Definition

Plasma cell disorders are a heterogeneous group of disorders characterized by a clonal population of hematopoietic B cells (plasma cells) that produce a monoclonal protein (M protein, or paraprotein). The clinical manifestations of these disorders result from the uncontrolled and progressive proliferation of a plasma cell clone, the effect of normal bone marrow replacement, and the overproduction of monoclonal proteins. Multiple myeloma is a plasma cell dyscrasia characterized by destructive lytic bone lesions, a plasma cell infiltrate in the bone marrow, and a monoclonal protein in the serum or urine. ¹²

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Incidence and risk factors

An estimated 16,000 patients were diagnosed with multiple myeloma in 2005, and about 11,300 patients died of their disease in the same year. Multiple myeloma is a disorder of older adults, with a median age at diagnosis of approximately 65 years. Males and African Americans have twice the incidence of multiple myeloma as females and whites, respectively. Specific genetic disorders and environmental exposures have not been clearly linked to the risk of multiple myeloma.

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Pathophysiology and natural history

Multiple myeloma is a neoplasm of malignant plasma cells phenotypically expressing CD38, CD56, and CD138. In addition, approximately 20% of malignant plasma cells express CD20. Overproduction of interleukin-6 (IL-6), an autocrine and paracrine plasma cell growth factor, is believed to be central to the pathogenesis of multiple myeloma. Alterations in other cytokines and signaling molecules such as tumor necrosis factor a (TNF-α), interleukin 1 (IL-1), vascular endothelial growth factor (VEGF), transforming growth factor b (TGF-β), and receptor activator of NF-kB (RANK) play key roles in the pathogenesis of multiple myeloma (Fig. 1). The interactions between malignant plasma cells and bone marrow stromal cells and osteoclasts are central to the pathogenesis and development of bone lesions and stimulation of bone marrow angiogenesis (Fig. 2). A number of cytogenetic abnormalities in the malignant plasma cell clone have been described. These include deletions of chromosome 13 (in about 30% of patients), chromosome 17 deletions, and translocations involving the immunoglobulin heavy chain. As a general rule, cytogenetic abnormalities presage an adverse outcome.

The natural history of multiple myeloma is one of progressive bone destruction, refractory cytopenias, and end-organ damage in the form of renal and cardiac dysfunction. Deficits in the humoral immune system, long-term corticosteroid therapy, and progressive leukopenia from bone marrow replacement place patients at increased risk for frequent infectious complications, usually with encapsulated microorganisms.

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Signs and symptoms

The clinical manifestations of multiple myeloma can be divided into three categories—plasma cell growth in bone marrow and skeletal disease, immunologic abnormalities, and effects of abnormal paraprotein.

Plasma Cell Growth in Bone Marrow and Skeletal Disease

The most common manifesting symptom of multiple myeloma is bone pain, usually involving the spine or chest. Although most back pain often results from bone marrow replacement, discrete lytic lesions, or vertebral compression fractures, spinal cord compression must always be considered and ruled out, especially when back pain is not well explained by routine x-rays. Diffuse osteoporosis is often noted radiographically. Characteristic lesions of multiple myeloma are lytic lesions (rounded, punched-out areas of bone) found most commonly in vertebral bodies, the skull, ribs, humerus, and femur (Fig. 3). Lytic lesions are not usually located in the distal extremities. Bone scans may not accurately reflect the destruction seen on radiographic films. Accordingly, skeletal surveys are used in the initial evaluation and follow-up of patients with multiple myeloma. Hypercalcemia in patients with multiple myeloma is secondary to bone turnover and is treated with bisphosphonate therapy, which is also useful for decreasing pain from lytic lesions and in skeleton-related events and may have an antimyeloma effect. ²⁰

Anemia is present in most patients at diagnosis and during follow-up. Anemia in multiple myeloma is multifactorial and is secondary to bone marrow replacement by malignant plasma cells, chronic inflammation, relative erythropoietin deficiency, and vitamin deficiency. Recombinant human erythropoietin is effective for the treatment of anemia in multiple myeloma. ¹⁵Mild neutropenia and mild thrombocytopenia are common, but severe cytopenias are uncommon at diagnosis. Plasma cell leukemia, a condition in which plasma cells comprise greater than 20% of peripheral leukocytes, is typically a terminal stage of multiple myeloma and is associated with short survival.

