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Definitions of Multiple Myeloma (MM)
Multiple myeloma is a hematologic malignancy characterized by presence of abnormal clonal plasma cells in the bone marrow, with potential for uncontrolled growth causing destructive bone lesions, kidney injury, anemia, and hypercalcemia.
Multiple myeloma is diagnosed in an estimated 34 920 people in the US and in approximately 588 161 people worldwide each year.
Multiple Myeloma (MM) Epidemiology
Incidence: According to the latest Global Cancer Observatory (GLOBOCAN) statistics, there were an estimated 160,000 cases of MM globally in 2018, accounting for 0.9% of all cancer diagnoses (Figure 1). Approximately 90,000 of those cases were male and 70,000 were female, which equals an age-standardized incidence of 2.1/100,000 and 1.4/100,000, respectively.
The cumulative risk of being diagnosed from birth to 74 is 0.24% among men and 0.17% among women, making the disease about 1.5× more likely in men. From 1990 to 2016, the global incidence of MM increased by 126%. In 2016, Multiple Myeloma cost 2.3 million disability-adjusted life years.
Figure (1)
Mortality
In 2018, an estimated 106,000 people globally perished of MM, accounting for 1.1% of all cancer deaths (Figure 2). Approximately, 59,000 of those deaths were male and 47,000 were female, equaling an age-standardized mortality of 1.3/100,000 and 0.9/100,000, respectively.
The risk of death from Multiple Myeloma was 0.15% among men and 0.10% among women, resembling the sex discrepancy in cancer risk (and suggesting similar survival between the sexes globally). Global deaths due to the neoplasm increased by 94% from 1990 to 2016.
Diagnosis:
Among patients with multiple myeloma, approximately 73% have anemia, 79% have osteolytic bone disease, and 19% have acute kidney injury at the time of presentation. Evaluation of patients with possible multiple myeloma includes measurement of hemoglobin, serum creatinine, serum calcium, and serum free light chain levels; serum protein electrophoresis with immunofixation; 24-hour urine protein electrophoresis; and full-body skeletal imaging with computed tomography, positron emission tomography, or magnetic resonance imaging.
Staging:
The Revised International Staging System combines data from the serum biomarkers β 2 microglobulin, albumin, and lactate dehydrogenase in conjunction with malignant plasma cell genomic features found on fluorescence in situ hybridization—t(4;14), del(17p), and t(14;16)—to assess estimated progression-free survival and overall survival. At diagnosis, 28% of patients are classified as having Revised International Staging stage I multiple myeloma, and these patients have a median 5-year survival of 82%.
Treatments:
Among all patients with multiple myeloma, standard first-line (induction) therapy consists of a combination of an injectable proteasome inhibitor (ie, bortezomib), an oral immunomodulatory agent (ie, lenalidomide), and dexamethasone and is associated with median progression-free survival of 41 months, compared with historical reports of 8.5 months without therapy.
This induction therapy combined with autologous hematopoietic stem cell transplantation followed by maintenance lenalidomide is standard of care for eligible patients.
Stem cell transplantation
Autologous stem cell transplantation (ASCT)
ASCT is not curative in Multiple Myeloma, but improves median OS by ~12 months. The treatment- related mortality rate is 1–2%. In ~50% of patients, ASCT can be done on an outpatient basis37. The preferred conditioning regimen for ASCT is melphalan, 200 mg/m 2 .
As discussed earlier, the early use of ASCT is preferred, but in some patients with standard-risk MM, ASCT can be delayed until first relapse, primarily based on patient choice. Three randomized trials conducted prior to the introduction of the VRd regimen showed that OS was similar whether ASCT is done early (after 3–4 cycles of initial therapy) or delayed (at the time of relapse as salvage therapy).
A recent randomized trial using VRd as initial therapy found improved PFS but no difference in OS with early ASCT compared to delayed ASCT at the time of first relapse. Thus, patient and physician preference play an important role in deciding the timing of ASCT, especially in standard-risk patients.
We still prefer early ASCT in most patients since it can be done with low risk, is logistically easier, and provides the longest duration of remission. There is a small risk of therapy-related secondary myelodysplastic syndrome and acute leukemia associated with ASCT.
Tandem transplantation
Tandem (double) ASCT refers to a second planned ASCT after recovery from the first transplantation. The role of tandem ASCT in myeloma is limited. A randomized trial conducted in the United States by the Bone Marrow Transplantation Clinical Trials Network (BMT-CTN) has found no benefit with tandem ASCT.
However, a survival benefit has been found in a randomized trial conducted by the European Myeloma Network. It is likely that the contradictory outcomes in these trials reflect access and availability of new treatment options in the salvage setting.
In the US, where multiple options for salvage therapy are available, there seems to be no benefit with tandem ASCT. At present, outside of a clinical trial setting, we consider tandem ASCT only in selected young patients with del 17p.
Allogeneic transplantation
Allogeneic transplantation remains investigational in MM. Its use should be restricted primarily to clinical trials, and to young patients (<60 years of age) with high-risk MM that is in first relapse. These patients must be counseled about the high treatment-related mortality rate associated with the procedure and the lack of definitive proof of benefit.
Author and compiler: Fatemeh Javani / Master of Hematology
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