Laboratory and pathologic features
Peripheral blood
The peripheral blood smear may reveal a normocytic, normochromic anemia with rouleaux formation. Plasma cells may also be seen.
Bone marrow
Bone marrow examination usually reveals an increased number of plasma cells. These cells are strongly positive for CD38, CD138, and a single class of cytoplasmic immunoglobulin (cIg). The majority of myeloma cells also express CD40 and CD56. Myeloma cells are negative for CD5, CD19, and surface Ig (sIg) expression. CD20 may be expressed in a subset of myeloma patients presenting with the t(11;14) translocation. CD10 expression is generally negative but has sometimes been noted in advanced disease. Monoclonality is frequently demonstrated by immunoperoxidase staining with κ and λ antibodies.
The pattern of bone marrow involvement in plasma cell myeloma may be macrofocal. As a result, plasma cell count may be normal when an aspirate misses the focal aggregates of plasma cells that are better visualized radiographically or on direct needle biopsy, where the degree of plasmacytosis will commensurably be high.
Monoclonal proteins
The types of monoclonal protein produced are IgG (60%), IgA (20%), IgD (2%), IgE (< 0.1%), or light-chain κ or λ only (18%). IgM myeloma is rare, but distinct from its lymphoplasmacytic counterpart, Waldenström's macroglobulinemia. Biclonal elevations of myeloma proteins occur in < 1% of patients, and < 5% of patients are considered to have nonsecretory disease, because their plasma cells do not secrete detectable levels of monoclonal Ig.
Staging and prognosis
Patients with symptomatic myeloma should be staged using either the Durie-Salmon system at diagnosis or the International Staging System (ISS), which is determined at the time systemic therapy is begun. These two systems are compared in Table 3. The Durie-Salmon staging system better provides information on tumor burden, whereas the ISS better serves as a prognostic indicator. The ISS is easier to use, and it classifies patients correctly regardless of their geographic origin (ie, North America, Europe, or Asia), age (ie, ≥ 65 years vs younger age), or type of treatment (ie, conventional chemotherapy vs high-dose therapy followed by autologous stem cell transplantation). More recent studies have provided evidence that the ISS is also reliable in patients treated with thalidomide(Drug information on thalidomide) (Thalomid), bortezomib(Drug information on bortezomib) (Velcade), or lenalidomide (Revlimid), and has prognostic value at relapse.
Durie-Salmon and International Staging systems for multiple myelomaPrognosis
Prognostic indicators may help guide treatment strategy, but the presence of poor prognostic features also should not result in initiation of therapy in patients with asymptomatic myeloma, although they should engender caution. Prognostic factors for risk stratification are well established for conventional chemotherapy. Use of bortezomib and, to some extent, lenalidomide may be able to overcome some features of poor risk, including adverse cytogenetics.
Cytogenetic abnormalities
Cytogenetic abnormalities detected by conventional karyotyping, especially loss of whole chromosome 13 (monosomy) or deletions of parts of chromosome 13 (13q), with hypodiploidy have been associated with inferior survival after both standard chemotherapy and high-dose therapy. Primary translocations involving 14q32 and 4p16 (fibroblast growth factor receptor 3 [FGFR3]), 16q23 (c-maf proto-oncogene), and del17p13 (TP53) detected by FISH in multivariate analysis have been shown to be important predictors of poor survival. These cryptic translocations are best detected using FISH, which has been shown to be prognostically useful to evaluate both at diagnosis and subsequently at relapse.
Beta-2-microglobulin
Serum beta-2-microglobulin level is an important and convenient prognostic indicator. When cytogenetic changes are not studied, beta-2-microglobulin is consistently the most important prognostic indicator on multivariate analysis and in combination with cytogenetics (including FISH) has strong predictive value. As beta-2-microglobulin is excreted by the kidneys, high levels are observed in patients with renal failure; even in this setting, elevated serum beta-2 microglobulin is associated with poor outcome.
LDH
High LDH levels also have been associated with plasmablastic disease, extramedullary tumor, plasma cell leukemia, plasma cell hypodiploidy, drug resistance, and shortened survival.
Other indicators
Other indicators of shortened survival include elevated CRP, DNA hypodiploidy, high plasma cell labeling indices, and plasmablastic histology. Patients with DNA hypodiploidy are also less likely to respond to conventional chemotherapy.
Treatment response criteria
Because the criteria for treatment response in patients with multiple myeloma have varied among institutions and evolved over time, response rates have been difficult to compare in the past. In responders, the Bence-Jones protein level is reduced more rapidly than is serum myeloma protein because of the rapid renal clearance of light chains.
The CIBMTR/EBMTR response criteria have been prospectively validated in numerous studies and are as follows:
Complete response requires all of the following:
• No serum/urine M protein by immunofixation electrophoresis for ≥ 6 weeks
• < 5% plasma cells in bone marrow aspirate
• No increase in the size or number of lytic bone lesions
• Disappearance of soft-tissue plasmacytomas.
Partial response requires all of the following:
• ≥ 50% reduction in serum M protein > 6 weeks
• ≥ 90% reduction in 24-hour urinary light-chain excretion
• ≥ 50% reduction in soft-tissue plasmacytomas.
Minimal response (but ≤ 49%) requires:
• ≥ 25% reduction in serum M protein for > 6 weeks
• ≥ 50%–89% reduction in 24-hour urinary light-chain excretion
• No increase in the size or number of lytic bone lesions.
The more recent Uniform Criteria for response proposed by the IMWG have sought to further refine these criteria by describing a stringent complete response and a very good partial response (> 90% reduction in the serum paraprotein level), as well as defining progressive disease in terms of minimum requirements of paraprotein increase, as opposed to changes in immunofixation alone. Near complete response is another modification of the criteria and has been applied to the EBMTR as part of a number of prospective studies.
