What are the symptoms and treatment options for Multiple Myeloma (MM)?

From the Guidelines

Multiple myeloma treatment should prioritize a combination approach with novel-agent-based induction, including a triple combination of bortezomib, with either adriamycin or thalidomide and dexamethasone, followed by autologous stem cell transplantation in medically fit patients, and maintenance therapy with lenalidomide or thalidomide to improve progression-free survival and overall survival.

Key Considerations

• The European Myeloma Network recommends risk stratification for all patients with symptomatic disease to classify patients for International Staging System stage and for cytogenetically defined high- versus standard-risk groups 1.
• Induction therapy should include a triple combination of bortezomib, with either adriamycin or thalidomide and dexamethasone, or with cyclophosphamide and dexamethasone 1.
• Autologous stem cell transplantation is recommended for medically fit patients, while allogeneic stem cell transplantation may be considered for young patients with high-risk disease, preferably in the context of a clinical trial 1.
• Maintenance therapy with lenalidomide or thalidomide increases progression-free survival and possibly overall survival, with lenalidomide-low-dose dexamethasone being a valuable option for transplant-ineligible patients 1.

Treatment Approach

• Treatment decisions should be individualized based on patient age, comorbidities, disease characteristics, and patient preferences.
• Regular monitoring of blood counts, kidney function, and paraprotein levels helps assess treatment effectiveness.
• Side effect management is crucial and includes preventing infections, managing bone disease with bisphosphonates, and addressing anemia.
• The Mayo Clinic's MSmart consensus guidelines also emphasize the importance of risk-adapted therapy, with a focus on disease- and patient-related factors, including cytogenetic features 2.

From the FDA Drug Label

14 CLINICAL STUDIES 14. 1 Newly Diagnosed Multiple Myeloma Combination Treatment with Lenalidomide and Dexamethasone in Patients Ineligible for Autologous Stem Cell Transplant

MAIA (NCT02252172), an open-label, randomized, active-controlled trial, compared treatment with DARZALEX 16 mg/kg in combination with lenalidomide and low-dose dexamethasone (DRd) to treatment with lenalidomide and low-dose dexamethasone (Rd) in patients with newly diagnosed multiple myeloma ineligible for autologous stem cell transplant. Efficacy was evaluated by progression free survival (PFS) based on International Myeloma Working Group (IMWG) criteria. MAIA demonstrated an improvement in Progression Free Survival (PFS) in the DRd arm as compared to the Rd arm; the median PFS had not been reached in the DRd arm and was 31.9 months in the Rd arm (hazard ratio [HR]=0.56; 95% CI: 0.43, 0.73; p<0. 0001), representing 44% reduction in the risk of disease progression or death in patients treated with DRd.

The treatment of Multiple Myeloma with daratumumab in combination with lenalidomide and dexamethasone (DRd) has shown to improve Progression Free Survival (PFS) compared to lenalidomide and dexamethasone (Rd) alone, with a 44% reduction in the risk of disease progression or death in patients treated with DRd 3.

• The median PFS was not reached in the DRd arm and was 31.9 months in the Rd arm.
• After a median follow-up of 64 months, the median PFS was 61.9 months in the DRd arm and 34.4 months in the Rd arm.
• The treatment also demonstrated an improvement in overall survival (OS) in the DRd arm compared to the Rd arm, with a 32% reduction in the risk of death in patients treated with DRd 4.

From the Research

Definition and Diagnosis of Multiple Myeloma

• Multiple myeloma is a hematologic malignancy characterized by the presence of abnormal clonal plasma cells in the bone marrow, with potential for uncontrolled growth causing destructive bone lesions, kidney injury, anemia, and hypercalcemia 5.
• The diagnosis requires ≥10% clonal bone marrow plasma cells or a biopsy-proven plasmacytoma plus evidence of one or more multiple myeloma defining events (MDE): CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) attributable to the plasma cell disorder, bone marrow clonal plasmacytosis ≥60%, serum involved/uninvolved free light chain (FLC) ratio ≥100, or >1 focal lesion on magnetic resonance imaging 6.

Treatment of Multiple Myeloma

• The standard first-line (induction) therapy consists of a combination of an injectable proteasome inhibitor (e.g., bortezomib), an oral immunomodulatory agent (e.g., lenalidomide), and dexamethasone, which is associated with median progression-free survival of 41 months 5.
• The combination of bortezomib with lenalidomide and dexamethasone (VRd) has shown significant efficacy in the setting of newly diagnosed multiple myeloma, with improved progression-free survival and overall survival compared to lenalidomide and dexamethasone alone 7.
• Carfilzomib, a next-generation proteasome inhibitor, in combination with lenalidomide and dexamethasone (KRd), has shown promising efficacy in phase 2 trials, but did not improve progression-free survival compared to VRd in a phase 3 trial 8.

Risk Stratification and Management

• The presence of del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del 1p, or p53 mutation is considered high-risk multiple myeloma, and the presence of any two high-risk factors is considered double-hit myeloma; three or more high-risk factors is triple-hit myeloma 6.
• Patients who are candidates for autologous stem cell transplantation should receive induction therapy with VRd followed by autologous stem cell transplantation (ASCT), while frail patients who are not candidates for transplant should be treated with VRd for approximately 8-12 cycles followed by maintenance or alternatively with daratumumab, lenalidomide, dexamethasone (DRd) until progression 6.