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Multiple myeloma represents a malignant proliferation of plasma cells derived from a single clone. The tumor, its products, and the host response to it result in a number of organ dysfunctions and symptoms, including bone pain or fracture, renal failure, susceptibility to infection, anemia, hypercalcemia, and occasionally clotting abnormalities, neurologic symptoms, and manifestations of hyperviscosity.
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The cause of myeloma is not known. Myeloma occurred with increased frequency in those exposed to the radiation of nuclear warheads in World War II after a 20-year latency. Myeloma has been seen more commonly than expected among farmers, wood workers, leather workers, and those exposed to petroleum products. A variety of chromosomal alterations have been found in patients with myeloma: hyperdiploidy, 13q14 deletions, translocations t(11;14)(q13;q32), t(4;14)(p16;q32), and t(14;16), and 17p13 deletions. Evidence is strong that errors in switch recombination—the genetic mechanism to change antibody heavy chain isotype—participate in the transformation process. However, no common molecular pathogenetic pathway has yet emerged. Genome sequencing studies have failed to identify any recurrent mutation with frequency >20%; N-ras, K-ras, and B-raf mutations are most common and combined occur in over 40% of patients. There is also evidence of complex clusters of subclonal variants at diagnosis that acquire additional mutations over time, indicative of genomic evolution that may drive disease progression. The neoplastic event in myeloma may involve cells earlier in B-cell differentiation than the plasma cell. Interleukin (IL) 6 may play a role in driving myeloma cell proliferation. It remains difficult to distinguish benign from malignant plasma cells based on morphologic criteria in all but a few cases (Fig. 18-3).
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INCIDENCE AND PREVALENCE
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An estimated 24,050 new cases of myeloma were diagnosed in 2014, and 11,090 people died from the disease in the United States. Myeloma increases in incidence with age. The median age at diagnosis is 70 years; it is uncommon under age 40. Males are more commonly affected than females, and blacks have nearly twice the incidence of whites. Myeloma accounts for 1.3% of all malignancies in whites and 2% in blacks, and 13% of all hematologic cancers in whites and 33% in blacks.
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GLOBAL CONSIDERATIONS
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The incidence of myeloma is highest in African Americans and Pacific Islanders; intermediate in Europeans and North American whites; and lowest in people from developing countries including Asia. The higher incidence in more developed countries may result from the combination of a longer life expectancy and more frequent medical surveillance. Incidence of multiple myeloma in other ethnic groups including native Hawaiians, female Hispanics, American Indians from New Mexico, and Alaskan natives is higher relative to U.S. whites in the same geographic area. Chinese and Japanese populations have a lower incidence than whites. Immunoproliferative small-intestinal disease with alpha heavy chain disease is most prevalent in the Mediterranean area. Despite these differences in prevalence, the characteristics, response to therapy, and prognosis of myeloma are similar worldwide.
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PATHOGENESIS AND CLINICAL MANIFESTATIONS
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Multiple myeloma (MM) cells bind via cell-surface adhesion molecules to bone marrow stromal cells (BMSCs) and extracellular matrix (ECM), which triggers MM cell growth, survival, drug resistance, and migration in the bone marrow milieu (Fig. 18-4). These effects are due both to direct MM cell–BMSC binding and to induction of various cytokines, including IL-6, insulin-like growth factor type I (IGF-I), vascular endothelial growth factor (VEGF), and stromal cell–derived growth factor (SDF)-1α. Growth, drug resistance, and migration are mediated via Ras/Raf/mitogen-activated protein kinase, PI3K/Akt, and protein kinase C signaling cascades, respectively.