Immunologic Abnormalities

Commonly, patients exhibit a reciprocal decrease in normal immunoglobulin values in the presence of an elevated M protein level. Patients with myeloma often suffer from repeated infections, similar to those seen in patients with reduced levels of immunoglobulins. Long-term corticosteroid use and use of chemotherapeutic agents also predispose patients to infectious complications. Intravenous immunoglobulins have been used as prophylaxis for patients with repeated severe infections.

Effects of Abnormal Paraprotein

Increased serum viscosity is occasionally noted in patients with multiple myeloma. It is more frequently noted in patients with heavy chain immunoglobulin A. Hyperviscosity is more frequently noted in patients with Waldenström’s macroglobulinemia. High viscosity interferes with efficient blood circulation of the brain, kidneys, and extremities. Symptoms of hyperviscosity include headache, dizziness, vertigo, and severe ischemia.

Although peripheral neuropathy secondary to antibodies to myelin-associated glycoprotein (MAG) is occasionally noted in patients with multiple myeloma, it is more often the result of therapeutic agents (e.g., thalidomide, bortezomib, vincristine). Antibodies to factor X are occasionally present in patients with multiple myeloma and result in abnormal bleeding. Abnormal platelet aggregation and function are often noted on laboratory testing and may result in clinical bruising.

Renal dysfunction can have many causes in patients with multiple myeloma and is present in about 50% of patients at diagnosis. Hypercalcemia, concomitant medications (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs], intravenous contrast agents, aminoglycoside antibiotics), and intravascular volume depletion are all possible causes. In addition, cast nephropathy (so-called myeloma kidney), amyloidosis, and light chain deposition should be considered when immediately reversible causes are excluded. Therapy directed at the malignant plasma cell clone often treats the myeloma kidney as well. The role of plasma exchange remains controversial, despite a recent trial that showed no advantage for this approach. Proteinuria is present in 90% of patients with multiple myeloma, and abnormal light chains (Bence Jones protein) are found in 80% of patients.

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Diagnosis

Multiple myeloma should be suspected in older adults presenting with back pain, constitutional symptoms (sweats, weight loss), and elevated total protein levels. In addition, unexplained renal dysfunction, anemia, or pathologic fracture should prompt evaluation for this diagnosis.

Diagnostic criteria for multiple myeloma from the International Myeloma Workshop rely on a combination of criteria (Table 1).¹ Evidence of end-organ damage (hypercalcemia, renal insufficiency, anemia, lytic bone lesions) is required for the diagnosis of symptomatic multiple myeloma. These criteria diverge from historical diagnostic criteria, which relied on the monoclonal protein concentration and the amount of bone marrow plasma cell infiltrate. These changes stem from the observation that 40% of patients with multiple myeloma have a serum M protein level lower than 30 g/L. Similarly, 5% of patients with multiple myeloma have less than 10% bone marrow plasmacytosis. The difficulty of the present staging system rests in determining whether end-organ dysfunction is related to the monoclonal gammopathy. Often, this requires the exclusion of other causes of end-organ damage.

The differential diagnosis of a patient with a monoclonal protein includes monoclonal gammopathy of undetermined significance (MGUS), amyloidosis, and light chain deposition disease, solitary plasmacytomas of bone or extramedullary plasmacytoma, Waldenström’s macroglobulinemia, lymphoproliferative disorders (e.g., chronic lymphocytic leukemia) and rheumatologic autoimmune conditions. In addition, patients with metastatic carcinoma occasionally have a monoclonal gammopathy. The metastatic carcinoma is often well characterized when the monoclonal protein is iden-tified and a search for a metastatic carcinoma is usually not recommended.

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Staging

The staging evaluation of patients with multiple myeloma should include diagnostic tests as well as prognostic tests. Box 1 details the recommended staging work-up of patients with multiple myeloma. The Durie and Salmon staging system for multiple myeloma dates back to 1975 and, although still widely used, is cumbersome in clinical practice (Table 2).¹² The Southwest Oncology Group has proposed a different staging system for multiple myeloma that relies only on serum β₂-microglobulin and serum albumin levels (Table 3).¹³ In addition, the latter staging system affords excellent prognostication.

