Multiple Myeloma

Multiple myeloma (MM) is a debilitating malignancy that is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to plasma cell leukemia. First described in 1848, MM is characterized by a proliferation of malignant plasma cells and a subsequent overabundance of monoclonal paraprotein (M protein).

Signs and symptomsThe presentation of MM can range from asymptomatic to severely symptomatic, with

complications requiring emergent treatment. Systemic ailments include bleeding, infection, and renal failure; pathologic fractures and spinal cord compression may occur.

Presenting symptoms of MM include the following:

Bone pain Pathologic fractures Weakness, malaise Bleeding, anemia Infection (often pneumococcal) Hypercalcemia Spinal cord compression Renal failure Neuropathies

DiagnosisMM is often discovered through routine blood screening when patients are being evaluated for

unrelated problems. In one third of patients, the condition is diagnosed after a pathologic fracture occurs, usually involving the axial skeleton.

Examination for MM may reveal the following:

HEENT examination: Exudative macular detachment, retinal hemorrhage, or cotton-wool spots Dermatologic evaluation: Pallor from anemia, ecchymoses or purpura from thrombocytopenia;

extramedullary plasmacytomas (most commonly in aerodigestive tract but also orbital, ear canal, cutaneous, gastric, rectal, prostatic, retroperitoneal areas)

Musculoskeletal examination: Bony tenderness or pain without tenderness Neurologic assessment: Sensory level change (ie, loss of sensation below a dermatome

corresponding to a spinal cord compression), neuropathy, myopathy, positive Tinel sign, or positive Phalen signAbdominal examination: Hepatosplenomegaly Cardiovascular evaluation: Cardiomegaly

In patients with multiple myeloma and amyloidosis, the characteristic examination findings include the following:

Shoulder pad sign Macroglossia Typical skin lesions Postprotoscopic peripalpebral purpura Carpal tunnel syndrome Subcutaneous nodules

Testing

The 2009 International Myeloma Workshop guidelines for standard investigative workup in patients with suspected MM include the following[1] :

Serum and urine assessment for monoclonal protein (densitometer tracing and nephelometric quantitation; immunofixation for confirmation)

Serum free light chain assay (in all patients with newly diagnosed plasma cell dyscrasias) Bone marrow aspiration and/or biopsy Serum beta2-microglobulin, albumin, and lactate dehydrogenase measurement Standard metaphase cytogenetics Fluorescence in situ hybridization Skeletal survey MRI

Routine laboratory tests include the following:

Complete blood count and differential Erythrocyte sedimentation rate Comprehensive metabolic panel (eg, levels of total protein, albumin and globulin, BUN, creatinine, uric

acid) 24-hour urine collection for quantification of the Bence Jones protein (ie, lambda light chains), protein,

and creatinine clearance; proteinuria greater than 1 g of protein in 24 hours is a major criterion C-reactive protein Serum viscosity in patients with CNS symptoms, nosebleeds, or very high M protein levels

The 2011 National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines on Oncology, Multiple Myeloma Version recommend the use of serum free light chain assay as well as fluorescence in situ hybridization (FISH) for 1q21 amplification as part of the initial diagnostic workup. [2]

Imaging studies

Simple radiography for the evaluation of skeleton lesions; skeletal survey, including the skull, long bones, and spine

MRI for detecting thoracic and lumbar spine lesions, paraspinal involvement, and early cord compression

PET scanning in conjunction with MRI potentially useful

ManagementThere is currently no cure for MM. However, advances in therapy have helped to lessen the

occurrence and severity of adverse effects of this disease, such as autologous stem cell transplantation, radiation, and surgical care in certain cases, as well as manage any associated complications. [3, 4, 5]

Chemotherapy and immunosuppression

Several drug therapies are valuable in the treatment of symptomatic MM. Clinicians treat many patients with high-dose therapy and peripheral blood or bone marrow stem cell transplantation.

Chemotherapy regimens used in patients with MM include the following:

Thalidomide, either as a single agent or in combination with steroids or with melphalan Lenalidomide plus dexamethasone Bortezomib plus melphalan VAD (vincristine, doxorubicin [Adriamycin], and dexamethasone) Melphalan plus prednisone

The 2011 NCCN guidelines for MM added the following therapies[2] :

The combination of bortezomib/cyclophosphamide/dexamethasone as primary induction therapy for transplant candidates

The combination of bortezomib/dexamethasone (without cyclophosphamide) as primary induction therapy for patients who are not candidates for transplantation

The combination of melphalan/prednisone/lenalidomide for primary induction therapy for nontransplant candidates

Patients with refractory disease or relapse may be treated with the following:

Any of the agents not previously used Bortezomib plus cyclophosphamide and dexamethasone[2, 6]

Carfilzomib (Kyprolis) Thalidomide Lenalidomide plus cyclophosphamide and dexamethasone[2]

Pomalidomide[7, 8]

BackgroundMultiple myeloma (MM) is a debilitating malignancy that is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to plasma cell leukemia. First described in 1848, MM is characterized by a proliferation of malignant plasma cells and a subsequent overabundance of monoclonal paraprotein (M protein). An intriguing feature of MM is that the antibody-forming cells (ie, plasma cells) are malignant and, therefore, may cause unusual manifestations.

The proliferation of plasma cells in MM may interfere with the normal production of blood cells, resulting in leukopenia, anemia, and thrombocytopenia. The cells may cause soft-tissue masses (plasmacytomas) or lytic lesions in the skeleton. Feared complications of MM are bone pain, hypercalcemia, renal failure, and spinal cord compression.

The aberrant antibodies that are produced lead to impaired humoral immunity, and patients have a high prevalence of infection, especially with encapsulated organisms such as Pneumococcus. The overproduction of these antibodies may lead to hyperviscosity, amyloidosis, and renal failure. (See Pathophysiology.)

The American Cancer Society estimated that about 20,580 new cases of MM (11,680 in men and 8,900 in women) would be diagnosed during 2009. In the United States, the lifetime risk of getting MM is 1 in 161 (0.62%).[9] About 10,580 Americans (5,640 men and 4,940 women) are expected to have died of MM in 2008.[9] (See Epidemiology.)

The 5-year relative survival rate for MM is around 35%. Survival is higher in younger people and lower in the elderly.[9, 10, 11] (See Prognosis.)

The presentation of MM can range from asymptomatic to severely symptomatic with complications requiring emergent treatment. Systemic ailments include bleeding, infection and renal failure; local catastrophes include pathologic fractures and spinal cord compression. (See Clinical Presentation.)

Although patients benefit from treatment (ie, longer life, less pain, fewer complications), currently no cure exists. Recent advances in therapy have helped to lessen the occurrence and severity of adverse effects of MM. (See Treatment and Management.)

Also see Imaging Multiple Myeloma.

PathophysiologyMM is characterized by neoplastic proliferation of plasma cells involving more than 10% of the bone marrow (see the images below). Increasing evidence suggests that the bone marrow microenvironment of tumor cells plays a pivotal role in the pathogenesis of myelomas.[12] This information has resulted in the expansion of treatment options.

Bone marrow aspirate demonstrating plasma cells of multiple myeloma. Note the blue cytoplasm, eccentric nucleus, and perinuclear pale zone (or halo). All images and text are (c) 2002 by the American Society of Hematology. All rights reserved.

Bone marrow biopsy demonstrating sheets of malignant plasma cells in multiple myeloma. All images and text are (c) 2002 by the American Society of Hematology. All rights reserved.

The malignant cells of MM, plasma cells, and plasmacytoid lymphocytes are the most mature cells of B-lymphocytes. B-cell maturation is associated with a programmed rearrangement of DNA sequences in the process of encoding the structure of mature immunoglobulins. It is characterized by overproduction of monoclonal immunoglobulin G (IgG), immunoglobulin A (IgA), and/or light chains, which may be identified with serum protein electrophoresis (SPEP) or urine protein electrophoresis (UPEP).

The role of cytokines in the pathogenesis of MM is an important area of research. Interleukin (IL)–6 is also an important factor promoting the in vitro growth of myeloma cells. Other cytokines are tumor necrosis factor and IL-1b.

The pathophysiologic basis for the clinical sequelae of MM involves the skeletal, hematologic, renal, and nervous systems, as well as general processes (see below).

Skeletal processesPlasma-cell proliferation causes extensive skeletal destruction with osteolytic lesions, anemia,

and hypercalcemia. Mechanisms for hypercalcemia include bony involvement and, possibly, humoral mechanisms. Isolated plasmacytomas (which affect 2-10% of patients) lead to hypercalcemia through production of the osteoclast-activating factor.

Destruction of bone and its replacement by tumor may lead to pain, spinal cord compression, and pathologic fracture. The mechanism of spinal cord compression symptoms may be the development of an epidural mass with compression, a compression fracture of a vertebral body destroyed by multiple myeloma, or, rarely, an extradural mass. With pathologic fracture, bony involvement is typically lytic in nature.

Hematologic processes

Bone marrow infiltration by plasma cells results in neutropenia, anemia, andthrombocytopenia. In terms of bleeding, M components may interact specifically with clotting factors, leading to defective aggregation.

Renal processesThe most common mechanisms of renal injury in MM are direct tubular injury, amyloidosis, or

involvement by plasmacytoma.[13, 14] Renal conditions that may be observed include hypercalcemic nephropathy, hyperuricemia due to renal infiltration of plasma cells resulting in myeloma, light-chain nephropathy, amyloidosis, and glomerulosclerosis.

Neurologic processesThe nervous system may be involved as a result of radiculopathy and/or cord compression due to

nerve compression and skeletal destruction (amyloid infiltration of nerves).

