion of osteoclast-activating factors such as RANKL (receptor activator of NF-κB ligand) and MIP-1 (macrophage inflammatory protein-1) with resultant bone damage; decreased production of the natural RANKL inhibitor OPG (osteoprotegerin); and impaired immunity, both cell mediated and humoral.

FIG. 27.1. Differentiation of B lymphocytes and plasma cells. A pleiotropic stem cell gives rise to the pre–B cell that has acquired the capacity to synthesize heavy chains (µ). The immature B cell can synthesize light chains so that a complete immunoglobulin M (IgM) molecule is formed and expressed on the cell surface. Mature B cells express both IgM and IgD on their surfaces. These cells can either mature into IgM-secreting plasmacytoid lymphocytes or undergo a class switch to express IgG, IgA, or IgE on their surfaces. The latter cells can undergo terminal differentiation into IgG- or IgE-secreting plasma cells. (From Stamatovannopoulos G, Nienhuis AW, Leder P, et al., eds. The molecular basis of blood diseases. Philadelphia: WB Saunders, 1987, with permission.)

CLINICAL FEATURES

  • Bone pain is present in 80% of patients with MM, and 70% of the patients develop pathologic fractures during the course of their disease. Any patient with spontaneous fractures, severe persistent bone pain, or unexplained severe osteoporosis should be evaluated for myeloma.

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  • Other common clinical features include fatigue, normocytic normochromic anemia, and hypercalcemia (20%).
  • Renal insufficiency is seen in at least 25% of patients at diagnosis and may be caused by hypercalcemia and related dehydration, light chain deposition in the tubules or glomeruli, or amyloid deposition. In some patients, amyloidosis can cause a nephrotic syndrome (<5%). Acquired Fanconi syndrome with glycosuria, phosphaturia, and aminoaciduria can occur.
  • Infections are an important cause of morbidity and mortality in patients with MM.
  • Hyperviscosity symptoms are rare except with immunoglobulin (Ig)A and IgG3 subtypes.

DIAGNOSIS

  • Minimal criteria for the diagnosis of MM include:
  1. Bone marrow containing more than 10% plasma cells or histologic proof of a plasmacytoma along with the following criteria.
  2. An M protein in the serum (>3g per dL) or M protein in the urine or lytic bone lesions.
  • An incidental detection of a serum M protein level of <3 g per dL in an asymptomatic patient with less than 10% bone marrow plasma cells and no other features of MM suggests the diagnosis of monoclonal gammopathy of undetermined significance(MGUS).

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  • In the asymptomatic patient, if the spike in serum M protein is >3 g per dL and if there are more than 10% bone marrow plasma cells but no other features of MM, smoldering multiple myeloma (SMM)is indicated.
  • The diagnostic and staging work-up of MM should include a complete blood count with differential; levels of serum electrolytes, blood urea nitrogen, serum creatinine, calcium, phosphate, magnesium, uric acid, β2-microglobulin, and lactate dehydrogenase; serum protein electrophoresis (SPEP) and immunofixation; 24-hour urine protein electrophoresis (UPEP) and immunofixation; quantitative immunoglobulins; 24-hour urine for Bence Jones reaction; at least a unilateral bone marrow aspirate and biopsy; and a radiographic skeletal survey. A nuclear medicine bone scan is not indicated because lytic lesions are not visualized on bone scans. Any patient with significant back pain should undergo a magnetic resonance imaging (MRI) of the spine to evaluate cord compression.
  • An SPEP alone is inadequate because some myeloma clones secrete only light chains, which are rapidly cleared from the plasma to the urine (see Fig. 27.2).
  • The circulating monoclonal protein is IgG in 50% of cases, IgA in 20%, light chain only (Bence Jones proteinemia) in 20%, IgD in 2%, and biclonal in 1%.

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  • Because bone marrow involvement may be focal rather than diffuse, repeated bone marrow sampling may be needed before diagnostic infiltrates of more than 10% plasma cells are identified.
  • Radiologic changes include punched-out lytic lesions, osteoporosis, and fractures.

FIG. 27.2. Electrophoretic pattern of (A) normal human serum, (B) hypergammaglobulinemia, and (C) immunoglobulin G (IgG) multiple myeloma. (From Lee GR, Bithell TC, Foerster J, et al., eds. Wintrobe's clinical hematology. Philadelphia: Lea & Febiger, 1993, with permission.)

STAGING

The Durie–Salmon staging system for multiple myeloma is shown in Table 27.1.