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Treatment

General Considerations and Supportive Care

Patients with multiple myeloma occasionally have associated complications that require immediate attention, including hypercalcemia, renal failure, and spinal cord compression. These complications should be promptly identified and managed before the institution of systemic therapy. Alternatively, patients with asymptomatic (smoldering) multiple myeloma may be followed without specific therapy until clear evidence of progression is noted. Ambulation and hydration should be maintained throughout the initial therapy. Avoidance of potentially nephrotoxic drugs (e.g., NSAIDs, aminoglycosides, IV contrast agent) is important for renal health.

Supportive care has also significantly evolved in the past few decades. Vertebroplasty and kyphoplasty have resulted in major improvement in regard to diminishing the pain of compression fractures. ¹¹ The use of bisphosphonates (pamidronate or zoledronic acid) is recommended for almost all myeloma patients with lytic lesions or significant osteoporosis and normal renal function. Bisphosphonate therapy has been shown to decrease the incidence of skeleton-related problems. ²⁰ In addition, bisphosphonate therapy has analgesic properties for pain related to lytic lesions and possibly antineoplastic properties, and is effective treatment for hypercalcemia in multiple myeloma patients. Immediate adverse effects of bisphosphonate therapy include flulike symptoms associated with the first infusion and renal dysfunction, which is in part related to the infusion rate. Long-term use of bisphosphonate therapy has been associated with osteonecrosis of the jaw. Baseline dental evaluation as well as prompt evaluation of jaw symptoms is recommended for patients receiving these agents. Radiation therapy for painful lytic lesions produces effective palliation of pain. Larger radiation fields are probably best avoided early in the course of the disease because they may impair bone marrow reserve and preclude subsequent therapies.

Granulocyte and erythropoietic growth factors are effective for the neutropenia and anemia of chemotherapy, respectively. In addition, recombinant human erythropoietin is effective for the treatment of anemia associated with relative erythropoietin deficiency.¹⁵ It has been shown to decrease transfusion requirement and possibly improve quality of life.

Patients with multiple myeloma are at increased risks for infectious complications. The use of intravenous immunoglobulins should be considered in the patient with decreased immunoglobulin levels and repeated bacterial infections. A dose of 0.4 g/kg is recommended on a monthly to tri-monthly basis.

Patients with plasma cell dyscrasias, and specifically multiple myeloma, have an increased risk of venous thromboembolic events. In addition, immunomodulatory drug therapy (thalidomide and lenalidomide) has also been associated with increased risk of thromboembolic events. Accordingly, particular attention to early mobilization and prophylaxis of thromboembolic events should be considered for patients undergoing surgical procedures or receiving immunomodulatory therapy. For the latter purpose, we recommend low-dose daily aspirin (81 mg) until completion of therapy.

Response Criteria

A number of response criteria have been used to assess the efficacy of therapy for multiple myeloma. Table 4describes the response criteria from the European Group for Blood and Marrow Transplantation (EBMT), which are widely used.⁷

Treatment for the Newly Diagnosed Patient

Induction Treatment

Although conventional therapy cannot cure multiple myeloma, it can effect a temporary remission. The past decade has witnessed the addition of a number of exciting novel therapeutic agents for relapsed and newly diagnosed myeloma. Because of recent advances, a standard first-line therapy has yet to be defined. Accordingly, the choice of first-line therapy is often guided by patient and disease characteristics. Clinical trial enrollment must be a consideration at all stages of therapy.

The combination of melphalan and prednisone has been historically used in that setting. It produces responses in approximately 50% of patients and a progression-free survival of approximately 15 months. A meta-analysis comparing combination chemotherapy with melphalan and prednisone has shown no statistically significant difference in survival, despite a higher response rate with more aggressive combination chemotherapy. Despite this finding, the combination of melphalan and prednisone was abandoned as induction therapy, because long-term therapy with alkylating agents compromises the ability to collect stem cells for high-dose therapy. Accordingly, dexamethasone-based chemotherapy is frequently used for induction, because it is believed to be safe for stem cell collection. The VAD regimen (infusional vincristine and doxorubicin combined with dexamethasone) results in a response rate of about 70% and does not compromise stem cell collection. Modifications of the VAD regimen have yielded the DVD regimen (pegylated liposomal doxorubicin, vincristine, and dexamethasone), which is given in an outpatient setting, and results in a similar response rate.¹⁹