General processesGeneral pathophysiologic processes include hyperviscosity syndrome . This syndrome is

infrequent in MM and occurs with IgG1, IgG3, or IgA. MM may involve sludging in the capillaries, which results in purpura, retinal hemorrhage, papilledema, coronary ischemia, or central nervous system (CNS) symptoms (eg, confusion, vertigo, seizure). Cryoglobulinemia causes Raynaud phenomenon , thrombosis, and gangrene in the extremities.

EtiologyThe precise etiology of MM has not yet been established. Roles have been suggested for a

variety of factors, including genetic causes, environmental or occupational causes, MGUS, radiation, chronic inflammation, and infection.

Genetic causesMM has been reported in 2 or more first-degree relatives and in identical twins, although no

evidence suggests a hereditary basis for the disease. A study by the Mayo clinic found MM in 8 siblings from a group of 440 patients; these 8 siblings had different heavy chains but the same light chains.

Some studies have shown that abnormalities of certain oncogenes, such as c-myc, are associated with development early in the course of plasma cell tumors and that abnormalities of oncogenes such as N-ras and K-ras are associated with development after bone marrow relapse. Abnormalities of tumor suppressor genes, such as TP53, have been shown to be associated with spread to other organs.[9]

Ongoing research is investigating whether human leukocyte antigen (HLA)-Cw5 or HLA-Cw2 may play a role in the pathogenesis of multiple myeloma.

Environmental or occupational causesCase-controlled studies have suggested a significant risk of developing MM in individuals with

significant exposures in the agriculture, food, and petrochemical industries. An increased risk has been reported in farmers, especially in those who use herbicides and insecticides, and in people exposed to benzene and other organic solvents. Long-term (>20 y) exposure to hair dyes has been tied to an excessive risk of developing MM.

MGUS/Smoldering Multiple Myeloma (SMM)

Monoclonal gammopathy of undetermined significance (MGUS) is defined by the presence of three criteria:

Serum monoclonal M protein (M-protein) concentration < 3 g/dL Bone marrow plasma cell concentration < 10% No evidence of end organ damage

MGUS is seen in 2-3% of the elderly Caucasian population. It is divided into the following three subtypes:

Non IgM MGUS IgM MGUS Light chain MGUS

Patients with non-IgM MGUS have a risk of progression to MM at rate of 1% per year. For these patients, risk factors for progression to MM are as follows:

M protein concentration > 1.5 g/dL Non-IgG isotype An abnormal free light chain (FLC) ratio

Patients with IgM MGUS have a risk of progression to Waldenstrom macroglobulinemia and less frequently lymphoma or amyloid light chain (AL) amyloidosis. IgM MGUS rarely progresses into MM. Light chain MGUS has a tendency to progress to light chain MM, AL amyloidosis, or light chain deposition disease.

A study by Wadhera et al examined secondary MGUS that developed in patients with MM. Of 1942 patients with MM, 128 (6.6%) developed a secondary MGUS at a median of 12 months from the diagnosis of MM. Overall survival was superior in patients with MM who developed secondary MGUS compared with the rest of the cohort.[15]

Smoldering MM is present when the serum M protein concentration is > 3 g/dL or the bone marrow plasma cell concentration is > 10% but there is no evidence of end-organ damage. Risk factors for progression of SMM to MM include any of the following:

M protein concentration > 3 g/dL Abnormal FLC ratio Bone marrow plasma cell concentration > 10%

The time to progression decreases with increasing numbers of risk factors, as follows:

One factor: 10 years Two factors: 5.1 years Three factors: 1.9 years

RadiationRadiation may play a role in some patients. An increased risk has been reported in atomic-bomb

survivors exposed to more than 50 Gy: In 109,000 survivors of the atomic bombing of Nagasaki during World War II, 29 died from multiple myeloma between 1950 and 1976. Some more recent studies, however, do not confirm that these survivors have an increased risk of developing multiple myeloma.

A recent study of workers at the Oak Ridge Diffusion Plant in eastern Tennessee showed only a weak correlation of risk of multiple myeloma to uranium exposure.[16]

Chronic inflammation

A relationship between MM and preexisting chronic inflammatory diseases has been suggested. However, a case-control study provides no support for the role of chronic antigenic stimulation.

InfectionHuman herpesvirus 8 (HH8) infection of bone marrow dendritic cells was found in patients with

MM and in some patients with MGUS.

EpidemiologyMM accounts for 10% of all hematologic cancers. [17, 18] The age-adjusted annual incidence of MM is

4.3 cases per 100,000 white men, 3 cases per 100,000 white women, 9.6 cases per 100,000 black men, and 6.7 cases per 100,000 black women.

The American Cancer Society estimated that in the United States, 20,580 new cases of MM would be diagnosed during 2009, with 11,680 cases occurring in men and 8,900 in women. The lifetime risk of getting MM is 1 in 161 (0.62%).[9]

The median age of patients with MM is 68 years for men and 70 years for women. Only 18% of patients are younger than 50 years, and 3% of patients are younger than 40 years. The male-to-female ratio of multiple myeloma is approximately 3:2.

In the United States, African Americans are twice as likely as whites to have myeloma, with a ratio of 2:1. Myeloma is rare among people of Asian descent, with an incidence of only 1-2 cases per 100,000 population.

According to a study of the ethnic disparities among patients with MM, Hispanics had the youngest median age at diagnosis (65 years) and Whites had the oldest (71 years). Asians had the best overall survival rates, while Hispanics had the worst.[19]

PrognosisMM is a heterogeneous disease, with survival ranging from 1 year to more than 10 years. Median survival in unselected patients with MM is 3 years. The 5-year relative survival rate is around 35%. Survival is higher in younger people and lower in the elderly. [9] It was estimated that about 10,580 Americans (5,640 men and 4,940 women) would die of multiple myeloma in 2008.[9]

The tumor burden and the proliferation rate are the 2 key indicators for the prognosis in patients with MM. Many schemas have been published to aid in determining the prognosis. One schema uses C-reactive protein (CRP) and beta-2 microglobulin (which is an expression of tumor burden) to predict survival as follows[20] :

If levels of both proteins are less than 6 mg/L, the median survival is 54 months. If the level of only one component is less than 6 mg/L, the median survival is 27 months. If levels of both protein values are greater than 6 mg/L, the median survival is 6 months.

Poor prognostic factors include the following:

Tumor mass Hypercalcemia Bence Jones proteinemia Renal impairment (ie, stage B disease or creatinine level >2 mg/dL at diagnosis)

The prognosis by treatment is as follows:

Conventional therapy: Overall survival is approximately 3 years, and event-free survival is less than 2 years.

High-dose chemotherapy with stem-cell transplantation: The overall survival rate is greater than 50% at 5 years.

Serum amyloid P retention: More than 50% of patients have a median survival of approximately 11 months.

Serum amyloid P retention: Median survival is 24 months.

Bacterial infection is the leading cause of death in patients with myeloma. [9]

A study by Larsen et al found that a significant reduction in plasma cell proliferation in patients with newly diagnosed MM is an important predictor of survival.[21]

HistoryPresenting symptoms of multiple myeloma (MM) include bone pain, pathologic fractures, weakness, anemia, infection (often pneumococcal), hypercalcemia, spinal cord compression, or renal failure. The diagnosis is incidental in 30% of cases. MM is often discovered through routine blood screening when patients are being evaluated for unrelated problems. Typically, a large gap between the total protein and the albumin levels observed on an automated chemistry panel suggests a problem (ie, protein minus albumin equals globulin).

In one third of patients, MM is diagnosed after a pathologic fracture occurs; such fractures commonly involve the axial skeleton. Two thirds of patients complain of bone pain, commonly with lower back pain. This bone pain is frequently located in the back, long bones, skull, and/or pelvis.

Patients may also complain of nonspecific constitutional symptoms related to hyperviscosity and hypercalcemia.

Bone painBone pain is the most common presenting symptom in MM. Most case series report that 70% of patients have bone pain at presentation. The lumbar spine is one of the most common sites of pain.

Pathologic fractures and bone lesionsPathologic fractures are very common in MM; 93% of patients have more than one site of bony involvement. A severe bony event is a common presenting issue.

Spinal cord compressionThe symptoms that should alert physicians to consider spinal cord compression are back pain, weakness, numbness, or dysesthesias in the extremities. Because spinal cord compressions in MM occur at multiple levels, comprehensive evaluation of the spine is warranted. Patients who are ambulatory at the start of therapy have the best likelihood of preserving function and avoiding paralysis.

BleedingOccasionally, a patient may come to medical attention for bleeding resulting from thrombocytopenia. Rarely, monoclonal protein may absorb clotting factors and lead to bleeding.

HypercalcemiaConfusion, somnolence, bone pain, constipation, nausea, and thirst are the presenting symptoms of hypercalcemia. This complication may be present in as many as 30% of patients with MM at presentation. In most solid malignancies, hypercalcemia carries an ominous prognosis, but in MM, its occurrence does not adversely affect survival.

InfectionAbnormal humoral immunity and leukopenia may lead to infection. Pneumococcal organisms are commonly involved, but shingles (ie, herpes zoster) andHaemophilus infections are also more common among patients with MM.

HyperviscosityHyperviscosity may be associated with a number of symptoms, including, generalized malaise, infection, fever, paresthesia, sluggish mentation, and sensory loss. Patients may report headaches and somnolence, and they may bruise easily and have hazy vision. Patients with MM typically experience these symptoms when their serum viscosity is greater than 4 times that of normal serum.

