What is the treatment and prognosis for multiple myeloma?

Treatment and Prognosis for Multiple Myeloma

Initial Treatment Strategy

For newly diagnosed multiple myeloma, the standard of care is induction therapy with bortezomib, lenalidomide, and dexamethasone (VRd), followed by autologous stem cell transplantation (ASCT) in eligible patients, and continuous lenalidomide maintenance until progression. 1, 2

Transplant-Eligible Patients

• Induction therapy: VRd triplet regimen consisting of bortezomib (1.3 mg/m² subcutaneously on days 1,4,8,11), lenalidomide (25 mg orally days 1-14), and dexamethasone (20 mg on specified days) for 12 cycles of 3 weeks 3
• Stem cell collection and transplantation: High-dose melphalan (200 mg/m²) with ASCT using peripheral blood progenitor cells as the preferred source 1
• Maintenance therapy: Continuous lenalidomide until disease progression, which provides median progression-free survival of 41 months 1, 4

Transplant-Ineligible Patients

• Primary regimen: VRd remains the preferred triplet regimen, with dose modifications for elderly patients (dexamethasone reduced to 20 mg weekly for patients >75 years, with further reduction to 8-20 mg weekly for frail patients) 5
• Alternative regimen: Daratumumab plus lenalidomide and dexamethasone (DRd) demonstrated superior outcomes with median PFS of 61.9 months versus 34.4 months with lenalidomide-dexamethasone alone 6
• Duration: Continuous therapy is strongly preferred over fixed-duration therapy, as it improves both progression-free survival and overall survival 5

High-Risk Cytogenetics Management

For patients with del(17p), t(4;14), t(14;16), or t(14;20):

• Induction: VRd followed by ASCT if eligible 1, 2
• Maintenance: Bortezomib-based maintenance therapy is preferred over lenalidomide alone, as bortezomib partially overcomes the adverse effects of t(4;14) and del(17p) 5
• Intensification: Consider tandem ASCT for high-risk patients, as they appear to benefit most from this approach 7

Treatment of Relapsed Disease

First Relapse

Triplet therapy with a monoclonal antibody-based regimen is the standard approach for first relapse, with daratumumab-lenalidomide-dexamethasone being the preferred option based on superior efficacy. 5

Treatment Selection Algorithm:

• Lenalidomide-refractory patients: Use proteasome inhibitor-based regimens (carfilzomib or bortezomib) plus daratumumab and dexamethasone 8
• Proteasome inhibitor-refractory patients: Use immunomodulatory drug-based regimens (lenalidomide or pomalidomide) plus daratumumab and dexamethasone 8
• Double-refractory patients: Pomalidomide-based regimens or daratumumab-based combinations 5, 8
• Early relapse (<18 months): Treat as high-risk disease requiring immediate aggressive triplet therapy 8
• Late relapse (>18 months): May repeat previous therapy if well-tolerated 5

Salvage ASCT Consideration

• Indication: Fit patients with indolent relapse who had meaningful response to first transplant (PFS >18 months) 5, 8
• Efficacy: Median time to progression of 19 months with second ASCT versus 11 months with cyclophosphamide 8

Prognosis

Overall Survival by Stage

• Revised International Staging System (R-ISS) Stage I: 82% 5-year survival (28% of patients at diagnosis) 4
• Standard-risk cytogenetics: Median PFS of 34-41 months with VRd induction 3, 4
• High-risk cytogenetics: Significantly shorter PFS and OS, with bortezomib-based therapy partially mitigating poor prognosis 5

Response Rates and Depth

With modern triplet therapy (VRd or DRd):

• Overall response rate: 86-93% 5, 6
• Complete response or better: 48% with DRd versus 25% with lenalidomide-dexamethasone alone 6
• MRD negativity: 24% with DRd versus 7% with lenalidomide-dexamethasone, which correlates with improved long-term outcomes 6

Relapsed Disease Outcomes

• First relapse with triplet therapy: Daratumumab-lenalidomide-dexamethasone provides superior PFS compared to doublet regimens across all cytogenetic risk groups 5
• Carfilzomib-lenalidomide-dexamethasone: PFS of 23 months in high-risk patients versus 29 months in standard-risk patients 5

Critical Management Considerations

Supportive Care Requirements

• Thromboprophylaxis: Mandatory for all patients on immunomodulatory drugs (aspirin or therapeutic anticoagulation based on risk factors) 2
• Herpes zoster prophylaxis: Required for all patients receiving proteasome inhibitors 2
• Bisphosphonates: Administer to reduce skeletal-related events 1
• Peripheral neuropathy prevention: Use subcutaneous bortezomib preferentially over intravenous administration 2

Dose Modifications

• Renal impairment: Lenalidomide requires dose reduction based on creatinine clearance; bortezomib does not require adjustment 5
• Elderly/frail patients: Reduce dexamethasone to 20 mg weekly (or 8-20 mg for very frail patients) 5

Common Pitfalls

• Avoiding carfilzomib in standard-risk disease: The ENDURANCE trial demonstrated that carfilzomib-lenalidomide-dexamethasone (KRd) provides no PFS benefit over VRd (34.6 vs 34.4 months, HR 1.04) but has significantly more toxicity, including higher rates of cardiotoxicity (4 deaths vs 1), dyspnea (7% vs 2% grade 3-4), and treatment-related deaths (2% vs <1%) 3
• Discontinuing maintenance prematurely: Continuous lenalidomide maintenance until progression provides superior outcomes compared to fixed-duration therapy 5
• Delaying treatment in biochemical relapse: Patients with high-risk cytogenetics, extramedullary disease, or early relapse after transplant require immediate treatment at biochemical relapse, not observation 5

Response Monitoring

• Frequency: Assess response with each treatment cycle using serum and urine protein electrophoresis and serum free light chains 5, 2
• Maintenance phase: Once best response achieved, monitor every 2-3 months 5
• Imaging: Repeat skeletal imaging (whole-body low-dose CT preferred) for new bone pain or suspected progression 5, 2