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Bone pain is the most common symptom in myeloma, affecting nearly 70% of patients. Unlike the pain of metastatic carcinoma, which often is worse at night, the pain of myeloma is precipitated by movement. Persistent localized pain in a patient with myeloma usually signifies a pathologic fracture. The bone lesions of myeloma are caused by the proliferation of tumor cells, activation of osteoclasts that destroy bone, and suppression of osteoblasts that form new bone. The increased osteoclast activity is mediated by osteoclast activating factors (OAFs) made by the myeloma cells (OAF activity can be mediated by several cytokines, including IL-1, lymphotoxin, VEGF, receptor activator of NF-κB [RANK] ligand, macrophage inhibitory factor [MIP]-1α, and tumor necrosis factor [TNF]). The bone lesions are lytic in nature and are rarely associated with osteoblastic new bone formation due to their suppression by dickhoff-1 (DKK-1) produced by myeloma cells. Therefore, radioisotopic bone scanning is less useful in diagnosis than is plain radiography. The bony lysis results in substantial mobilization of calcium from bone, and serious acute and chronic complications of hypercalcemia may dominate the clinical picture (see below). Localized bone lesions may expand to the point that mass lesions may be palpated, especially on the skull (Fig. 18-5), clavicles, and sternum; and the collapse of vertebrae may lead to spinal cord compression. The next most common clinical problem in patients with myeloma is susceptibility to bacterial infections. The most common infections are pneumonias and pyelonephritis, and the most frequent pathogens are Streptococcus pneumoniae, Staphylococcus aureus, and Klebsiella pneumoniae in the lungs and Escherichia coli and other gram-negative organisms in the urinary tract. In ~25% of patients, recurrent infections are the presenting features, and >75% of patients will have a serious infection at some time in their course. The susceptibility to infection has several contributing causes. First, patients with myeloma have diffuse hypogammaglobulinemia if the M component is excluded. The hypogammaglobulinemia is related to both decreased production and increased destruction of normal antibodies. Moreover, some patients generate a population of circulating regulatory cells in response to their myeloma that can suppress normal antibody synthesis. In the case of IgG myeloma, normal IgG antibodies are broken down more rapidly than normal because the catabolic rate for IgG antibodies varies directly with the serum concentration. The large M component results in fractional catabolic rates of 8–16% instead of the normal 2%. These patients have very poor antibody responses, especially to polysaccharide antigens such as those on bacterial cell walls. Most measures of T-cell function in myeloma are normal, but a subset of CD4+ cells may be decreased. Granulocyte lysozyme content is low, and granulocyte migration is not as rapid as normal in patients with myeloma, probably the result of a tumor product. There are also a variety of abnormalities in complement functions in myeloma patients. All these factors contribute to the immune deficiency of these patients. Some commonly used therapeutic agents, e.g., dexamethasone, suppress immune responses and increase susceptibility to bacterial and fungal infection, and bortezomib predisposes to herpesvirus reactivation.
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Renal failure occurs in nearly 25% of myeloma patients, and some renal pathology is noted in more than 50%. Many factors contribute to this. Hypercalcemia is the most common cause of renal failure. Glomerular deposits of amyloid, hyperuricemia, recurrent infections, frequent use of nonsteroidal anti-inflammatory agents for pain control, use of iodinated contrast dye for imaging, bisphosphonate use, and occasional infiltration of the kidney by myeloma cells all may contribute to renal dysfunction. However, tubular damage associated with the excretion of light chains is almost always present. Normally, light chains are filtered, reabsorbed in the tubules, and catabolized. With the increase in the amount of light chains presented to the tubule, the tubular cells become overloaded with these proteins, and tubular damage results either directly from light chain toxic effects or indirectly from the release of intracellular lysosomal enzymes. The earliest manifestation of this tubular damage is the adult Fanconi’s syndrome (a type 2 proximal renal tubular acidosis), with loss of glucose and amino acids, as well as defects in the ability of the kidney to acidify and concentrate the urine. The proteinuria is not accompanied by hypertension, and the protein is nearly all light chains. Generally, very little albumin is in the urine because glomerular function is usually normal. When the glomeruli are involved, nonselective proteinuria is also observed. Patients with myeloma also have a decreased anion gap [i.e., Na+ – (Cl− + HCO3−)] because the M component is cationic, resulting in retention of chloride. This is often accompanied by hyponatremia that is felt to be artificial (pseudohyponatremia) because each volume of serum has less water as a result of the increased protein. Renal dysfunction due to light chain deposition disease, light chain cast nephropathy, and amyloidosis is partially reversible with effective therapy. Myeloma patients are susceptible to developing acute renal failure if they become dehydrated.