Epistaxis may be a presenting symptom of MM with a high tumor volume. Occasionally, patients may have such a high volume of monoclonal protein that their blood viscosity increases, resulting in complications such as stroke, myocardial ischemia, or infarction.

Neurologic symptomsCarpal tunnel syndrome is a common complication of myeloma. Meningitis (especially that resulting from pneumococcal or meningococcal infection) is more common in patients with MM. Some peripheral neuropathies have been attributed to MM. Long-term neurologic function is directly related to the rapidity of the diagnosis and the institution of appropriate therapy for MM.

AnemiaAnemia, which may be quite severe, is the most common cause of weakness in patients with MM.

ExaminationOn head, ears, eyes, nose, and throat (HEENT) examination, the eyes may show exudative macular detachment, retinal hemorrhage, or cotton-wool spots. Pallor from anemia may be present. Ecchymoses or purpura from thrombocytopenia may be evident.

Bony tenderness is not uncommon in MM, resulting from focal lytic destructive bone lesions or pathologic fracture. Pain without tenderness is typical. Pathologic fractures may be observed. In general, painful lesions that involve at least 50% of the cortical diameter of a long bone or lesions that involve the femoral neck or calcar femorale are at high (50%) risk for a pathologic fracture. The risk of fracture is lower in upper-extremity lesions than in lower-extremity lesions. Even a small cortical defect can decrease torsional strength by as much as 60% (stress riser effect).

Neurologic findings may include a sensory level change (ie, loss of sensation below a dermatome corresponding to a spinal cord compression), neuropathy, myopathy, a Tinel sign, or a Phalen sign due to carpel tunnel compression secondary to amyloid deposition.

Extramedullary plasmacytomas, which consist of soft-tissue masses of plasma cells, are not uncommon. Plasmacytomas have been described in almost every site in the body. Although the aerodigestive tract is the most common location, reports also describe orbital, ear canal, cutaneous, gastric, rectal, prostatic, and retroperitoneal lesions.

On evaluation of the abdomen, hepatosplenomegaly may be discovered. Cardiovascular system examination may reveal cardiomegaly secondary to immunoglobulin deposition.

Amyloidosis may develop in some patients with MM. The characteristic physical examination findings that suggest amyloidosis include the following:

Shoulder pad sign Macroglossia Typical skin lesions Postprotoscopic peripalpebral purpura

The shoulder pad sign is defined by bilateral swelling of the shoulder joints secondary to amyloid deposition. Physicians describe the swelling as hard and rubbery. Amyloidosis may also be associated with carpal tunnel syndrome and subcutaneous nodules.

Macroglossia may occur secondary to amyloid deposition in the tongue and is a common finding in patients with amyloidosis (see the image below).

Amyloidosis infiltrating the tongue in multiple myeloma. All images and text are (c) 2002 by the American Society of Hematology. All rights reserved.

Skin lesions that have been described as waxy papules or nodules may occur on the torso, ears, or lips.

Postprotoscopic peripalpebral purpura strongly suggests amyloidosis. Patients may develop raccoonlike dark circles around their eyes following any procedure that parallels a prolonged Valsalva maneuver. The capillary fragility associated with amyloidosis may account for this observation. In the past, this correlation was observed when patients underwent rectal biopsies to make the diagnosis.

StagingStaging is a cumulative evaluation of all of the diagnostic information garnered and is a useful tool for stratifying the severity of patients’ disease. Currently, 2 staging systems for multiple myeloma are in use: the Salmon-Durie system, which has been widely used since 1975; and the International Staging System, developed by the International Myeloma Working Group and introduced in 2005. [27, 28]

Salmon-Durie staging systemThe Salmon-Durie classification of MM is based on 3 stages and additional subclassifications.

In stage I, the MM cell mass is less than 0.6 × 1012 cells/m2, and all of the following are present:

Hemoglobin value greater than 10 g/dL Serum calcium value less than 12 mg/dL (normal) Normal bone structure (scale 0) or only a solitary bone plasmacytoma on radiographs Low M-component production rates (IgG value less than 5 g/dL, IgA value less than 3 g/dL, urine light-

chain M component on electrophoresis less than 4 g/24 h)In stage II, the MM cell mass is 0.6-1.2 × 1012 cells/m2. The other values fit neither those of stage I nor those of stage III.

In stage III, the MM cell mass is greater than 1.2 × 1012 cells/m2, and all of the following are present:

Hemoglobin value equal to 8.5 g/dL Serum calcium value greater than 12 mg/dL Advanced lytic bone lesions (scale 3) on radiographs High M-component production rates (IgG value greater than 7 g/dL, IgA value greater than 5 g/dL, urine

light-chain M component on electrophoresis greater than 12 g/24 h)

Subclassification A includes relatively normal renal function (serum creatinine value < 2 mg/dL), whereas subclassification B includes abnormal renal function (serum creatinine value > 2 mg/dL)

Median survival is as follows:

Stage I, >60 months Stage II, 41 months Stage III, 23 months

Disease in subclassification B has a significantly worse outcome (eg, 2-12 mo survival in 4 separate series).

International Staging SystemThe International Staging System of the International Myeloma Working Group is also based on 3 stages.

Stage I consists of the following:

Beta-2 microglobulin less than or equal to 3.5 g/dL and albumin ≥3.5 g/dL CRP ≥4.0 mg/dL Plasma cell labeling index < 1% Absence of chromosome 13 deletion Low serum IL-6 receptor Long duration of initial plateau phase

Stage II consists of the following:

Beta-2 microglobulin level ≥3.5 to < 5.5 g/dL, or Beta-2 microglobulin < 3.5 g/dL and albumin < 3.5 g/dL

Stage III consists of the following:

Beta-2 microglobulin of 5.5 g/dL or moreMedian survival is as follows:

Stage I, 62 months Stage II, 44 months Stage III, 29 months

Approach ConsiderationsPhysicians must understand both the natural history of multiple myeloma (MM) and the limitations of current therapy in the treatment of the disease.

Practice guidelines

In May 2013, the International Myeloma Working Group released practice guidelines for the management of MM-related bone disease.[29] The recommendations, which were based on a review of the literature through August 2012 and a consensus of an interdisciplinary panel of experts, include the following:

Consideration of bisphosphonates (BPs) in all patients with MM receiving first-line antimyeloma therapy, regardless of presence of osteolytic bone lesions on conventional radiography

Intravenous (IV) zoledronic acid or pamidronate for preventing skeletal-related events in patients with MM

Because of its potential antimyeloma effects and survival benefits, zoledronic acid is preferred in newly diagnosed patients with MM

Bisphosphonates should be administered IV every 3 to 4 weeks during initial therapy, but preventive strategies must be instituted to avoid renal toxicity or osteonecrosis of the jaw

Zoledronic acid or pamidronate should be continued in patients with active disease and should be resumed after disease relapse

Kyphoplasty should be considered for symptomatic vertebral compression fractures Orthopedic consultation should be sought for long-bone fractures, spinal cord compression, and

vertebral column instability Low-dose radiation therapy can be used for palliation of uncontrolled pain, impending pathologic

fracture, or spinal cord compression

Progression of disease and timing of treatmentAn important study by Dimopoulos and associates evaluated the risk of disease progression in asymptomatic subjects with MM.[30] This study evaluated 638 consecutive untreated subjects with MM. Of these subjects, 95 were asymptomatic and were not treated until their M protein value rose to greater than 5 g/dL. These subjects developed increased bone disease or symptoms of bone disease.

The individuals in this group were designated as either low risk (ie, no bone disease, M protein level < 3 g/dL, or Bence Jones protein level < 5 g/24 h) or high risk (ie, lytic bone disease and serum M protein level >3 g/dL or Bence Jones protein level >5 g/24 h). Intermediate-risk subjects did not have bone disease or an M protein level greater than 3 g/dL or a Bence Jones protein level greater than 5 g/24 h. The patients were evaluated every 2 months.

The median time for disease progression was 10 months in the high-risk group, 25 months in the intermediate-risk group, and 61 months in the low-risk group. [30] At the time of progression, subjects were treated with standard chemotherapy. Their response rates did not significantly differ from those of unselected populations. Median survival time from the institution of chemotherapy did not differ among the groups. Thus, asymptomatic subjects did not benefit from early treatment, and delayed treatment did not affect treatment efficacy (ie, survival).

A systematic review by He et al demonstrated a reduction in vertebral compressions and time to progression with early systemic treatment for asymptomatic patients, but this study also revealed an increase in acute leukemia in the early treatment group. [31] The failure to demonstrate improved survival may be due to the small number of patients studied.

The 2011 NCCN Guidelines for MM determined that the term “progression to stage II or higher disease” should be replaced by the term “progression to symptomatic disease”. [2]

The 2009 International Myeloma Workshop concluded that detection of any cytogenic abnormality suggests higher-risk disease, including chromosomal 13 or 13q deletion, t(4;14), and del17p and fluorescence in situ hybridization detection of t(4;14), t(14;16), and del17p. [32] Fluorescence in situ hybridization detection of 13q deletion alone is not considered a high-risk feature. International Staging System stages II and II and high serum beta(2)-microglobulin levels are suggestive of higher risk disease.

A study by Klein et al determined that the prognostic significance of t(4;14) may be eliminated or lessened among patients who receive lenalidomide and dexamethasone; however, del(17p13) and +1q21 are still associated with a dismal overall survival. [33] A study by Neben et al concludes that long-term administration of bortezomib in patients with del(17p13) may result in better overall and progression-free survival. [34]

Current therapeutic approachesOverall, the care of patients with MM is complex and should focus on treatment of the disease process and any associated complications.[3, 4, 5] Although MM remains incurable, several drug therapies are valuable in the treatment of patients with MM, as are autologous stem cell transplantation, radiation, and surgical care in certain cases.

