Multiple Myeloma and Related Disorders
Summary of Key Points
Multiple Myeloma
• Multiple myeloma accounts for approximately 10% of hematologic malignancies.
• An estimated 22,000 new cases occurred in the United States in 2012.
• Almost all cases are thought to evolve from an asymptomatic premalignant stage termed monoclonal gammopathy of undetermined significance (MGUS).
Diagnosis
• The most common presenting symptoms are fatigue and bone pain.
• Osteolytic bone lesions are the hallmark of the disease.
• Hypercalcemia is found in one fourth of patients; the serum creatinine level is elevated in almost one half of patients.
• Diagnosis requires 10% or more clonal plasma cells in the bone marrow and/or a biopsy-proven plasmacytoma, monoclonal (M) protein in the serum and/or urine (except in patients with true nonsecretory myeloma), and evidence of end organ damage (hypercalcemia, renal insufficiency, anemia, or bone lesions) attributable to the underlying plasma cell disorder. Patients with 60% or more clonal plasma cells in the bone marrow are considered to have multiple myeloma even in the absence of end organ damage.
• M proteins can be detected by serum protein electrophoresis (SPEP) and immunofixation in 93% of patients; addition of urine protein electrophoresis (UPEP) and urine immunofixation or the serum free light chain (FLC) assay will increase sensitivity to 97% or higher.
Prognosis
• The International Staging System (ISS) divides patients into three distinct stages and prognostic groups based on the β2-microglobulin and albumin levels in the serum.
• High-risk myeloma is defined as the presence of any one or more of the following: deletion 17p, immunoglobulin heavy-chain (IgH) translocations t(14;16) or t(14;20), plasma cell leukemia, increased lactate dehydrogenase level, and high-risk signature on gene expression profiling studies. The translocation t(4;14) is considered intermediate risk, and all others indicate standard risk.
Treatment
• Newly diagnosed patients are categorized as having standard-, intermediate-, and high-risk myeloma based on specific prognostic factors.
• Initial therapy for patients with standard-risk disease is with regimens such as lenalidomide–low-dose dexamethasone (Rd) or bortezomib-cyclophosphamide-dexamethasone (VCD). A bortezomib-containing regimen is preferred as initial therapy for patients with intermediate- and high-risk myeloma.
• After 4 months of initial therapy, patients eligible for transplantation can pursue early or delayed autologous stem cell transplantation (ASCT). If early ASCT is used, a second ASCT is considered in patients who do not achieve a very good partial response or better with the first ASCT. If transplant is delayed, patients will continue on the induction chemotherapy drugs at lower doses until plateau or progression occurs.
• Options for relapsed disease include thalidomide, lenalidomide, bortezomib, alkylating agents, anthracyclines, and corticosteroids alone or in combination.
Monoclonal Gammopathy of Undetermined Significance (MGUS)
• MGUS is an asymptomatic, premalignant, clonal plasma cell proliferative disorder defined by the presence of a serum M protein level less than 3 g/dL, bone marrow plasma cells less than 10%, and absence of anemia, hypercalcemia, lytic bone lesions, or renal failure that can be attributed to the plasma cell proliferative disorder.
• MGUS is found in approximately 3% of the general population 50 years of age and older.
• Patients with three adverse risk factors, namely, an abnormal serum FLC ratio, non-immunoglobulin G (IgG) MGUS, and a high serum M protein level (≥15 g/L), have a risk of progression to multiple myeloma or related malignancy at 20 years of 58% (high-risk MGUS) compared with 37% in patients with any two of these risk factors present (high-intermediate risk MGUS), 21% with one risk factor present (low-intermediate risk MGUS), and 5% when none of the risk factors was present (low-risk MGUS).
• The current standard of care for MGUS is observation alone, without therapy.
Smoldering Multiple Myeloma (SMM)
• SMM is defined by the presence of a serum IgG or IgA M protein greater than or equal to 3 g/dL and/or bone marrow plasma cells of 10% to 60% and absence of anemia, hypercalcemia, lytic bone lesions, or renal failure that can be attributed to plasma cell proliferative disorder.
• The risk of progression to myeloma or related malignancy is much higher in SMM compared with MGUS, at 10% per year versus 1% per year, respectively.
• The standard of care is observation alone until evidence of progression to myeloma.
Waldenström Macroglobulinemia
• Waldenström macroglobulinemia is a clonal IgM M protein–secreting lymphoid/plasma cell disorder that currently also includes the entity referred to previously as lymphoplasmacytic lymphoma.
• Median survival is approximately 5 years.
• There are four options for initial therapy: rituximab, purine nucleoside analogs, alkylators, and combination chemotherapy. Unfortunately, there are no randomized data to determine the best option; therapy is typically decided based on the age of the patient and the aggressiveness of the presentation.