TABLE 27.1. Durie–Salmon (1) Staging System for Multiple Myeloma

Stage

Criteria

Myeloma cell mass (× 1012 cells/m2)

I

All of the following:

<0.6 (low)

Hemoglobin >10 g/dL

Serum calcium level ≤12 mg/dL (normal)

Normal bone or solitary plasmacytoma on x-ray

Low M-component production rate:
IgG <5 g/dL
IgA <3 g/dL
Bence Jones protein <4 g/24 h

II

Not fitting stage I or III

0.6–1.2 (intermediate)

III

One or more of the following:

>1.2 (high)

Hemoglobin <8.5 g/dL

Serum calcium level >12 mg/dL

Multiple lytic bone lesions on x-ray

High M-component production rate:
IgG >7 g/dL
IgA >5 g/dL
Bence Jones protein >12 g/24 h

Subclassification

A: Serum creatinine <2 mg/dL

B: Serum creatinine >2 mg/dL

PROGNOSIS

  • The β2-microglobulin level at diagnosis is the best single simple prognostic factor available for all patients with multiple myeloma. High levels of β2-microglobulin predict poor prognosis.
  • A high plasma-cell–labeling index also strongly predicts poor prognosis, but this test is not commonly available.
  • Abnormalities in chromosome 13 detected by cytogenetic analysis predict poor outcome even with autologous or allogeneic transplantation.
  • Median survival is less than 1 year in untreated patients and is 2 to 3 years with standard melphalan and prednisone (MP) regimen. More recent studies on unselected patients using autologous transplantation for those patients younger than 60 with good organ function and standard chemotherapy for other patients indicate that median survival has increased to 4 years or more for both groups.

TREATMENT

  • MGUS:Patients with MGUS are monitored indefinitely without treatment because 20% to 25% of them will eventually progress to myeloma at a rate of approximately 1% per year.

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Checking serum or UPEP every 6 months along with watchful waiting for other symptoms is appropriate. Early intervention studies to date have shown no benefit for thalidomide or steroids.

  • SMM or stage I MM:These patients can also be observed closely without therapy. Treatment is indicated when there is evidence of disease progression to stage II or higher stage MM (median time to progression is 2 years for SMM).
  • Solitary plasmacytoma:These patients are treated with radiation therapy (solitary bone) and/or surgical removal (extraosseous plasmacytomas) of the affected area, followed by close monitoring of M protein because of the risk of overt MM.
  • Multiple myeloma:To date, there is no clear curative therapy available for most MM patients. Patients may achieve a plateau phase with therapy, characterized by a stable M protein level and persistent bone marrow plasma cells, but by an absence of symptoms. The goal of standard therapy is to improve quality of life and to delay disease progression. With these objectives in mind, the choice of therapy (i.e., What intensity of therapy? When to start?) is guided by consideration of symptoms, prognosis, age, and performance status (see Fig. 27.3). Eligible patients should always be considered for enrollment in clinical trials that evaluate novel treatment strategies. The proposed criteria given by the European Group for Blood and Marrow Transplantation (EBMT) for evaluating disease response and progression in myeloma patients are outlined in Table 27.2 (2).

TABLE 27.2. Criteria for Evaluating Response, Relapse, and Progression in Myeloma Patients (1)

Criteria

Complete response (CR)

Partial response (PR)

Minimal response (MR)

Relapse from CR

Progressive disease for patients not in CR

From Blade J, Samson D, Reece D et al., European Group for Blood and Marrow Transplantation. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma subcommittee of the EBMT. Br J Haematol 1998;102(5):1115–1123, with permission.

Serum M protein

Absent by immunofixation for 6 wk

≥50% Decrease for 6 wk

25%–49% Decrease for 6 wk

Reappearance by immunofixation or electrophoresis

>25% increase and absolute increase of ≥ 0.5 g/dL

Urinary M protein

Absent by immunofixation for 6 wk

≥90% Decrease in 24 h excretion or <200 mg/24 h for 6 wk

50%–89% Decrease in 24 h excretion for 6 wk

Reappearance by immunofixation or electrophoresis

>25% increase in 24 h excretion and absolute increase of ≥ 200 mg/24 h

Bone marrow plasma cells in aspirate and biopsy, if biopsy is performed

<5%

≥50% Decrease for nonsecretory myeloma for 6 wk

25%–49% Decrease for nonsecretory myeloma for 6 wk

≥5%

>25% increase and absolute increase of ≥10%

Lytic bone lesions

No change in size or number

No change in size or number

No change in size or number

Increase in size of bone lesions or new lytic lesions

Increase in size of bone lesions or new lytic lesions

Soft tissue plasmacytoma

Absent

≥50% Decrease

25%–49% Decrease

New soft tissue plasmacytoma

New soft tissue plasmacytoma

Hypercalcemia

N/A

N/A

N/A

Corrected serum calcium level >11.5 mg/dL

Corrected serum calcium level >11.5 mg/dL

FIG. 27.3. A suggested treatment algorithm. All patients should receive supportive care and must be considered for bisphosphonate treatment and clinical trials.