Several studies are evaluating the role of treatment in patients with high-risk smoldering multiple myeloma (SMM). Previous smaller studies evaluating thalidomide did not show a clear evidence of benefit with treatment in patients with SMM; however, these included patients with all risk levels of SMM.

In a recent phase III trial that was restricted to patients with high-risk SMM, the PETHEMA group found evidence of benefit from treatment with lenalidomide versus observation. After a median follow-up of 40 months, study patients who were randomized to lenalidomide and dexamethasone induction followed by lenalidomide maintenance demonstrated significantly prolonged median time to progression (median not reached vs 21 months) and higher 3-year survival rate (94% vs. 80%). [35] Larger trials are ongoing to validate this benefit. Concern for second primary malignancies (SPMs) with the use of lenalidomide is also a significant issue. Consequently, watchful observation and frequent monitoring remains the standard of care for patients with SMM.

Patients with MM for whom therapy is indicated typically receive chemotherapy. Our understanding of the cell biology of MM and the ability to identify prognostic factors has led to the increasing individualization of treatment for affected patients. Physicians treat many patients with high-dose therapy and peripheral blood or bone marrow stem cell transplantation. A randomized prospective study showed that this approach results in higher response rates and better disease-free survival rates.

The 2011 NCCN MM guidelines added the following therapies[2] :

The combination of bortezomib/cyclophosphamide/dexamethasone as primary induction therapy for transplant candidates

The combination of bortezomib/dexamethasone (without cyclophosphamide) as primary induction therapy for patients who are not candidates for transplantation

The combination of melphalan/prednisone/lenalidomide for primary induction therapy for nontransplant candidates

The resistance mechanisms to chemotherapy in MM are reduced drug concentration at the target site of action, alterations in the drug target, and inhibition of drug-induced apoptosis. Factors mediating myeloma cell growth, patient survival rates, and the complex interaction of MM cells with the bone marrow microenvironment have provided a framework for the rational design of therapeutic agents that may ultimately lead to improved disease-free survival and, potentially, a cure.

Recent advances in pharmacologic treatment include establishment of thalidomide, lenalidomide, and bortezomib as active agents in MM. Patients with MM who are treated with lenalidomide or thalidomide are at significantly increased risk for thrombotic events, and many physicians incorporate anticoagulation strategies in their management.

A study by Jakubowiak et al found that the combination of lenalidomide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone (RVDD) was generally well tolerated and highly active in newly diagnosed patients with multiple myeloma.[36]

A study by Palumbo et al determined that aspirin and low-dose warfarin had similar efficacy in reducing serious thromboembolic events, acute cardiovascular events, and sudden deaths in patients with myeloma receiving thalidomide-based regimens compared with low-molecular weight heparin, except in elderly patients.[37]

As monotherapy or in combination, interferon alfa-2b and prednisone modestly prolong the disease-free interval.

A study by the Southwest Oncology Group compared lenalidomide plus dexamethasone to placebo plus dexamethasone in patients with newly diagnosed myeloma. [38] The study determined that lenalidomide plus dexamethasone had superior 1-year progression-free survival, overall response rate, and very good partial response rate, suggesting that it is safe and effective as initial therapy for patients with newly diagnosed myeloma.

A phase 3 randomized, open-label trial of 119 patients with high-risk smoldering MM found that early treatment with lenalidomide plus dexamethasone, followed by maintenance therapy with lenalidomide, delayed progression to symptomatic disease and increased overall survival. [39, 40]

Adjunctive therapy for MM includes radiation therapy to target areas of pain, impending pathologic fracture, or existing pathologic fracture. Bisphosphonate therapy serves as prophylaxis (ie, primary, secondary) against skeletal events (eg, hypercalcemia, spinal cord compression, pathologic fracture, need for surgery, need for radiation). Early evidence suggests that it may be effective in treating bone pain and in decreasing the likelihood of lesion recurrence.[41, 42, 43, 44, 45, 46, 47]

Adjunctive therapy may also include erythropoietin, corticosteroids, surgical intervention, or plasmapheresis, as appropriate.

Chemotherapy and ImmunosuppressionIn patients with symptomatic MM, chemotherapy is required. In asymptomatic patients with MM, treatment is delayed until disease clinically progresses or until serum or urine levels of M protein substantially increase.

The M-component level in serum and/or urine is an indicator of the tumor burden; its reduction after chemotherapy is used as a sign of response. A 50% reduction in M-component is considered a good clinical response (according to the Chronic Leukemia-Myeloma Task Force). MP induces a response in 50-60% of patients with MM. Disappearance of the M component on electrophoresis occurs in only 3% of patients, and cure is extraordinarily rare.

The first step before starting therapy in MM is to determine whether a patient is a candidate for an autologous stem cell transplant. Eligibility depends primarily on the patient’s age and comorbidities. Typically an age of 65 years is used as a cut-off point for transplant eligibility. Thus, treatment for MM is best looked at in terms of the following three categories of patients:

Young, newly diagnosed patients who are potential transplant candidates High-risk patients who are potential transplant candidates Newly diagnosed elderly patients who are not transplant candidates

Young, newly diagnosed patients who are potential transplant candidatesConventionally, VAD (vincristine, doxorubicin [Adriamycin], and dexamethasone) chemotherapy

has been used to decrease the tumor burden in MM as preparation for transplantation. VAD is administered as a 4-day continuous intravenous infusion of vincristine and doxorubicin, with 4 daily oral doses of dexamethasone. Patients require a central venous catheter for delivery of the infusion. In selected patients, this therapy can be performed in an outpatient setting.

Many researchers feel that the high-dose steroid component of VAD accounts for much of its efficacy. In some patients, high-dose dexamethasone alone may produce significant clinical responses.

Significant concerns with the use of infusion therapy include the risk of soft-tissue injury if the chemotherapy agent infiltrates, the risk of cardiac injury from the doxorubicin, and the risk of infection or hyperglycemia from the high-dose steroids. Some patients also experience adverse central nervous system (CNS) effects from the high-dose steroids. Given these risks, and the higher response rates of new agents (thalidomide, lenalidomide, and bortezomib), VAD is now considered suboptimal treatment.

Thalidomide has proved effective against MM. The superiority of induction regimens containing thalidomide was demonstrated in randomized trials that compared VAD with thalidomide plus dexamethasone[48] ; thalidomide and doxorubicin plus dexamethasone[49] ; and thalidomide plus VAD.[50]

Thalidomide has a well-established role as first-line therapy, either as a single agent or in combination with steroids in patients with MM. The toxicity of this drug is predominantly sensory neuropathy, and because of the drug’s teratogenicity, close monitoring is required to avoid inadvertent administration during pregnancy.

An analogue of thalidomide, lenalidomide (Revlimid) is now a standard component of MM therapy.

In July 2013, Celgene Corp announced that a phase 3 trial of lenalidomide (Revlimid) met the main goal of improving progression-free survival in patients with newly diagnosed MM. [51] The drug is already approved for use in previously treated MM, mantle cell lymphoma, and transfusion-dependent anemia caused by myelodysplastic syndromes.

In the late-stage study, treatment with lenalidomide combined with dexamethasome in patients with newly diagnosed MM resulted in a significant improvement in survival without the cancer worsening, compared to treatment with a regimen consisting of melphalan, prednisone and thalidomide (MPT). [51]Evaluation of safety and efficacy is ongoing.

In a randomized, double-blind, placebo-controlled trial, lenalidomide plus high-dose dexamethasone proved superior to high-dose dexamethasone alone as treatment for newly diagnosed MM. [48] The overall response rate was 84% in the lenalidomide plus high-dose dexamethasone group versus 53% in the high-dose dexamethasone group, with 22% of patients achieving complete remission in the lenalidomide plus high-dose dexamethasone arm.

Progression-free survival and overall survival favored lenalidomide plus high-dose dexamethasone, but 12-month survival for both arms was >90%. A very important observation, however, was the high incidence of deep venous thrombosis in the lenalidomide plus high-dose dexamethasone arm. [48]

In another randomized trial of lenalidomide plus high-dose dexamethasone (LD) versus lenalidomide plus low-dose dexamethasone (Ld) in newly diagnosed MM, Rajkumar found that the overall response rate for LD was superior (82%) to that for Ld (70%), with an improvement in the VGPR-or-better rate for LD (44% vs 26%) evaluated after 4 months.[52]

When best overall response was compared, LD again was superior, with an overall response rate of 82% compared with 71% for Ld. However, there was no difference in progression-free survival between the 2 arms. Overall survival continued to favor the Ld arm; however, for patients younger than 65 years, there was no benefit in survival for Ld over LD.[52]

The second interim analysis from Rajkumar et al was completed after 1 year; the data demonstrated that lenalidomide plus low-dose dexamethasone (Ld) was superior to lenalidomide plus high-dose dexamethasone (LD).[53] Overall survival was 96% in the Ld group compared with 87% in the LD group. As a result, the trial was stopped, and patients on high-dose therapy were crossed over to low-dose therapy.

Another trial assessed the safety and efficacy of the combination regimen clarithromycin (Biaxin), lenalidomide (Revlimid), and dexamethasone (BiRD) as first-line therapy for MM. [54] Of the 72 patients enrolled, 65 had an objective response (90.3%). A combined stringent and conventional complete response rate of 38.9% was achieved, and 73.6% of the patients achieved at least a 90% decrease in M-protein levels. BiRD was found to be an effective regimen with manageable side effects in the treatment of symptomatic, newly diagnosed MM.