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Normocytic and normochromic anemia occurs in ~80% of myeloma patients. It is usually related to the replacement of normal marrow by expanding tumor cells, to the inhibition of hematopoiesis by factors made by the tumor, to reduced production of erythropoietin by the kidney, and to the effects of long-term therapy. In addition, mild hemolysis may contribute to the anemia. A larger than expected fraction of patients may have megaloblastic anemia due to either folate or vitamin B12 deficiency. Granulocytopenia and thrombocytopenia are rare except when therapy-induced. Clotting abnormalities may be seen due to the failure of antibody-coated platelets to function properly; the interaction of the M component with clotting factors I, II, V, VII, or VIII; antibody to clotting factors; or amyloid damage of endothelium. Deep venous thrombosis is also observed with use of thalidomide, lenalidomide, or pomalidomide in combination with dexamethasone. Raynaud’s phenomenon and impaired circulation may result if the M component forms cryoglobulins, and hyperviscosity syndromes may develop depending on the physical properties of the M component (most common with IgM, IgG3, and IgA paraproteins). Hyperviscosity is defined based on the relative viscosity of serum as compared with water. Normal relative serum viscosity is 1.8 (i.e., serum is normally almost twice as viscous as water). Symptoms of hyperviscosity occur at a level greater than 4 centipoise (cP), which is usually reached at paraprotein concentrations of ~40 g/L (4 g/dL) for IgM, 50 g/L (5 g/dL) for IgG3, and 70 g/L (7 g/dL) for IgA; however, depending on chemical and physical properties of the paraprotein molecule, it can occasionally be observed at lower levels.
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Although neurologic symptoms occur in a minority of patients, they may have many causes. Hypercalcemia may produce lethargy, weakness, depression, and confusion. Hyperviscosity may lead to headache, fatigue, shortness of breath, exacerbation or precipitation of heart failure, visual disturbances, ataxia, vertigo, retinopathy, somnolence, and coma. Bony damage and collapse may lead to cord compression, radicular pain, and loss of bowel and bladder control. Infiltration of peripheral nerves by amyloid can be a cause of carpal tunnel syndrome and other sensorimotor mono- and polyneuropathies. Neuropathy associated with monoclonal gammopathy of undetermined significance (MGUS) and myeloma is more frequently sensory than motor neuropathy and is associated with IgM more than other isotypes. In >50% of patients with neuropathy, the IgM monoclonal protein is directed against myelin-associated globulin (MAG). Sensory neuropathy is also a side effect of thalidomide and bortezomib therapy.
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Many of the clinical features of myeloma, e.g., cord compression, pathologic fractures, hyperviscosity, sepsis, and hypercalcemia, can present as medical emergencies. Despite the widespread distribution of plasma cells in the body, tumor expansion is dominantly within bone and bone marrow and, for reasons unknown, rarely causes enlargement of spleen, lymph nodes, or gut-associated lymphatic tissue.
