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I. MULTIPLE MYELOMA
A. Subjective. Presenting symptoms of multiple myeloma (MM) may include bone pain, fatigue, and recurrent bacterial infections. Lethargy is a common complaint, occurring in up to one-third of patients at diagnosis and usually attributable to ongoing anemia and metabolic derangements. Symptomatic hypercalcemia is common at diagnosis and may occur in approximately 30% of patients. Weight loss may be an accompanying sign in up to 20% of patients. More uncommon events include neuropathy secondary to the monoclonal paraprotein (M protein), a feature of roughly 5% of newly diagnosed MM patients. Tumor fever is rare, and is a diagnosis of exclusion; febrile MM patients are infected until proven otherwise. One-third of patients have a prior diagnosis of a plasma cell proliferative process preceding the diagnosis of MM.
B. Objective. Physical examination may reveal pallor, bony tenderness, a subcutaneous mass secondary to a plasmacytoma, or focal neurologic signs due to spinal cord compression. Hepatomegaly, splenomegaly, and lymphadenopathy are rare.
C. Workup and staging
1. Laboratory. Anemia is present in three-quarters of patients at diagnosis and is generally normochromic and normocytic. White blood cell (WBC) and platelet counts are usually preserved, although marrow replacement by MM may lead to pancytopenia. Examination of the peripheral smear may reveal rouleaux formation. The erythrocyte sedimentation rate (ESR) is generally elevated in MM. Almost 20% of patients will have a creatinine level of more than 2.0 mg/dL at diagnosis. Hypercalcemia due to extensive bone involvement and hyperuricemia can worsen renal function. Albumin has prognostic significance and is a component of the International Staging System. A serum protein electrophoresis (SPEP) and urinary protein electrophoresis (UPEP) should be performed on patients in whom the diagnosis of MM is suspected. Immunofixation is more sensitive than electrophoresis and is done to confirm the presence and type of a paraprotein (M protein). An M protein is detectable in the serum of more than 90% of patients. The paraprotein is an IgG in approximately half the cases and an IgA in 20% of cases. IgD, IgE, and IgM paraproteins are very rare. IgM paraproteins are almost always associated with Waldenstrom’s macroglobulinemia (WM). Free light chains are present in approximately 15% of patients. Kappa (κ) light chains are more common than lambda (λ) by approximately 2:1. Bence–Jones proteinuria occurs when light chains are freely filtered at the glomerulus and are excreted in the urine. The light chain is rarely detected on SPEP, but will be detected on UPEP. If light chains are detected in the urine, a 24-hour urine specimen should be collected to quantify the protein and monitor response to treatment. The serum-free light chain (SFLC) assay now allows for quantification of light chains in the serum in a direct and efficient manner. Nonsecretory myeloma constitutes less than 5% of patients. These patients have no paraprotein detectable on SPEP, UPEP, and immunofixation. However, a majority will have an abnormal SFLC κ:λ ratio.
2. Radiographic imaging. All patients should have a skeletal survey including the skull, spine, pelvis, femurs, and humeri. Almost 80% of patients have at least one abnormality on radiographs with two-thirds of patients having punched-out lytic lesions. Pathologic fractures, vertebral compression fractures, or osteoporosis are each present in one-fourth of patients. Radionuclide bone scans detect osteoblastic response and are therefore less sensitive than plain radiographs in detecting skeletal involvement by MM. Magnetic resonance imaging (MRI) of the spine is more sensitive than plain radiographs in detecting early lesions, and may be considered in patients with negative skeletal surveys or as clinically indicated for suspicious symptoms. Patients thought to have solitary plasmacytomas should undergo MRI imaging to exclude systemic disease. 18F-fluorodeoxyglucose positron emission tomography (FDG PET) is now approved for initial workup and follow-up of patients with MM. It is of particular benefit in those with nonsecretory or oligosecretory disease, an increasing problem in refractory and relapsed patients.