Patients tolerate lenalidomide therapy well, and nausea is usually minimal. Patients typically experience total alopecia, but other adverse effects (eg, peripheral neurotoxicity, constipation) are usually mild. Pancytopenia is expected, but is not severe enough to require hospitalization for infection or transfusion unless the patient also has some other cause of bone marrow suppression.

Bortezomib, a proteosome inhibitor, has shown striking activity against MM. Objective responses as high as 27.7% in patients with relapsed and heavily pretreated MM [55] led to its approval by the US Food and Drug Administration (FDA) in 2003. Subsequent studies reported response rates as high as 80% when bortezomib is combined with melphalan.

A randomized trial compared bortezomib plus dexamethasone with VAD for induction, showing response rates of 80% for the bortezomib plus dexamethasone arm versus 62.8% for the VAD arm. [56] This regimen has been shown to be active not only before but also after transplantation. Following high-dose therapy and autologous transplantation, the rate of very good partial response or better continued to favor bortezomib plus dexamethasone. This benefit was observed independent of beta-2 microglobulin or adverse cytogenetic risk groups.

Similarly, a superior response rate was seen when the combination of bortezomib, thalidomide, and dexamethasone was compared with thalidomide plus dexamethasone in a large phase III study: 93% in the bortezomib-thalidomide-dexamethasone arm versus 80% in the thalidomide-dexamethasone arm, in which patients went on to receive tandem autologous stem cell transplantation. [57] As in other studies, response was independent of adverse prognostic risk factors.

The phase III Velcade as initial standard therapy in MM (VISTA) trial found the combined treatment of bortezomib, melphalan, and prednisone (VMP) significantly prolongs overall survival compared with melphalan and prednisone (MP) after lengthy follow-up and extensive subsequent antimyeloma therapy.[58]

A study by Harousseau et al confirms the role of Velcade in the initial nonintensive management of multiple myeloma.[59]

A study by Sher et al found that a combination of bortezomib (V), pegylated liposomal doxorubicin (D), and thalidomide (T), known as the VDT regimen, had overall response rate and complete response plus near complete response rates of 78% and 35%, respectively. [60] The study concluded VDT was a tolerable and effective regimen that may induce high response rates among patients considered to be poor candidates for steroid-based treatments.

A notable outcome of this study showed that first-line bortezomib use does not induce more resistant relapse. VMP used upfront appears more beneficial than first treating with conventional agents and saving bortezomib-based and other novel agent-based treatment until relapse. [58]

Bortezomib appears to be of especial benefit in patients with plasma cell leukemia and renal failure. The predominant adverse effects were neuropathy, hypotension, and thrombocytopenia. Despite these results, the exact timing of bortezomib administration in the treatment plan of patients with newly diagnosed multiple myeloma is still evolving through ongoing research.

Varicella-zoster virus reactivation occurs in 10%-60% of patients with MM treated with bortezomib. Antiviral prophylaxis (eg, acyclovir, 400 mg daily) has been found effective for preventing these reactivations.[61]

The FDA approved administration of bortezomib by the subcutaneous route in January 2012. A study by Moreau et al found that the efficacy of subcutaneous bortezomib is not inferior to the efficacy of standard intravenous administration and that the safety profile of the subcutaneous administration is improved. Moreau also observed the incidence of grade 2 or greater peripheral neuropathy was 24% for SC compared with 41% for IV; grade 3 or higher occurred in 6% when administered SC vs 16% for IV administration.[62] Starting therapy with SC administration may be considered for patients with pre-existing or at high risk of peripheral neuropathy.

A study by Mateos et al found that patients with cytogenetic abnormalities had similar response to bortezomib therapy but shorter survival. The authors concluded that the present treatment schema does not overcome the negative prognosis associated with high-risk cytogenetic abnormalities. [63]

Overall, the data on these novel agents are very encouraging and promising. Nevertheless, oncologists will need further studies to help define the exact timing and role of novel agents in the treatment of MM.

High-risk patients who are potential transplant candidatesHigh-risk MM patients are those with advanced-stage disease (stage III according to the International Staging System); those with poor cytogenetics, such as t (4:14), t (14:16), and t (14:20), deletion of chromosome 13, inactivation of TP53; and those with a complex karyotype. Patients with very high proliferative rates are also included in this classification.

This group represents about 25% of those with newly diagnosed MM, with an expected median survival of 2 years or less. Although they respond to traditional therapies for induction, these individuals tend to relapse rapidly. Therefore, novel agents should be considered up front for these patients.

The advent of thalidomide, lenalidomide, and bortezomib has substantially improved outcomes in these high-risk groups. In fact, these novel agents appear to overcome the influence contributed by high-risk cytogenetics.[64, 65] Once a response has been achieved, then these patients can be brought to autologous stem cell transplantation.

Newly diagnosed elderly patients who are not transplant candidatesAll of the above regimens may be used in patients who are not being considered for autologous stem cell transplantation. The following, however, can only be used in patients not going for transplantation, as they impair stem cell reserve.

The gold standard has been the MP regimen as far back as the 1950s. This regimen typically consists of melphalan 9 mg/m2 and prednisone 100 mg given on days 1-4, with courses repeated at 4- to 6-week intervals for at least 1 year. A meta-analysis of 4930 patients from 20 randomized trials compared MP to other drug combinations and showed a significantly higher response rate (60%) with this combination, with a response duration of 18 months and overall survival of 24 to 36 months. [66]

A 3-arm study looked at MP plus thalidomide versus MP versus VAD induction, followed by high-dose melphalan and autologous stem cell transplantation in 447 patients between ages 65 and 75 years. [67] The patients were randomized, with overall survival as the primary endpoint. The response rate in the MP plus thalidomide arm and transplantation arm was similar; the complete response rate was significantly better in the MP plus thalidomide and the transplantation arms than in the MP arm. [67]

MP plus thalidomide is now recommended as first-line treatment. MP plus lenalidomide has also shown promise.[68]

Hulin et al conducted a randomized, placebo-controlled, phase III trial to investigate the efficacy of adding thalidomide to MP in 229 elderly patients (> 75 y) newly diagnosed with MM. [69] During each 6-week cycle, melphalan 0.2 mg/kg/d plus prednisone 2 mg/kg/d was given to all patients on days 1-4 for 12 cycles. In addition, patients were randomly assigned to receive thalidomide 100 mg/d PO (n = 113) or placebo (n = 116), continuously for 72 weeks.

Overall survival was significantly longer in the group that received thalidomide (median, 44 mo) compared with placebo (median, 29.1 mo).[69] Progression-free survival was also significantly prolonged in the thalidomide group (median, 24.1 mo) relative to the placebo group (median, 18.5 mo). However, the investigators noted peripheral neuropathy and neutropenia were significantly increased in the thalidomide group.[69]

A randomized, controlled trial evaluated the addition of thalidomide to standard MP chemotherapy in elderly patients with previously untreated MM. Although no impact on survival was observed, more patients in the thalidomide group achieved an objective response. Of note, thromboembolic events did not increase in the thalidomide group.[70]

A separate study by Fayers et al concluded that thalidomide added to MP therapy improved overall survival and progression-free survival in previously untreated elderly patients with multiple myeloma, extending the mean survival time by an average of 20%.[71]

A study by Gay et al assessed the addition of thalidomide and/or bortezomib to standard oral melphalan-prednisone treatment in 1175 elderly patients with newly diagnosed myeloma. [72] The study found that these novel agents helped achieve maximal response in these patients.

A study by Morgan et al found that cyclophosphamide, thalidomide, and dexamethasone (CTD) produced higher response rates than melphalan and prednisolone among newly diagnosed elderly patients with multiple myeloma; however, CTD was not associated with improved survival outcomes.[73]

Maintenance therapyIn spite of advances in treatment, multiple myeloma remains an incurable disease. To improve overall survival (OS) in these patients, a number of trials have evaluated the role of maintenance therapy in both transplant-eligible and transplant- ineligible patients.

Five large phase III studies have looked at role of thalidomide maintenance after autologous stem cell transplant (ASCT). Three initial studies showed an improvement in both progression-free survival (PFS) and OS.[74, 75, 76] However, two recent studies—including one large study with 1970 patients—did not show an improvement in OS with thalidomide maintenance. [77, 78] Long-term use of thalidomide is also associated with significant neuropathy, thus limiting its use in maintenance therapy.

Given its favorable toxicity profile and efficacy at low doses, lenalidomide has also been studied for maintenance therapy. Two large trials, CALGB 100104 and IFM 05-02, have evaluated the role of lenalidomide in maintenance therapy, using slightly different protocols and having somewhat different outcomes.[79, 80] Patients in both studies received induction treatment followed by ASCT. In the IFM 05-02 study, however, all patients received 2 months of consolidation treatment with lenalidomide before being randomized to lenalidomide or placebo.

Both studies showed a significant improvement in time to progression (46 vs 27 months in CALGB study and 41 vs 23 months in IFM study). However, CALGB 100104 study showed significant improvement in OS (85 % vs 77 %), whereas IFM 05-02 did not show an improvement in OS. Both studies showed an increased incidence of hematologic toxicity and second primary malignancies (SPMs), particularly AML/MDS in the lenalidomide arm.

The reason for the difference in the two studies in terms of OS benefit is not very clear. Since all the patients in the IFM trial received 2 months of consolidation treatment with lenalidomide following ASCT, it is possible that only short period of maintenance therapy, rather than continuous maintenance therapy, is required to achieve all the OS benefit seen in the CALGB trial.