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DIAGNOSIS AND STAGING
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The diagnosis of myeloma requires marrow plasmacytosis (>10%), a serum and/or urine M component, and end organ damage detailed in Table 18-1. Bone marrow plasma cells are CD138 and either monoclonal kappa or lambda light chain positive. The most important differential diagnosis in patients with myeloma involves their separation from individuals with MGUS or smoldering multiple myeloma (SMM). MGUS is vastly more common than myeloma, occurring in 1% of the population older than age 50 years and in up to 10% of individuals older than age 75 years. The diagnostic criteria for MGUS, SMM, and myeloma are described in Table 18-1. Although ~1% of patients per year with MGUS go on to develop myeloma, all myeloma is preceded by MGUS. Non-IgG subtype, abnormal kappa/lambda free light chain ratio, and serum M protein >15 g/L (1.5 g/dL) are associated with higher incidence of progression of MGUS to myeloma. Absence of all three features predicts a 5% chance of progression, whereas higher risk MGUS with the presence of all three features predicts a 60% chance of progression over 20 years. The features responsible for higher risk of progression from SMM to MM are bone marrow plasmacytosis >10%, abnormal kappa/lambda free light chain ratio, and serum M protein >30 g/L (3 g/dL). Patients with only one of these three features have a 25% chance of progression to MM in 5 years, whereas patients with high-risk SMM with all three features have a 76% chance of progression. There are two important variants of myeloma—solitary bone plasmacytoma and solitary extramedullary plasmacytoma. These lesions are associated with an M component in <30% of the cases, they may affect younger individuals, and both are associated with median survivals of ≥10 years. Solitary bone plasmacytoma is a single lytic bone lesion without marrow plasmacytosis. Extramedullary plasmacytomas usually involve the submucosal lymphoid tissue of the nasopharynx or paranasal sinuses without marrow plasmacytosis. Both tumors are highly responsive to local radiation therapy. If an M component is present, it should disappear after treatment. Solitary bone plasmacytomas may recur in other bony sites or evolve into myeloma. Extramedullary plasmacytomas rarely recur or progress.
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The clinical evaluation of patients with myeloma includes a careful physical examination searching for tender bones and masses. Chest and bone radiographs may reveal lytic lesions or diffuse osteopenia. Magnetic resonance imaging (MRI) offers a sensitive means to document extent of bone marrow infiltration and cord or root compression in patients with pain syndromes. A complete blood count with differential may reveal anemia. Erythrocyte sedimentation rate is elevated. Rare patients (~1%) may have plasma cell leukemia with >2000 plasma cells/μL. This may be seen in disproportionate frequency in IgD (12%) and IgE (25%) myelomas. Serum calcium, urea nitrogen, creatinine, and uric acid levels may be elevated. Protein electrophoresis and measurement of serum immunoglobulins and free light chains are useful for detecting and characterizing M spikes, supplemented by immunoelectrophoresis, which is especially sensitive for identifying low concentrations of M components not detectable by protein electrophoresis. A 24-h urine specimen is necessary to quantitate Bence Jones protein excretion. Serum alkaline phosphatase is usually normal even with extensive bone involvement because of the absence of osteoblastic activity. It is also important to quantitate serum β2-microglobulin and albumin (see below).
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The serum M component will be IgG in 53% of patients, IgA in 25%, and IgD in 1%; 20% of patients will have only light chains in serum and urine. Dipsticks for detecting proteinuria are not reliable at identifying light chains, and the heat test for detecting Bence Jones protein is falsely negative in ~50% of patients with light chain myeloma. Fewer than 1% of patients have no identifiable M component; these patients usually have light chain myeloma in which renal catabolism has made the light chains undetectable in the urine. In most of these patients, light chains can now be detected by serum free light chain assay. IgD myeloma may also present with light chain disease. About two-thirds of patients with serum M components also have urinary light chains. The light chain isotype may have an impact on survival. Patients secreting lambda light chains have a significantly shorter overall survival than those secreting kappa light chains. Whether this is due to some genetically important determinant of cell proliferation or because lambda light chains are more likely to cause renal damage and form amyloid than are kappa light chains is unclear. The heavy chain isotype may have an impact on patient management as well. About half of patients with IgM paraproteins develop hyperviscosity compared with only 2–4% of patients with IgA and IgG M components. Among IgG myelomas, it is the IgG3 subclass that has the highest tendency to form both concentration- and temperature-dependent aggregates, leading to hyperviscosity and cold agglutination at lower serum concentrations.