3. Bone marrow evaluation. Patients should undergo bone marrow biopsy and aspiration for quantification of bone marrow plasma cells. The malignant plasma cells stain positive for CD138. Monoclonality is established by immunostains that demonstrate κ– or λ-restricted cytoplasmic immunoglobulin staining. Karyotyping is now recommended as a prognostic tool. Conventional cytogenetic analysis in MM is often difficult because of the low-growth fraction and paucity of mitotic cells. However, using a variety of fluorescent in situ hybridization (FISH) probes (del 13q, t[4;14], t[11;14], del 17p, t(14, 16), t(14, 20)) on interphase cells, cytogenetic abnormalities are commonly found in MM. The plasma cell labeling index (PCLI) performed on bone marrow biopsy measures the percentage of MM cells that synthesize DNA; an elevated labeling index implies a more aggressive MM and poor prognosis. Assessment by multiparameter flow cytometry is currently under investigation for the identification of minimal residual disease (MRD). Patients who achieve an MRD negative complete response (CR) may have an improved prognosis as compared with those with persistent disease after treatment.
D. Diagnosis. The historic criteria for the diagnosis of MM have been supplanted by the International Myeloma Working Group (IMWG) criteria for the diagnosis of plasma cell dyscrasias (Table 29-1). End-organ damage is the defining feature that separates MM from a monoclonal gammopathy or smoldering myeloma. Revised criteria have recently been published that update the IMWG criteria (Table 29-2). These criteria add several biomarkers as well as radiographic findings as MM defining events.
E. Staging. In the past, MM was staged according to the Durie–Salmon staging system. In the modern era, this system has been replaced by the International Staging System (Table 29-3), a simplified system that utilizes only the β-2-microglobulin and albumin.
F. Treatment. The initial treatment decision revolves around whether or not a patient is considered a transplant candidate.
1. Transplant eligible. High-dose chemotherapy (HDT) with autologous stem cell transplant is considered standard of care for transplant-eligible patients. Response rates (RRs) to HDT approach 90% with approximately half the number of patients achieving CR.
a. Induction therapy. Patients suitable for transplant usually undergo induction therapy with 4 to 6 months of a two- or three-drug regimen including a proteasome inhibitor, immunomodulatory agent (Thalidomide or Lenalidomide), and corticosteroid.
Three drug regimens such as Bortezomib (bortezomib), Lenalidomide (Revlimid), and Dexamethasone (VRD) or Bortezomib, Cyclophosphamide, and Dexamethasone (VCD) have shown improved efficacy with increased rates of CR when compared with two-drug regimens. Long-term data for an overall survival (OS) benefit with these regimens are still maturing. Since there are only limited data comparing the available regimens, the therapeutic decisions should be made on the basis of patient characteristics and side-effect profiles. Alkylating agents, such as melphalan, should be avoided prior to stem cell collection in transplant-eligible patients as they are toxic to stem cells.
b. Stem cell collection and transplant. Following induction therapy, patients undergo stem cell collection, consolidative HDT, and transplant. Alternatively, patients may undergo harvest and stem cell storage first, and then proceed with additional conventional therapies, postponing transplant until first relapse. Randomized trials have shown equivalent survival with these two approaches. However, quality-of-life analysis and event-free survival favor early transplant. Conditioning for transplant with single-agent melphalan is the standard of care. Although controlled trials of transplant generally excluded patients older than 65 years, improvements in supportive care have allowed the application of high-dose therapy and autologous transplant to patients older than 70. Medicare approves this procedure for patients up to 78 years of age. Toxicities of high-dose therapy include mucositis and infectious complications. The overall transplant-related mortality is 1% to 2%. Repeated HDT and transplant within 6 months (“tandem transplant”) may provide a survival benefit in patients who have less than a very good partial response (less than 90% reduction in paraprotein) after their first transplant.