A recent meta-analysis shows the benefit of maintenance lenalidomide, with a 51% reduction in the risk of recurrence.[81] This benefit outweighs the risk of SPM seen in the trials of lenalidomide maintenance.

Bortezomib has also been shown to be effective for maintenance therapy in the recently published HOVON-65/GMMG-HD4 trial.[82] In this trial, patients were randomized to either PAD (bortezomib, doxorubicin [Adriamycin], and dexamethasone) induction followed by bortezomib maintenance or to VAD induction followed by thalidomide maintenance. PFS in the PAD arm was significantly better than in the VAD arm (35 vs 28 months). Patients with high-risk cytogenetics, especially del(17p13) and t(4;14) abnormalities, seemed to benefit more with bortezomib maintenance.

Although several trials have shown the benefit of maintenance therapy after ASCT, the risk of SPM and the need for continuous treatment should be kept in mind. Individual patient characteristics should be taken in consideration before recommending maintenance therapy.

Maintenance therapy has also been evaluated in non–transplant eligible patients. Thalidomide has been studied as maintenance in a number of trials; most of the trials have shown only advantage in PFS, with

no advantage in OS. The main problem with thalidomide has been the high incidence of neuropathy in these patients.

A trial of lenalidomide as maintenance therapy after induction with melphalan, prednisone, and lenalidomide showed a significant improvement in PFS (26 vs 7 months) but similar 4-year OS. Patients in the lenalidomide arm had more hematologic toxicity, including neutropenia, thrombocytopenia, and higher risk of second primary malignancy. However, given its overall tolerability, lenalidomide is a good option for induction and maintenance therapy in transplant-ineligible patients. [83]

A number of trials have also evaluated bortezomib in maintenance therapy. All of them have showed benefit in PFS but no clear OS benefit. Bortezomib given once a week in maintenance seems to be better tolerated and associated with lesser neuropathy.[84]

Patients with refractory disease or relapsePatients who have a relapse after initial disease control may be treated with any of the agents not already utilized. If the MM relapse occurs longer than 6 months after the initial therapy, then the initial regimen can be used again.

Bortezomib has a well-established role as salvage therapy based on a phase III randomized trial showing a response rate of 38% relative to 18% in patients receiving dexamethasone only. [55] Median progression-free survival was 6.22 months in the bortezomib arm versus 3.49 months in the dexamethasone-only group. According to the 2011 NCCN MM guidelines, adding cyclophosphamide and dexamethasone to bortezomib is a recommended combination for salvage therapy. [2]

On July 20, 2012, the FDA approved carfilzomib (Kyprolis) for the treatment of patients with multiple myeloma who have received at least 2 prior therapies including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of therapy completion. The approval was based on a phase 2b, single-arm, multicenter clinical study of 266 patients with relapsed multiple myeloma with other therapies. The study assessed for overall response rate (ORR), which was 22.9% over a median duration of 7.8 months.[85]

Thalidomide is useful in the treatment of patients with relapsing and refractory MM. Its antiangiogenic properties have become increasingly apparent as a critical step in the proliferation and spread of malignant neoplasm.[86, 87] In a Mayo Clinic study, nearly one third of patients with advanced MM in whom current standard chemotherapy or stem cell transplantation failed were shown to respond to thalidomide for a median duration of nearly 1 year.[88]

An important prospective placebo-controlled trial of the addition of lenalidomide to dexamethasone in relapsed cases of MM demonstrated spectacular results. [89] The major response rate with lenalidomide was 61% compared with 19.9% in the placebo arm. There was a significant improvement in time to progression (11.1 in the lenalidomide plus dexamethasone group vs 4.7% in the placebo group). Overall survival was significantly improved.[89] The 2011 NCCN MM guidelines recommend the addition of cyclophosphamide and dexamethasone to lenalidomide as an effective combination for salvage therapy. [2]

A study by Lacy et al found that pomalidomide overcame resistance in MM that was refractory to both lenalidomide and bortezomib.[90] In February 2013, pomalidomide was approved by the FDA for use in patients with MM who have received at least 2 previous therapies (including lenalidomide and bortezomib) and have disease progression on or within 60 days of completion of the last therapy. [7, 8]

This approval was supproted by a phase II study comparing pomalidomide plus low-dose dexamethasone with pomalidomide alone in patients with relapsed MM refractory to their last therapy who had received lenalidomide and bortezomib. Of the 221 patients who were evaluable for response, 29.2% in the pomalidomide plus low-dose dexamethasone arm achieved a partial response or better, compared with 7.4% in the pomalidomide-alone arm.[7] The median duration of response for the former was 7.4 months; the median had not been reached for the latter.

In a more recent study, Miguel et al found that the combination of pomalidomide with low-dose dexamethasone yielded a longer median progression-free survival (PFS) in 455 patients with refractory or relapsed and refractory MM than high-dose dexamethasone alone.[91] In the open-label, randomized study patients received 28-day cycles of either pomalidomide (4 mg/day on days 1-21) plus low-dose dexamethasone (40 mg/day on days 1, 8, 15, and 22) or only high-dose dexamethasone (40 mg/day on days 1-4, 9-12, and 17-20). At follow-up (median, 10 months), median PFS was 4.0 months for the combination therapy group, compared with 1.9 months for the monotherapy group, for a hazard ratio of 0.48. Rates of most adverse events were similar in the 2 groups. [91]

TransplantationUsing the patient’s own (ie, autologous) bone marrow or peripheral blood stem cells facilitates more intense therapy for MM. After harvesting the stem cells from the patient, physicians can use otherwise lethal doses of total body irradiation and chemotherapy and then “rescue” the patient by reinfusing the harvested cells. This process of myeloablative therapy, followed by the reinfusion of stem cells, is termed autologous stem cell transplantation.

This sequence of therapy allows physicians to use melphalan at an approximately 10-20 times higher dose than is used in standard therapy.[49] In autologous transplantation, the reinfused stem cells or bone marrow act as a support to the patient but do not offer additional anticancer effects.

Tandem autologous transplantation has been proposed as a way of overcoming the incomplete response to a single transplant. A 2-arm trial of single versus tandem transplantation revealed no difference in overall survival at 54 months.[92]

Another 2-arm study that compared single versus tandem transplants for newly diagnosed MM showed that whereas double autologous stem cell transplantation effected superior complete or near-complete response rates, relapse-free survival, and event-free survival (EFS), it failed to significantly prolong overall survival.[93]Benefits offered by double autologous stem cell transplantation were particularly evident among patients who failed to achieve at least a near-complete response after one autotransplantation.

A review of long-term outcomes of several autotransplantation trials for MM found that tandem transplantations were superior to both single transplantations and standard therapies and that tandem transplantations with thalidomide were superior to trials without thalidomide. [94] However, postrelapse survival (PRS) was superior when initial EFS exceeded 1280 days and when tandem transplantations had been administered, whereas PRS was shorter when EFS lasted 803 days or less and when trials had included thalidomide and bortezomib.[94]

Two randomized prospective studies compared standard chemotherapy with high-dose autologous transplantation. In the first study of 200 subjects, researchers observed better response rates (ie, 81% for the transplantation group vs 57% for the conventionally treated group) and better 5-year event-free survival rates (ie, 28% vs 10%).[95] The second study also showed a significant improvement in event-free survival rates and superior quality of life for subjects treated with the high-dose approach.

In highly selected patients with MM, physicians may use allogeneic (ie, from someone else) transplantation. In this approach, physicians administer myeloablative therapy and infuse stem cells (ie, peripheral blood or bone marrow) obtained from a donor, preferably a human leukocyte antigen (HLA)-identical sibling.

The advantage of this approach over autologous transplantation is that the patient is not at risk of being reinfused with MM cells. In addition, the donor’s immune system may fight the recipient’s cancer (ie, graft vs myeloma effect). Unfortunately, the donor’s immune system may also attack the recipient’s body (ie, graft vs host effect).

Physicians use allogeneic transplantation less often than autologous transplantation in MM patients, for several reasons. First, the risks of complications and death from allogeneic transplantation increase with age, and most patients with multiple myeloma are older than the ideal age for allogeneic transplantation.

Second, the transplantation-related mortality rate is quite high in patients with MM who undergo allogeneic transplantation. The death rate within 100 days of transplantation ranges from 10% to 56% in different case series.

Third, although some survivors experience long-term disease-free results after allogeneic transplantation, a retrospective case-matched analysis of allogeneic versus autologous transplantation showed a median survival of 34 months for the autologous transplantation group and 18 months for the allogeneic group.

The exception to this rule is the rare patient with a twin donor. In a limited study of 25 transplantations involving twins, outcomes with syngeneic transplantations were superior, with reduced transplantation-related mortality.

The development of a nonmyeloablative preparative regimen for MM allogeneic transplantation is changing the equation. A republished report of 52 high-risk patients who underwent nonmyeloablative transplants described a 17% mortality rate.[96] Progression-free survival at 18 months was roughly 30%.

A recently reported phase II trial of autologous stem cell transplantation followed by a nonmyeloablative matched sibling related donor transplant demonstrated this approach to be feasible, with low treatment-related mortality.[97] Further studies are needed to evaluate relative efficacy.

Allotransplants have markedly reduced activity; therefore, the use of nonmyeloablative regimens (mini-allotransplantation) may hold promise for more widely exploiting this feature. [98, 99]

A study by Moreau et al determined that achievement of very good partial response (VGPR) after induction therapy is an important prognostic factor in patients undergoing autologous stem cell transplantation.[100] VGPR was significantly improved with bortezomib-dexamethasone induction therapy.