Thalidomide, an oral immunomodulatory drug, is efficacious for patients with relapsed and refractory multiple myeloma. It has been combined with dexamethasone, and a recent clinical trial noted a higher response rate (70%) with that combination when compared with dexamethasone alone (50%). ¹⁷ However, the thalidomide-dexamethasone combination also results in a higher rate of adverse events, notably neuropathy, somnolence, and deep venous thrombosis. Although survival data are not mature, a survival benefit from the combination was not observed. The increased response rate in that setting must be weighed against increased side effects of the combination; treatment decisions must be individualized. Table 5presents chemotherapeutic regimens for multiple myeloma using these combination therapies. More recently, lenalidomide (a thalidomide analogue), and bortezomib (a proteasome inhibitor) are being evaluated in different combinations with chemotherapy, dexamethasone, or both.^16,18,19 Although the observed response rates of these combinations are exciting, survival information is as yet inconclusive for these combinations.

High-Dose Therapy and Autologous Peripheral Blood Stem Cell Transplantation

Autologous stem cell transplantation generally consists of a collection of the patient’s peripheral blood progenitor cells following stimulation by granulocyte colony-stimulating factor (G-CSF), with or without chemotherapy. The patient is then given high-dose chemotherapy (usually melphalan, 200 mg/m²) as the high-dose preparative regimen of choice. High-dose chemotherapy followed by autologous peripheral blood stem cell transplantation has been demonstrated to result in an increased complete response rate (40% to 50% compared with 3% to 5%) as well as event-free survival (28% versus 10% at 5 years) as compared with conventional chemotherapy.^2,3,4,9 In addition, a few randomized clinical trials have noted a prolonged overall survival with this approach. The more recent U.S. intergroup study (S9321) did not show a benefit of high-dose therapy (using melphalan and total body irradiation) when compared with standard therapy.⁴ Possible explanations for this finding include the inferiority of total body irradiation as a preparative regimen in multiple myeloma (when compared with high-dose melphalan), and the more intensive standard chemotherapy arm in this study, which consisted of VBMCP therapy (vincristine, carmustine, melphalan, cyclophosphamide, and prednisone in 5-week cycles) for 1 year. Patients randomized to standard therapy in this study had similar response rates as patients who received high-dose therapy, thus implying that a response achieved with either therapy has similar prognostic implications. The combinations of novel therapies in newly diagnosed patients often result in high responses rates, similar to those achieved with high-dose therapy.

Accordingly, the precise role of high-dose therapy in the era of novel agents with high response rates remains to be determined. In vitro purging of peripheral stem cells has not been demonstrated to result in superior outcomes and is not routinely recommended. Alternatively, in vivo purging of stem cell by induction chemotherapy before stem cell collection is believed to be beneficial.

Tandem Autologous Stem Cell Transplantation

The success of high-dose therapy followed by peripheral blood stem cell transplantation has prompted French investigators to evaluate tandem autologous stem cell transplantation. The landmark study included 399 patients with newly diagnosed multiple myeloma who underwent three or four cycles of VAD chemotherapy. Patients were subsequently randomized to receive a single autologous stem cell transplant with melphalan, 140 mg/m², and total body irradiation or a tandem autologous stem cell transplant; the first transplant consisted of melphalan, 140 mg/m², alone and the second consisted of melphalan, 140 mg/m², with total body irradiation.³ A complete response was observed in 42% of patients with a single transplant compared with 50% in the tandem transplant group. The 7-year event-free survival was 10% versus 20% (P = .03), favoring the tandem transplants. In addition, the 7-year overall survival was 21% versus 42% (P = .01), also favoring the tandem transplants.³ Treatment-related deaths were 4% versus 6% (P = .4), favoring the single transplant. A planned subgroup analysis has suggested that patients with suboptimal responses who have not achieved a good partial response are more likely to benefit from the second transplant. The Southwest Oncology Group is currently evaluating tandem high-dose therapy.