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Initial Therapies

  • Cycles of pulse oral melphalan and prednisone(MP) have been the standard treatment regimen for MM for many decades and may still be appropriate for patients for whom high-dose chemotherapy and autologous stem cell transplantation (HDC/auto SCT) are not being considered because of poor performance status or because the patients are older than 65 to 70 years (see Table 27.3) (3). MP should only be given for three to six cycles and should be discontinued once a plateau in the M protein level is reached in responding patients or after two cycles without response in nonresponding patients. More than six cycles of MP are associated with an increased risk of secondary myelodysplasia (MDS) or acute myelogenous leukemia (AML), the risk approaching 20% to 30% after 24 months of MP.
  • Aggressive combination chemotherapyregimens containing vincristine, carmustine, melphalan, cyclophosphamide, and prednisone have somewhat higher initial response rates but offer no significant survival benefit compared to MP (4,5,8). At present, there are no indications for these regimens.
  • Three to four cycles of infusional therapy with vincristine, doxorubicin, and dexamethasone (VAD)is commonly used as an induction regimen prior to autologous SCT because of the absence of myelotoxic agents (alkylating agents and nitrosoureas) in this combination (7). Response to VAD is more rapid than the response to MP, therefore it is also indicated in any patient with ongoing serious organ dysfunction due to high levels of paraprotein while instituting the therapy. Only two to three cycles are generally needed to reach a plateau.
  • Dexamethasone accounts for almost 85% of the activity of VAD, and high dose pulse dexamethasone alonehas been shown to induce an overall response rate of 43% in previously untreated myeloma patients (6). For this reason and because of reduced toxicity, high-dose pulse dexamethasone alone is a good alternative for VAD for pretransplantation induction therapy, especially in patients with very poor marrow function due to marrow replacement by tumor or in those patients receiving concurrent radiation therapy for a pathologic fracture.
  • The addition of thalidomide, bortezomib, or other newer agentsto initial treatment regimens is under investigation, but at present, no mature data are available on the efficacy of these agents in prolonging time to progression or survival. Thalidomide can be used alone or in combination with other initial therapies such as dexamethasone or VAD without detriment in terms of collecting adequate stem cells for autologous transplantation. Thalidomide in combination with dexamethasone as initial therapy for myeloma has been shown to yield a response rate of 64% (13).
  • Interferon-αhas been evaluated in many randomized trials either in combination with induction chemotherapy or as remission maintenance therapy following conventional chemotherapy (CC) in MM patients. Some of these trials have suggested benefit, whereas others have indicated no benefit. Meta-analyses of the randomized trials suggest small but significant improvement in the progression-free survival (PFS) as well as in overall survival, both when used in combination with induction chemotherapy and when given as remission maintenance therapy (20,21). However, these small benefits must be balanced against high treatment-related toxicity and cost.
  • Two large randomized trials [InterGroupe Francophone du Myelome 90 IFM 90) trial and the Medical Research Council Myeloma VII Trial] demonstrated that (high-dose therapy(HDT) followed by autologous SCT significantly improves response rate and survival compared to CC in myeloma patients younger than 65 years with good performance status (see Table 27.4) (14,15). The IFM 95 randomized trial demonstrated that 200 mg per m2 of melphalan is less toxic and at least as effective a conditioning regimen as total body irradiation of 8 Gy with 140 mg per m2 melphalan before autologous SCT (22). Although SCT is commonly performed following three to four cycles of induction chemotherapy, a randomized trial comparing early versus late transplantation demonstrated that SCT can be delayed until relapse without compromising survival provided that the stem cells are harvested and cryopreserved early in the disease course. Therefore, the timing of SCT is based on patient preference and other clinical conditions (23).