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Serum β2-microglobulin is the single most powerful predictor of survival and can substitute for staging. β2-Microglobulin is a protein of 11,000 mol wt with homologies to the constant region of immunoglobulins that is the light chain of the class I major histocompatibility antigens (HLA-A, -B, -C) on the surface of every cell. Patients with β2-microglobulin levels <0.004 g/L have a median survival of 43 months, and those with levels >0.004 g/L have a survival of only 12 months. Combination of serum β2-microglobulin and albumin levels forms the basis for a three-stage International Staging System (ISS) (Table 18-2) that predicts survival. With the use of high-dose therapy and the newer agents, the Durie-Salmon staging system is unable to predict outcome and thus is no longer used. High labeling index, circulating plasma cells, performance status, and high levels of lactate dehydrogenase are also associated with poor prognosis.
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Other factors that may influence prognosis are the presence of cytogenetic abnormalities and hypodiploidy by karyotype, fluorescent in situ hybridization (FISH)–identified chromosome 17p deletion, and translocations t(4;14), (14;16), and t(14;20). Chromosome 13q deletion, previously thought to predict poor outcome, is not a predictor following the use of newer agents. Microarray profiling and comparative genomic hybridization have formed the basis for RNA- and DNA-based prognostic staging systems, respectively. The ISS system, along with cytogenetic changes, is the most widely used method for assessing prognosis (Table 18-2).
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TREATMENT Multiple Myeloma
No specific intervention is indicated for patients with MGUS. Follow-up once a year or less frequently is adequate except in higher risk MGUS, where serum protein electrophoresis, complete blood count, creatinine, and calcium should be repeated every 6 months. A patient with MGUS and severe polyneuropathy is considered for therapeutic intervention if a causal relationship can be assumed, especially in absence of any other potential causes for neuropathy. Therapy can include plasmapheresis and occasionally rituximab in patients with IgM MGUS or myeloma-like therapy in those with IgG or IgA disease. About 10% of patients with myeloma are asymptomatic (SMM) and will have an indolent course demonstrating only very slow progression of disease over many years. For these patients, no specific therapeutic intervention is indicated, although early intervention with lenalidomide and dexamethasone may prevent progression from high-risk SMM to active MM. At present, patients with SMM only require antitumor therapy when the disease becomes symptomatic with development of anemia, hypercalcemia, progressive lytic bone lesions, renal dysfunction, or recurrent infections. Patients with solitary bone plasmacytomas and extramedullary plasmacytomas may be expected to enjoy prolonged disease-free survival after local radiation therapy at a dose of around 40 Gy. There is a low incidence of occult marrow involvement in patients with solitary bone plasmacytoma. Such patients are usually identified because their serum M component falls slowly or disappears initially, only to return after a few months. These patients respond well to systemic therapy.
Patients with symptomatic and/or progressive myeloma require therapeutic intervention. In general, such therapy is of two sorts: (1) systemic therapy to control the progression of myeloma and (2) symptomatic supportive care to prevent serious morbidity from the complications of the disease. Therapy can significantly prolong survival and improve the quality of life for myeloma patients.
The therapy of myeloma includes an initial induction regimen followed by consolidation and/or maintenance therapy and, on subsequent progression, management of relapsed disease. The therapy is partly dictated by the patient’s age and comorbidities, which may affect a patient’s ability to undergo high-dose therapy and transplantation.