IMWG Classification System |
Multiple myeloma | M protein in serum and/or urine |
| Bone marrow (clonal) plasma cells ≥10% and/or plasmacytoma |
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Smoldering myeloma | M protein in serum ≥3.0 g/dL or |
| Bone marrow clonal plasma cells ≥10% |
| No evidence of related end-organ dysfunctiona |
MGUS | M protein in serum <3.0 g/dL |
| Bone marrow clonal plasma cells <10% |
| No evidence of other B-cell proliferative disorders |
| No evidence of related end-organ dysfunctiona |
Solitary plasmacytoma of bone | No M protein in serum and/or urinec |
| Single area of bone destruction due to clonal plasma cells |
| Bone marrow not consistent with multiple myeloma |
| Normal skeletal survey (and MRI of spine and pelvis if done) |
| No related organ or tissue impairment (other than solitary bone lesion)a |
Extramedullary plasmacytoma | No M protein in serum and/or urinec |
| Extramedullary tumor of clonal plasma cells |
| Normal bone marrow |
| Normal skeletal survey |
| No related organ or tissue impairmenta |
MGUS, monoclonal gammopathy of unknown significance; MRI, magnetic resonance imaging.
aCRAB criteria: include hypercalcemia ≥10.5 mg/dL, renal insufficiency with Cr >2 mg/dL, anemia >2 g/dL below lower limit of normal or <10 g/dL, or bone lesions (lytic lesions or osteoporosis).
bA variety of other types of end-organ dysfunctions can occasionally occur and lead to a need for therapy. Such dysfunction is sufficient to support a classification of myeloma if proven to be myeloma related.
cA small M-component may sometimes be present.
Revised International Myeloma Working Group Classification System |
Multiple myeloma | M protein in serum and/or urine |
| Bone marrow (clonal) plasma cells cells ≥ 10% and/or plasmacytoma |
| Related end-organ dysfunction (≥1 of CRAB Criteria)a,c Any one or more biomarker of malignancyb |
Smoldering myeloma | M protein in serum ≥3.0 g/dL or urinary M protein ≥500mg |
| Clonal bone marrow plasma cells 10–60% |
| Absence of myeloma defining eventsb or amyloidosis |
MGUS, monoclonal gammopathy of unknown significance; MRI, magnetic resonance imaging.
aCRAB Criteria: includes hypercalcemia ≥11 mg/dL or 1mg/dL > than upper limit of normal, renal insufficiency with CrCl <40mL/min or serum Creatinine >2 mg/dL, anemia >2 g/dL below lower limit of normal or <10 g/dL, or bone lesions (lytic lesions seen on skeletal radiography, CT or PET-CT).
bClonal bone marrow plasma cell percentage ≥ 60%, Involved: uninvolved serum free light chain ratio of ≥100, >1 focal lesions on MRI studies.
cA variety of other types of end-organ dysfunctions can occasionally occur and lead to a need for therapy.
Such dysfunction is sufficient to support a classification of myeloma if proven to be myeloma related.
2. Transplant ineligible. Newly diagnosed patients ineligible for transplant constitute the majority of cases. The goals of therapy are to gain quick control of disease and limit complications. Numerous regimens exist for management of these patients. Historically, Melphalan and Prednisone (MP) had been the mainstay of therapy. With the advent of novel agents, randomized trials noted superior results for therapies combining MP with newer agents. The addition of Thalidomide (MPT) conferred a survival benefit compared with MP. Likewise, MP plus Lenalidomide (MPR) showed a superior RR and Progression Free Survival (PFS) when compared with MP alone. Bortezomib in combination with MP (VMP) has additionally shown improvements in RRs, time to progression, and OS as compared with MP. While triple-drug Melphalan-based regimens improved results for transplant-ineligible patients, recent data suggest that two-drug novel regimens such as Lenalidomide and Dexamethasone may be as good as triple-drug Melphalan-based therapies.
3.
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