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  • The recently published IFM 94 trial established that double transplantationis superior to single autologous transplantation and should be considered as a treatment option, especially for patients younger than 60 years who do not have a very good partial response (defined as greater than 90% reduction in serum M protein level) after single transplantation (see Table 27.5) (24).
  • Allogeneic transplantationmay potentially benefit a small percentage of patients because of a powerful graft versus myeloma effect. However, myeloablative allotransplants were associated with high treatment-related mortality (TRM) of up to 50% because of severe graft versus host disease, opportunistic infections, and complications resulting from a second aggressive conditioning regimen in patients already surviving and relapsing following autologous transplantation.
  • The recent experience with nonmyeloablative allogeneic transplantationsuggests that the TRM could be reduced to less than 10% to 20%, but this strategy should currently be considered investigational (25). Nevertheless, up to 50% of patients relapse following allogeneic transplantation; therefore, at present, this option is far from ideal for most patients.
  • The benefit of posttransplantation maintenance therapywith agents such as interferon-α, prednisone, and thalidomide has not been established and therefore should be used only in the context of a clinical trial.
  • Bisphosphonateshave become part of the standard armamentarium against MM and are generally thought to be beneficial in all patients with myeloma; however, randomized trials showing benefit in morbidity and time to progression exist only for patients with advanced myeloma and bone disease. Intravenous pamidronate given monthly reduced bone pain and the incidence of pathologic fractures and the need for surgery or irradiation to the bone in patients with Durie–Salmon stage III myeloma (17). A recent randomized trial demonstrated that zoledronic acid is safe and is as effective as pamidronate in reducing skeletal complications, in addition to having the advantage of a shorter administration time (18,19). The beneficial effects of the bisphosphonates may be a result of their effects on bone resorption as well as the direct antitumor effects and/or immune stimulation.

TABLE 27.3. Chemotherapy Regimens in Multiple Myeloma

Regimen

Treatment description

Cycle duration

Response rate

Reference

SCT, stem cell transplantation; HDT, high dose therapy.

MP

Melphalan 10 mg/m2/d PO d 1–4 (total dose/cycle = 40 mg/m2)

4–6 wk

53% in untreated patients

3,4,5

Prednisone 60 mg/m2/d PO d 1–4 (total dose/cycle = 240 mg/m2)

Pulse dexamethasone

Dexamethasone 40 mg/d PO d 1–4, 9–12, and 17–20 for odd cycles and d 1–4 for even cycles (total dose/cycle = 480 mg for odd cycles and 160 mg for even cycles)

28 d

43% in untreated patients

6

VAD

Vincristine 0.4 mg/m2/d continuous i.v. infusion d 1–4 (total dose/cycle = 1.6 mg/m2)

21 d

55%–84% in untreated patients

7

Doxorubicin 9 mg/m2/d continuous i.v. infusion d 1–4 (total dose/cycle = 36 mg/m2)

Dexamethasone 40 mg/d PO d 1–4, 9–12, and 17–20 for odd cycles and d 1–4 for even cycles (total dose/cycle = 480 mg for odd cycles and 160 mg for even cycles)

VMCP alternates with VBAP every 3 wk

Vincristine 1 mg/m2 i.v. d 1 (total dose/cycle = 1 mg/m2)

21 d

60% in untreated patients

4,5,8

Melphalan 6 mg/m2/d PO d 1–4 (total dose/cycle = 24 mg/m2)

Cyclophosphamide 125 mg/m2/d PO d 1–4 (total dose/cycle = 500 mg/m2)

Prednisone 60 mg/m2/d PO d 1–4 (total dose/cycle = 240 mg/m2)

VBAP

Vincristine 1 mg/m2 i.v. d 1 (total dose/cycle = 1 mg/m2)

21 d

60% in untreated patients

4,5,8

Carmustine (BCNU) 30 mg/m2 i.v. d 1 (total dose/cycle = 30 mg/m2)

Doxorubicin 30 mg/m2 i.v. d 1 (total dose/cycle = 30 mg/m2)

Prednisone 100 mg/d PO d 1–4 (total dose/cycle = 400 mg)

DCEP

Dexamethasone 40 mg/d PO d 1–4 (total dose/cycle = 160 mg)

4–6 wk

41% in refractory patients

9,10

Cyclophosphamide 400 mg/m2/d continuous i.v. infusion d 1–4 (total dose/cycle = 1,600 mg/m2)

Etoposide 40 mg/m2/d continuous i.v. infusion d 1–4 (total dose/cycle = 160 mg/m2)

Cisplatin 10 mg/m2/d continuous i.v. infusion d 1–4 (total dose/cycle = 40 mg/m2)

DTPACE

Dexamethasone 40 mg/d PO d 1–4 (total dose/cycle = 160 mg)

4–6 wk

40% in refractory patients

11

Thalidomide 400 mg/d PO daily at bedtime (continuous)

Cisplatin 10 mg/m2/d continuous i.v. infusion d 1–4 (total dose/cycle = 40 mg/m2)

Doxorubicin 10 mg/m2/d continuous i.v. infusion d 1–4 (total dose/cycle = 40 mg/m2)

Cyclophosphamide 400 mg/m2/d continuous i.v. infusion d 1–4 (total dose/cycle = 1,600 mg/m2)