A study by Harousseau et al also concluded that this combination significantly improved postinduction and posttransplantation complete response/near response rate at at least VGPR rates compared with VAD.[101] Cavo et al also concluded that this combination represents a new standard of care for patients with multiple myeloma who are eligible for transplant.[102]

In MM patients with progressive or relapsing disease following autologous stem-cell transplantation, treatment with the combination of bortezomib, thalidomide and dexamethasone is more effective than treatment with thalidomide and dexamethasone alone, although triple therapy is associated with a greater risk of grade 3 neurotoxicity.[103]

Prophylactic Platelet TransfusionThe results of the Trial of Prophylactic Platelets (TOPPS) showed the benefit of prophylactic platelet transfusions for reducing rates of clinically significant bleeding events in patients with hematologic cancers.[104, 105] In this study of 600 blood cancer patients, 301 were randomly assigned to the no-prophylaxis group and 299 to the group that received prophylactic platelet transfusions.

The proportion of patients who had bleeding events of World Health Organization (WHO) grade 2, 3, or 4 was reduced by 7% in the group that received prophylactic platelet transfusions, as compared with the group that did not.[105] Bleeding of WHO grade 2, 3, or 4 occurred in 151 of 300 patients in the no-prophylaxis group and in 128 of 299 in the prophylaxis group (50% vs 43%; adjusted difference in proportions, 8.4 percentage points; 90% confidence interval [CI], 1.7-15.2; P = .06 for noninferiority).

Interferon Alfa TherapyIntense research has focused on the use of interferon alfa to treat MM. This drug does not appear to be effective for inducing remission, and a randomized controlled trial showed that patients do not benefit from the addition of interferon to melphalan and prednisone. [106] Interferon alfa does appear to prolong remission in selected patients with MM. For this use, it may be administered after conventional chemotherapy or bone marrow (ie, stem cell) transplantation has been completed.

The toxicity of interferon and the availability of alternate interventions have significantly limited the role of interferon alfa.

Radiation TherapyMM is extremely sensitive to radiation. Physicians use radiation to treat symptomatic lesions and to stabilize bones at risk for fracture. Physicians also use radiation to treat spinal cord compression. Low-dose, double-hemibody irradiation has been studied as systemic therapy for refractory or relapsed MM, but without dramatic success.

If the pain is mild and if less than 50% of the bone is involved, a course of irradiation can be initiated. Radiation treatment can result in additional early bone loss due to inflammation, and weight bearing should be limited for the first 4-6 weeks.

Bisphosphonate TherapyBisphosphonates are specific inhibitors of osteoclastic activity and are used to treat bone resorption. They also have a role in the secondary prevention of bony complications in MM, including hypercalcemia, pathologic fracture, and spinal cord compression. Intravenous (IV) pamidronate (Aredia) has been shown to be effective in preventing skeletal complications; zoledronic acid (Zometa) may be significantly more potent than pamidronate. A study by Morgan et al found that the early use of zoledronic acid was superior to clodronic acid in preventing skeletal-related events among patients with newly diagnosed MM, irrespective of bone disease status at baseline.[107]

A randomized placebo-controlled trial of pamidronate in subjects with MM who had experienced one skeletal event demonstrated that the medication reduced the likelihood of a second skeletal event from 41% to 24% after 9 months of therapy.[108] The investigators also noted improvements in pain, narcotic usage, and quality of life scores.

A 2007 systematic review of the use of bisphosphonates in MM confirmed a number-needed-to-treat (NNT) of 10 for the prevention of vertebral fractures, although no impact on mortality was seen. [109]

Recent evidence suggests that osteonecrosis of the jaw may occur in some patients receiving bisphosphonate therapy.[110] The management of osteonecrosis of the jaw is evolving, and no definitive data have yet been published. Collaboration with knowledgeable dentists and oral surgeons is essential. Dental extractions appear to be a risk factor, and guidelines recommend avoiding this where possible.

The American Society of Clinical Oncology (ASCO) issued a clinical practice guideline governing bisphosphonate therapy for MM patients who have lytic destruction of bone or compression fracture of the spine from osteopenia.[111]ASCO recommends IV pamidronate, 90 mg delivered over at least 2 hours, or zoledronic acid, 4 mg delivered over at least 15 minutes every 3-4 weeks. Because the risk for osteonecrosis of the jaw is 9.5-fold greater with zoledronic acid than with pamidronate, patients may prefer pamidronate.[111]

Zoledronic acid doses should be reduced in patients with preexisting mild to moderate renal impairment (estimated creatinine clearance, 30-60 mL/min); the drug is not recommended for use in patients with severe renal impairment.[111] All patients receiving pamidronate or zoledronic acid therapy should be screened every 3-6 months for albuminuria. If unexplained albuminuria (>500 mg/24 hours) is found, ASCO recommends discontinuation of the drug until the renal problems resolve. [111]

A study by Morgan et al revealed the anticancer properties of zoledronic acid in addition to its ability to reduce skeletal-related events in multiple myeloma.[112]

Adjunctive Therapy for ComplicationsPotential complications of MM include the following:

Skeletal complications (eg, pain, hypercalcemia, pathologic fracture, spinal cord compression) Infection

Anemia Renal failure Amyloidosis

According to the 2011 NCCN MM guidelines, novel drugs such as bortezomib can be used with dexamethasone as primary treatment for amyloidosis. The combination of cyclophosphamide/thalidomide/dexamethasone is also recommended for the primary treatment of amyloidosis.[2]

Treatment for myeloma-induced hypercalcemia is the same as that for other malignancy-associated hypercalcemia; however, the dismal outcome observed with hypercalcemia in solid tumors is not observed in MM.

To treat pathologic fractures, physicians should orthopedically stabilize (ie, typically pin) and irradiate these lesions. Careful attention to a patient’s bony symptoms, intermittent radiographic surveys, and the use of bisphosphonates may be useful to prevent fractures. [109, 113, 114] (See Surgical Care and Bisphosphonate Therapy.)

Spinal cord compression is one of the most severe adverse effects of MM. The dysfunction may be reversible, depending on the duration of the cord compression; however, once established, the dysfunction is only rarely fully reversed. Patients who may have spinal cord compression need a rapid evaluation, which may necessitate urgent transfer to a center equipped with MRI for diagnosis or a center with a radiation oncologist for urgent therapy.

Patients with spinal cord compression due to MM should begin corticosteroid therapy immediately to reduce swelling. Urgent arrangements must be made for radiation therapy in order to restore or stabilize neurologic function. Surgery may be indicated. (See Surgical Care.)

Erythropoietin may ameliorate anemia resulting from either MM alone or from chemotherapy and has been shown to improve quality of life. [115] A systematic review failed to demonstrate a survival advantage for the use of erythropoietin agents in the treatment of patients with cancer-related anemia. [116]

Acute renal impairment related to MM is typically managed with plasmapheresis to rapidly lower circulating abnormal proteins. Data about this approach are limited, but a small randomized study showed a survival advantage with the use of apheresis. [14] Hydration (to maintain a urine output of >3 L/d), management of hypercalcemia, and avoidance of nephrotoxins (eg, intravenous contrast media, antibiotics) are also key factors. Conventional therapy may take weeks to months to show a benefit.

Renal impairment resulting from MM is associated with a very poor prognosis. A recent case series demonstrated that patients with renal failure from myeloma may benefit from autologous stem cell transplants, and as many as one third may demonstrate improvement in their renal function with this approach.[117] A report by Ludwig et suggests that bortezomib-based therapy may restore renal function in MM patients with renal failure.[13]

Surgical CareSurgical therapy for MM is limited to adjunctive therapy. It consists of prophylactic fixation of pending fractures, decompression of the spinal cord when indicated, and treatment of pathologic fractures.

Prophylactic treatment of impending fractures and the treatment of pathologic fractures may involve bracing. In general, bracing is not effective for the long bones, though it may be effective for treating spinal involvement without neurologic compromise.

Intramedullary fixation is the procedure of choice when surgery is necessary. If the metaphysis or joint surface is involved, resection of the diseased bone and reconstruction with a total joint or, more typically, a hemiarthroplasty is indicated. Modular implants may be required. Severe destruction of the diaphysis may require reconstruction with combinations of methylmethacrylate, intramedullary nails, or resection and prosthetic replacement.

Although surgical decompression of the spinal cord is sometimes appropriate, posterior laminectomy in this population has been reported to have a mortality rate of 6-10% and to not be superior to radiation. This surgical approach is probably best reserved for cases of MM in which radiation fails. Newer surgical interventions, such as kyphoplasty, in which cement is injected into compressed vertebrae, have been shown to improve function with few complications, although the studies reported have been small.

Dietary MeasuresPatients with MM who are receiving bisphosphonate therapy should include adequate calcium in their diet.

The dietary supplement curcumin may slow the progression of smoldering multiple myeloma. [118]

Physical ActivityPatients with MM should be encouraged to be physically active to the extent appropriate for their individual bone status. Physical activity may help maintain bone strength.

In general, patients with activity-related pain in either the femur or the tibia should be given a walker or crutches until a radiographic workup has been completed. Radiation therapy elicits an inflammatory response, and for the first 6 weeks or so, bony resorption may actually weaken the target bone. Given that prophylactic treatment of an impending fracture is usually easier than reconstruction of a pathologic fracture, one should have a low threshold for initiating protected weight bearing.

Prevention of Multiple MyelomaNo preventive measures for MM are known. A study by Chang et al found that routine residential UV radiation exposure may have a protective effect against lymphomagenesis through mechanisms that may be independent of vitamin D.[119]

ConsultationsPatients with MM often benefit from the expertise of an orthopedic surgeon who is versed in oncologic management because prophylactic fixation of impending pathologic fractures is occasionally warranted.