Allogeneic Stem Cell Transplantation

Despite single and tandem high-dose therapy, patients with multiple myeloma relapse. Some investigators have noted prolonged disease-free survival for patients who underwent allogeneic transplantation. A graft–versus–multiple myeloma effect is believed to confer benefits to this approach. Accordingly, the U.S. intergroup (S9321) study included an arm that evaluated allogeneic stem cell transplantation in multiple myeloma. In this study, after three or four cycles of induction therapy with VAD, 36 patients received an allogeneic transplant. The preparative regimen consisted of melphalan, 140 mg/m², and total body irradiation. The treatment-related mortality rate was 39% and the overall mortality 53%; this arm was stopped early on the recommendation of the data safety monitoring board. ⁴ However, at 7 years of follow-up, 22% of patients were disease free. Nonmyeloablative allogeneic transplantation has reduced the transplant-related mortality and is currently the subject of investigation. ⁴ In view of the high transplantation-related mortality, allogeneic transplantation should be considered for young patients in the context of a clinical trial.

Maintenance Treatment

Maintenance therapy following response after first-line therapy has been studied. A number of randomized clinical trials and a meta-analysis have shown a modest benefit to interferon alfa-2b maintenance therapy. Because of significant adverse events from interferon therapy, negative impact on quality of life, and only a modest benefit, this approach has been largely abandoned. Corticosteroid maintenance therapy (prednisone, 50 mg, every other day) has been shown to increase survival in one randomized study and pulsed dexamethasone maintenance therapy has been used by others, with promising results. ⁵ More recently, preliminary results of a randomized clinical trial conducted by the Intergroupe Français du Myelome (IFM) have suggested a role for thalidomide maintenance therapy.

Treatment for the Relapsed or Refractory Patient

Despite effective first-line therapy, all patients with multiple myeloma will experience a progression of their disease. A number of principles are inherent to the treatment of patients with relapsed or refractory multiple myeloma. In the event of progression after 12 months of completion of therapy, the use of the same therapy is likely to produce responses. Alternatively, a shorter time to progression or refractoriness to therapy implies a change in treatment. Table 5 lists commonly used therapeutic regimens, and Table 6 describes common adverse events of novel agents used for the management of multiple myeloma.

Other combinations of active agents have been reported to result in higher response rates but not in clearly improved outcomes. Clinical trial enrollment should be particularly emphasized in this setting. Novel agents, such as histone deacetylase inhibitors, mammalian target of rapamycin inhibitors (mTORi), RANK-L antibodies, and other immunomodulatory drugs (e.g., CC-4047 [Actimid]) are currently the subjects of ongoing investigations.

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Prognosis

Clinical, laboratory, and cytogenetic prognosticators have been identified. Adverse clinical prognosticators include advanced age, decreased performance status, and the presence of extramedullary plasmacytomas. Adverse laboratory prognostic variables in multiple myeloma include high serum β₂-microglobulin, high serum lactate dehydrogenase, low serum albumin, and high creatinine and C-reactive protein levels. In addition, high plasma cell labeling index is believed to indicate a poor outcome but this test is not routinely performed in all laboratories. Plasmablastic morphology has been associated with worse outcomes. Cytogenetic abnormalities by metaphase cytogenetics are identified in approximately 50% of multiple myeloma patients. The most frequent abnormalities include deletion of chromosomes 13 and 17, as well as immunoglobulin heavy chain rearrangement with the cyclin D1 and FGFR3 genes. Most cytogenetic abnormalities are associated with adverse outcomes in multiple myeloma.⁸

Summary

• In addition to multiple myeloma, plasma cell dyscrasias include monoclonal gammopathy of undetermined significance, smoldering myeloma, primary systemic amyloidosis, and Waldenström’s macroglobulinemia.
• Multiple myeloma is a plasma cell neoplasm characterized by a monoclonal gammopathy, bone marrow plasmacytosis, and end-organ damage.
• Cytogenetic determinations of bone marrow aspirates and serum β₂-microglobulin and albumin are important prognostic tools.
• Multidisciplinary treatment includes systemic therapy—chemotherapy, corticosteroids, and immunomodulatory agents—and the prevention and treatment of skeletal, renal, and infectious complications.

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