Thalidomide (200 mg daily), when combined with dexamethasone, achieved responses in two-thirds of newly diagnosed MM patients. Subsequently, lenalidomide (25 mg/d on days 1–21 every 4 weeks), an immunomodulatory derivative of thalidomide, and bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11 every 3 weeks), a proteasome inhibitor, have each been combined with dexamethasone (40 mg once every week) and obtained high response rates (>80%) in newly diagnosed patients with MM. Importantly, their superior toxicity profile with improved efficacy has made them the preferred agents for induction therapy. Efforts to improve the fraction of patients responding and the degree of response have involved adding agents to the treatment regimen. The combination of lenalidomide, bortezomib, and dexamethasone achieves close to a 100% response rate and 30% complete response rate, making it one of the preferred induction regimens in transplant-eligible patients. Other similar three-drug combinations (bortezomib, thalidomide, and dexamethasone or bortezomib, cyclophosphamide, and dexamethasone) also achieve >90% response rate. Herpes zoster prophylaxis is indicated if bortezomib is used, and neuropathy attendant to bortezomib can be decreased both by its subcutaneous administration and administration on a weekly schedule. Lenalidomide use requires prophylaxis for deep vein thrombosis (DVT) with either aspirin or warfarin or low-molecular-weight heparin if patients are at a greater risk of DVT. In patients receiving lenalidomide, stem cells should be collected within 6 months, because the continued use of lenalidomide may compromise the ability to collect adequate numbers of stem cells. Initial therapy is continued until maximal cytoreduction. In patients who are transplant candidates, alkylating agents such as melphalan should be avoided because they damage stem cells, leading to decreased ability to collect stem cells for autologous transplant.
In patients who are not transplant candidates due to physiologic age >70 years, significant cardiopulmonary problems, or other comorbid illnesses, the same two- or three-drug combinations described above are considered standard of care as induction therapy. Previously, therapy consisting of intermittent pulses of melphalan, an alkylating agent, with prednisone (MP; melphalan, 0.25 mg/kg per day, and prednisone, 1 mg/kg per day for 4 days) every 4–6 weeks was used. However, a number of studies have combined novel agents with MP and reported superior response and survival outcomes. In patients >65 years old, combining thalidomide with MP (MPT) obtains higher response rates and overall survival compared with MP alone. Similarly, significantly improved response (71 vs 35%) and overall survival (3-year survival 72 vs 59%) were observed with the combination of bortezomib and MP compared with MP alone. Lenalidomide added to MP followed by lenalidomide maintenance also prolonged progression-free survival compared with MP alone. These combinations of novel agents with MP also achieve high complete response rates (MPT, ~15%; MP plus bortezomib, ~30%; MP plus lenalidomide, ~20%; and MP, ~2–4%). Although combinations of MP with newer agents are an alternative in these patients, most studies favor continuous therapy with non-MP-containing regimens (e.g., lenalidomide plus dexamethasone) due to longer term safety profile and efficacy.
Improvement in the serum M component may lag behind the symptomatic improvement. The fall in M component depends on the rate of tumor kill and the fractional catabolic rate of immunoglobulin, which in turn depends on the serum concentration (for IgG). Light chain excretion, with a functional half-life of ~6 h, may fall within the first week of treatment. Because urine light chain levels may relate to renal tubular function, they are not a reliable measure of tumor cell kill, especially in patients with renal dysfunction; however, improvements in serum free light chain measurement are often seen sooner. Although patients may not achieve complete remission, clinical responses may last for long periods of time.
High-dose therapy and consolidation/maintenance are standard practice in the majority of eligible patients. Randomized studies comparing standard-dose therapy to high-dose melphalan therapy (HDT) with hematopoietic stem cell support have shown that HDT can achieve high overall response rates, with up to 25–40% additional complete responses and prolonged progression-free and overall survival; however, few, if any, patients are cured. Although two successive HDTs (tandem transplantations) are more effective than single HDT, the benefit is only observed in the subset of patients who do not achieve a complete or very good partial response to the first transplantation, which is rare. Moreover, a randomized study failed to show any significant difference in overall survival between early transplantation after induction therapy versus delayed transplantation at relapse. These data allow an option to delay transplantation, especially with the availability of more agents and combinations. Allogeneic transplantations may also produce high response rates, but treatment-related mortality may be as high as 40%. Nonmyeloablative allogeneic transplantation can reduce toxicity but is recommended only under the auspices of a clinical trial to exploit an immune graft-versus-myeloma effect while avoiding attendant toxicity.
