Multiple Myeloma
Epidemiology and Etiology
Multiple myeloma (MM) is the second most frequent hematologic malignancy after NHL with an estimated 32,270 new cases in the US in 2020.1 The median age at diagnosis is 66 years.
Clinical Presentation
The most common presentation is anemia. Patients can also have bone pain, renal failure, fatigue, weight loss, hypercalcemia, and recurrent infections. Patients with extramedullary plasmacytomas can present with radiculopathy, cord compression, or CNS involvement.
Diagnostic Testing
Initial evaluation includes routine blood work, #946;2-microglobulin (B2M), serum and urine protein electrophoresis, serum free light chain assessment, bone marrow examination, and cross-sectional imaging with either whole body LDCT, PET CT, or whole body MRI. Of note, cross-sectional imaging is preferred over skeletal survey with plain radiographs due to increased sensitivity for bone lesions. The diagnosis of MM is confirmed by the presence of 10% or more clonal plasma cells in the bone marrow or a biopsy-proven plasmacytoma, with evidence of end-organ damage (CRAB Criteria: hypercalcemia, renal dysfunction, anemia, or bone lesions). A clonal marrow plasma cell percentage of #8805;60%, #954; or #955; free light chain ratio of #8805;100, and the presence of one or more focal lesions on MRI are also criteria (SLiM Criteria) for diagnosis of MM because they are associated with a high risk of progression to end-organ damage.40
Staging and Risk Stratification
The Revised-International Staging System (R-ISS) for MM uses B2M, albumin, LDH, and the presence/absence of high-risk cytogenetic abnormalities to stratify patients (Table 22-11).
| REVISED-INTERNATIONAL STAGING SYSTEM AND RISK STRATIFICATION IN MYELOMA | |
| R-ISS Stage I | B2M lt;3.5 mg/dL, albumin gt;3.5 g/dL, normal LDH, and absence of del(17p), t(4;14), or t(14;16) by FISH |
| R-ISS Stage II | Neither stage I nor stage III R-ISS |
| R-ISS Stage III | B2M gt;5.5 mg/dL plus LDH elevation and/or presence of del(17p), t(4;14), or t(14;16) by FISH |
| Standard Risk Cytogenetics | Trisomies (hyperdiploidy), t(11;14), and t(6;14) |
| High Risk Cytogenetics | Del(17p) or TP53 deletion, t(4;14), t(14;16), t(14;20), gain 1q |
B2M, #946;2-microglobulin; LDH, lactic dehydrogenase.
TREATMENT
• Transplant-eligible patients are typically offered 4-6 cycles of induction therapy with a four-drug regimen including an anti-CD38 mAb (daratumumab), a proteasome inhibitor (bortezomib), an immunomodulatory agent (lenalidomide), and dexamethasone followed by a melphalan-conditioned autologous stem cell transplantation.
In transplant-ineligible patients who are otherwise fit, the induction regimen may be continued for 12-18 months, whereas in frail patients an immunomodulatory agent (e.g., lenalidomide) and dexamethasone alone may be considered.• Maintenance therapy (lenalidomide or bortezomib) is often considered following initial therapy, with selection of agent typically based on the patient's risk category.
• For relapsed and refractory disease, various combinations of several classes of drugs including chemotherapy (cyclophosphamide, melphalan, melflufen), additional immunomodulatory agents (pomalidomide) and proteosome inhibitors (carfilzomib, ixazomib), monoclonal antibodies targeting CD38 (daratumumab, isatuximab) and SLAMF7 (elotuzumab), histone deacetylase inhibitors (e.g., panobinostat), nuclear export inhibitors (selinexor), BCMA targeted ADCs (belantamab-mafodotin), and a BCMA CAR-T therapy (idecabtagene vicleucel) are now FDA approved.40