Etoposide 40 mg/m2/d continuous i.v. infusion d 1–4 (total dose/cycle = 160 mg/m2)

Thalidomide

Thalidomide Start at 200 mg/d PO daily at bedtime for 2 wk; increase dose by 200 mg every 2 wk to a maximum of 800 mg/d

Continuous

32% in refractory patients

12

Thalidomide + dexamethasone

Dexamethasone 40 mg/d PO d 1–4, 9–12, and 17–20 for odd cycles and d 1–4 for even cycles

28 d

64% in untreated patients

13

Thalidomide 200 mg/d PO daily at bedtime

Bortezomib

Bortezomib 1.3 mg/m2/d i.v. on d 1, 4, 8, and 11 (total dose/cycle = 5.2 mg/m2)

21 d

35% in refractory patients

14

Dexamethasone 20 mg/d PO on d 1, 2, 4, 5, 8, 9, 11, and 12 may be added for patients with suboptimal response

HDT + AutoSCT

Conditioning regimen:

N/A

>80% in untreated patients

15,16

Melphalan 200 mg/m2 i.v. infusion over 30 min on d 2 (total dose/cycle = 200 mg/m2)

PBSC transplantation on day 0

Pamidronate

Pamidronate 90 mg i.v. infusion over 2 h (total dose/cycle = 90 mg)

Monthly

N/A

17

Zoledronic acid

Zoledronic acid 4 mg i.v. infusion over 15 min (total dose/cycle = 4 mg)

Monthly

N/A

18,19

TABLE 27.4. Conventional Chemotherapy (CC) Versus High-dose Therapy (HDT) Followed by Autologous Stem Cell Transplantation (SCT)

Treatment

OR (CR + PR)

CR

Median overall survival

Median event-free survival

OR, overall response; CR, complete response; PR, partial response; IFM, InterGroupe Francophone du Myelome; CC, conventional chemotherapy; HDT, high-dose therapy; EFS, event-free survival; MRC, Medical Research Council; PFS, progression free survival.

IFM 90 Trial (CC vs. HDT) (14)

57% vs. 81%

5% vs. 22%

44 vs. 57 mo

18 vs. 28 mo (EFS)

MRC7 Trial (CC vs. HDT) (15)

48% vs. 86%

8% vs. 44%

42 vs. 54 mo

20 vs. 32 mo (PFS)

TABLE 27.5. Single Versus Double Autologous Stem Cell Transplantation (SCT) [InterGroupe Francophone du Myelome (IFM) 95 Trial] (23)

Treatment

OR (CR + PR) (%)

CR + very good PR (%)

Median overall survival (mo)

Median event-free survival (mo)

Treatment-related mortality

OR, overall response; CR, complete response; PR, partial response; SCT, stem cell transplantation.

Single autoSCT

84

42

48

25

4%

Double autoSCT

88

50

58

30

6%

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SUPPORTIVE MEASURES

  • Supportive measures in myeloma include adequate analgesia and/or local irradiation for bone pain, radiation or surgery for spinal cord compression, surgery for impending pathologic fractures, erythropoietin for anemia, treatment and prevention of hypercalcemia, avoidance of dehydration by a high fluid intake of around 3 L per day to maintain renal function, and dialysis if necessary. Intravenous immunoglobulin therapy may be beneficial for patients with recurrent life-threatening infections.

REFRACTORY OR RELAPSED DISEASE

  • In a patient who progresses during MP or other initial therapy (refractory disease) or who relapses within 6 months of stopping induction therapy, VADor high-dose pulse dexamethasone is a suitable second-line regimen (7,26). Other salvage regimens that have shown efficacy include DCEP and DTPACE (9,10,11).
  • In a treatment-refractory patient with significant cytopenias, pulse dexamethasonealone can be considered (26).
  • Oral thalidomideat doses of 200 to 800 mg per day has been reported to produce a decrease in myeloma protein in patients who are refractory to other therapies, including HDC (12). The overall response rate to thalidomide as a single agent in this group of patients was 32%. Thalidomide is not marrow suppressive; thus it can be used in patients with poor marrow function following transplantation or in combination with chemotherapy or irradiation. Side effects are rarely dangerous, but severe fatigue and neuropathies limit dose intensification. Thalidomide analogs with fewer side effects are under development.
  • Recently, bortezomib(formerly known as PS-341), a member of a new class of anticancer drugs called proteasome inhibitors, has been shown to induce response rates of 35% in myeloma patients refractory to multiple lines of standard and high-dose regimens (including thalidomide) (14). Combinations of bortezomib with chemotherapy agents and/or thalidomide are currently being evaluated in clinical trials.

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