Maintenance therapy prolongs remissions following standard-dose regimens as well as HDT. Two phase 3 studies have demonstrated improved progression-free survival, and one study showed prolonged overall survival in patients receiving lenalidomide compared to placebo as maintenance therapy after HDT. In nontransplant candidates, another phase 3 study showed prolonged progression-free survival with lenalidomide maintenance after MP plus lenalidomide induction therapy. Although there is concern regarding an increased incidence of second primary malignancies in patients receiving lenalidomide maintenance, its benefits far outweigh the risk of progressive disease and death from myeloma. In patients with high-risk cytogenetics, lenalidomide and bortezomib have been combined and show promise as maintenance therapy after transplantation.
Relapsed myeloma can be treated with a number of agents including lenalidomide and/or bortezomib. These agents in combination with dexamethasone can achieve a partial response rate of up to 60% and a 10–15% complete response rate in patients with relapsed disease. The combination of bortezomib and liposomal doxorubicin is active in relapsed myeloma. Thalidomide, if not used as initial therapy, can achieve responses in refractory cases. The second-generation proteasome inhibitor carfilzomib and immunomodulatory agent pomalidomide have shown efficacy in relapsed and refractory MM, even MM refractory to lenalidomide and bortezomib. High-dose melphalan and stem cell transplantation, if not used earlier, also have activity as salvage therapy in patients with refractory disease.
The median overall survival of patients with myeloma is 7–8+ years, with subsets of younger patients surviving more than 10 years. The major causes of death are progressive myeloma, renal failure, sepsis, or therapy-related myelodysplasia. Nearly a quarter of patients die of myocardial infarction, chronic lung disease, diabetes, or stroke—all intercurrent illnesses related more to the age of the patient group than to the tumor.
Supportive care directed at the anticipated complications of the disease may be as important as primary antitumor therapy. Hypercalcemia generally responds well to bisphosphonates, glucocorticoid therapy, hydration, and natriuresis, and rarely requires calcitonin as well. Bisphosphonates (e.g., pamidronate 90 mg or zoledronate 4 mg once a month) reduce osteoclastic bone resorption and preserve performance status and quality of life, decrease bone-related complications, and may also have antitumor effects. Osteonecrosis of the jaw and renal dysfunction can occur in a minority of patients receiving aminobisphosphonate therapy. Treatments aimed at strengthening the skeleton such as fluorides, calcium, and vitamin D, with or without androgens, have been suggested, but are not of proven efficacy. Kyphoplasty or vertebroplasty should be considered in patients with painful collapsed vertebra. Iatrogenic worsening of renal function may be prevented by maintaining a high fluid intake to prevent dehydration and enhance excretion of light chains and calcium. In the event of acute renal failure, plasmapheresis is ~10 times more effective at clearing light chains than peritoneal dialysis; however, its role in reversing renal failure remains controversial. Importantly, reducing the protein load by effective antitumor therapy with agents such as bortezomib may result in improvement in renal function in over half of the patients. Use of lenalidomide in renal failure is possible but requires dose modification, because it is renally excreted. Urinary tract infections should be watched for and treated early. Plasmapheresis may be the treatment of choice for hyperviscosity syndromes. Although the pneumococcus is a dreaded pathogen in myeloma patients, pneumococcal polysaccharide vaccines may not elicit an antibody response. Prophylactic administration of intravenous γ globulin preparations is used in the setting of recurrent serious infections. Chronic oral antibiotic prophylaxis is not warranted. Patients developing neurologic symptoms in the lower extremities, severe localized back pain, or problems with bowel and bladder control may need emergency MRI and local radiation therapy and glucocorticoids if cord compression is identified. In patients in whom neurologic deficit is increasing or substantial, emergent surgical decompression may be necessary. Most bone lesions respond to analgesics and systemic therapy, but certain painful lesions may respond most promptly to localized radiation. The anemia associated with myeloma may respond to erythropoietin along with hematinics (iron, folate, cobalamin). The pathogenesis of the anemia should be established and specific therapy instituted, whenever possible.