From the orthopedic perspective, because patients with MM have significant systemic comorbidities—including potentially severe hematologic, infectious, and metabolic diseases—the orthopedic surgeon treating the skeletal disease in a patient with myeloma should work in conjunction with the radiation oncologists and the medical oncologists.

Long-Term MonitoringPatients with MM may require hospitalization for the treatment of pain or bony pathology.

Patients with MM are at high risk of infection, especially from encapsulated organisms. Vaccinations against pneumococcal organisms and influenza are recommended. Consider vaccinating patients against Haemophilus influenzae B. Consideration of the use of the herpes zoster vaccine should be given.

The following laboratory results are helpful in the follow-up care of patients with MM:

Complete blood count (CBC), chemical profile 7 (especially blood urea nitrogen [BUN] and serum creatinine), serum calcium, and serum uric acid, and serum protein electrophoresis (SPEP) findings.

M-component level in the serum and/or urine. (This is an indicator of tumor burden; a reduction with chemotherapy is used as a sign of a treatment response.)

Serum beta-2 microglobin. (An elevated level indicates a large malignant cell mass, renal impairment, or both.)

Serum lactic dehydrogenase (LDH) level. (A high level is predictive of an aggressive lymphomalike course.)

Medication SummaryMultiple myeloma (MM) is treated with several categories of medications. Chemotherapeutic agents are used to reduce the disease burden, and bisphosphonates are used to promote bone healing and to provide secondary prophylaxis against skeletal-related events (eg, hypercalcemia, bone fracture, spinal cord compression, need for radiation, and need for surgery). In addition, erythropoietin is used to treat anemia, either alone or in conjunction with chemotherapy.

Chemotherapeutic AgentsClass SummaryThe choice of chemotherapy depends on several factors, including the patient’s performance status, age, renal function, desire for inpatient or outpatient therapy, and likelihood of receiving future autologous stem cell transplantation.

In patients with renal failure or highly aggressive disease, therapy with vincristine, Adriamycin (doxorubicin), and dexamethasone (VAD) may be preferred. In elderly patients or patients in whom autologous transplantation is not possible in the future, melphalan and prednisone (MP) therapy is preferred because of its ease of administration and low toxicity.

View full drug informationCyclophosphamide (Cytoxan, Neosar) 

Cyclophosphamide is chemically related to nitrogen mustards. It is an alkylating agent, and its mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

View full drug informationMelphalan (Alkeran) 

The most widely used regimen is MP. Melphalan is an alkylating agent and a derivative of mechlorethamine that inhibits mitosis by cross-linking DNA strands. It is indicated for the palliative treatment of multiple myeloma.

View full drug informationDoxorubicin (Adriamycin, Rubex) 

Doxorubicin is part of VAD therapy. It inhibits topoisomerase II and produces free radicals, which may cause destruction of DNA; these 2 events, in turn, can inhibit growth of neoplastic cells.

View full drug informationVincristine (Oncovin) 

Vincristine inhibits cellular mitosis by inhibition of intracellular tubulin function, binding to microtubules, and synthesis of spindle proteins in the S phase. Vincristine is part of VAD therapy. Its mechanism of action is complex and includes depolymerization of microtubules.

View full drug informationBortezomib (Velcade) 

Bortezomib is the first drug approved in the group of anticancer agents known as proteasome inhibitors. The proteasome pathway is an enzyme complex existing in all cells, which degrades ubiquitinated proteins that control the cell cycle and cellular processes and maintains cellular homeostasis. Reversible proteasome inhibition disrupts pathways supporting cell growth, thus decreasing cancer cell survival. Bortezomib is indicated for patients with multiple myeloma. Development of peripheral neuropathy is a limiting factor. A decreased incidence of peripheral neuropathy has been observed with SC administration compared with the IV route.

View full drug information

Doxorubicin liposomal (Doxil) 

Doxorubicin liposomal is a pegylated formulation that protects the liposomes and, thereby, increases blood circulation time. The drug inhibits topoisomerase II and produces free radicals, which may cause destruction of DNA; these 2 events can, in turn, inhibit growth of neoplastic cells.

View full drug informationCarfilzomib (Kyprolis) 

Proteasome inhibitor; elicits antiproliferative and proapoptotic activities in vitro in solid and hematologic tumor cells. Indicated for the treatment of multiple myeloma in patients who have received at least 2 prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy.

CorticosteroidsClass SummaryCorticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body’s immune response to diverse stimuli.

View full drug informationPrednisone (Deltasone, Orasone, Meticorten) 

The most widely used regimen is MP. Prednisone stabilizes lysosomal membranes and suppresses lymphocyte and antibody production.

View full drug informationDexamethasone (Decadron) 

Dexamethasone is part of VAD therapy. Many believe that the high-dose steroid component of VAD accounts for much of its efficacy. In some patients, high-dose dexamethasone alone may produce significant clinical responses. Dexamethasone stabilizes lysosomal membranes and suppresses lymphocyte and antibody production.

InterferonsClass SummaryInterferons are naturally produced proteins with antiviral, antitumor, and immunomodulatory actions. Alfa-, beta-, and gamma-interferons may be administered topically, systemically, and intralesionally.

Interferon alfa-2A (Roferon A) 

Interferon alfa-2A is a protein product manufactured by recombinant DNA technology. The mechanism of the antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of the host immune response may play important roles.

View full drug informationInterferon alfa-2B (Intron A) 

Interferon alfa-2B is a protein product manufactured by recombinant DNA technology. The mechanism of antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles.

BisphosphonatesClass SummaryBisphosphonates inhibit bone resorption via action on osteoclasts or osteoclast precursors.

View full drug information

Pamidronate (Aredia) 

Pamidronate inhibits normal and abnormal bone resorption. It appears to inhibit bone resorption without inhibiting bone formation and mineralization. The optimal timing and duration of therapy are being studied. Pamidronate is administered intravenously (IV) over 2 hours. Newer drugs similar in structure and function are being studied and may have improved efficacy and greater convenience.

View full drug informationZoledronic acid (Zometa) 

Zoledronic acid inhibits bone resorption, possibly by acting on osteoclasts or osteoclast precursors. It is effective in treating the hypercalcemia of malignancy.

Colony-stimulating FactorsClass SummaryColony-stimulating factors induce erythropoiesis.

View full drug informationEpoetin alfa, erythropoietin (Epogen, Procrit) 

Erythropoietin stimulates the division and differentiation of committed erythroid progenitor cells and induces the release of reticulocytes from bone marrow into the blood stream.

Erythropoietin is a naturally occurring hormone produced by the kidneys to stimulate bone marrow production of red blood cells. In patients with MM, administration of exogenous erythropoietin may correct anemia, leading to a significant improvement in performance status and quality of life.

Immunosuppressant AgentsClass SummaryImmunosuppressant agents inhibit key factors in the immune system that are responsible for immune reactions.

Thalidomide (Thalomid) 

Thalidomide, when used in combination with dexamethasone, is indicated for the treatment of patients with newly diagnosed multiple myeloma. Thalidomide is an immunomodulatory agent that may suppress excessive production of tumor necrosis factor (TNF)-alpha and may down-regulate selected cell-surface adhesion molecules involved in leukocyte migration. Because of concerns regarding teratogenicity, thalidomide can only be prescribed by registered physicians and is dispensed by registered pharmacists. Patients must participate in ongoing surveys to receive therapy, and only a 28-d supply can be prescribed at a time.

Lenalidomide (Revlimid) 

Lenalidomide in combination with dexamethasone is indicated for multiple myeloma in patients treated with at least 1 year of prior therapy. It is structurally similar to thalidomide. Lenalidomide elicits immunomodulatory and antiangiogenic properties. It inhibits proinflammatory cytokine secretion and increases anti-inflammatory cytokines from peripheral blood mononuclear cells.

PrognosisMM is a heterogeneous disease, with survival ranging from 1 year to more than 10 years. Median survival in unselected patients with MM is 3 years. The 5-year relative survival rate is around 35%. Survival is higher in younger people and lower in the elderly.[9] It was estimated that about 10,580 Americans (5,640 men and 4,940 women) would die of multiple myeloma in 2008.[9]

The tumor burden and the proliferation rate are the 2 key indicators for the prognosis in patients with MM. Many schemas have been published to aid in determining the prognosis. One schema uses C-reactive protein (CRP) and beta-2 microglobulin (which is an expression of tumor burden) to predict survival as follows[20] :

If levels of both proteins are less than 6 mg/L, the median survival is 54 months. If the level of only one component is less than 6 mg/L, the median survival is 27 months. If levels of both protein values are greater than 6 mg/L, the median survival is 6 months.

Poor prognostic factors include the following:

Tumor mass Hypercalcemia Bence Jones proteinemia Renal impairment (ie, stage B disease or creatinine level >2 mg/dL at diagnosis)

The prognosis by treatment is as follows:

Conventional therapy: Overall survival is approximately 3 years, and event-free survival is less than 2 years.

High-dose chemotherapy with stem-cell transplantation: The overall survival rate is greater than 50% at 5 years.

Serum amyloid P retention: More than 50% of patients have a median survival of approximately 11 months.

Serum amyloid P retention: Median survival is 24 months.Bacterial infection is the leading cause of death in patients with myeloma. [9]

A study by Larsen et al found that a significant reduction in plasma cell proliferation in patients with newly diagnosed MM is an important predictor of survival.[21]