• Options listed for initial therapy can also be tried at the time of relapse. The same initial therapy can be tried again at relapse if there was an adequate interval between cessation of therapy and relapse. Other options for relapsed, refractory disease include stem cell transplantation, interferon-α, thalidomide, and bortezomib.
• Plasmapheresis is indicated for the treatment of hyperviscosity syndrome.
Systemic AL (Immunoglobulin Light Chain) Amyloidosis
• Amyloid is a fibrillar proteinaceous material detected with Congo red staining based on a characteristic apple-green birefringence under polarized light.
• It consists of rigid, linear, nonbranching fibrils, 7.5 to 10 nm in width, aggregated in a β-pleated sheet conformation. There are several distinct types of amyloidosis classified based on the protein composition of the amyloid material.
• AL (immunoglobulin light chain) amyloidosis refers to the type of amyloidosis derived from the variable portion of a monoclonal light chain. It should be suspected when patients with the appropriate clinical syndrome (e.g., nephrotic syndrome, axonal neuropathy, restrictive cardiomyopathy) display evidence of a plasma cell proliferative disorder such as a serum or urine M protein.
• Patients are offered ASCT if eligible. Patients not eligible for ASCT (as shown by poor performance status, major comorbidities, three or more organs involved, and advanced cardiac amyloidosis) are treated with melphalan plus high-dose dexamethasone or with a bortezomib-based regimen.
• Thalidomide (or lenalidomide) plus dexamethasone are second-line treatment options for patients with systemic AL amyloidosis.
Solitary Plasmacytoma
• Solitary plasmacytomas may be confined to bone (solitary bone plasmacytoma) or occur in extramedullary sites (extramedullary plasmacytoma).
• Patients with solitary plasmacytoma are at risk for progression to multiple myeloma.
• Treatment consists of radiation in the range of 40 to 50 Gy to the involved site.
• Disease-free survival rate at 10 years ranges from 25% to 50%.
1. A 50-year-old patient has immunoglobulin A (IgA) λ M protein of 2.5 g/dL, small monoclonal IgA κ fragment in the urine, 15% clonal plasma cells in the bone marrow, and no bone lesions, hypercalcemia, or renal failure. His hemoglobin value is 14.8 g/dL, with normal bone marrow cytogenetics. The most likely diagnosis is:
2. Which of the following indicates high-risk myeloma?
3. Methods by which bortezomib neuropathy can be lowered include
4. Which of the following is not recommended as initial therapy for elderly myeloma patients not eligible for stem cell transplantation?
A Melphalan-prednisone-thalidomide (MPT)
B Bortezomib-melphalan-prednisone (VMP)
C Thalidomide-dexamethasone (TD)
5. Which of the following agents can be administered safely in patients with acute renal failure due to cast nephropathy?
1. Answer: B. This patient has smoldering multiple myeloma. Despite 15% plasma cells in the marrow, there are no signs of end organ damage. End organ damage that can be attributed to the plasma cell proliferative disorder or a finding of more than 60% bone marrow plasma cells is needed for the diagnosis of multiple myeloma. A diagnosis of MGUS requires clonal bone marrow plasma cells of less than 10%. Idiopathic Bence Jones proteinuria requires significant excretion of free monoclonal light chains without intact immunoglobulin in the urine. Waldenström macroglobulinemia is IgM in nature, and the diagnosis requires evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder.
2. Answer: A. The presence of 17p deletion, t(14;16), t(14;20) is considered indicative of high-risk myeloma. Hyperdiploidy is due to the presence of trisomies and is standard risk. Similarly, t(11;14) is also considered standard risk. With modern therapy, t(4;14) is considered intermediate risk.
3. Answer: E. Results of clinical trials show that the rate of severe bortezomib neuropathy can be markedly decreased by subcutaneous administration and by using a once-weekly schedule. The twice-weekly schedule is associated with a 15% risk of grade 3 or higher neuropathy.
4. Answer: C. Thalidomide-dexamethasone (TD) is associated with inferior overall survival in elderly patients compared with melphalan and prednisone. Therefore, it is not recommended as initial therapy. MPT and VMP have shown survival benefit in randomized trials compared with melphalan and prednisone. Rd has shown safety and efficacy in elderly patients. VCD is a modification of VMP that is associated with less toxicity.
5. Answer: E. Bortezomib and thalidomide are not renally excreted and can be used safely in renal failure without any dose modification. Lenalidomide requires major dose adjustment in renal failure, and the optimum dosing schedule, safety, and efficacy of this agent in acute renal failure is not well known.
