Treatment Options for Multiple Myeloma
For newly diagnosed transplant-eligible patients, induction with bortezomib-lenalidomide-dexamethasone (VRd) followed by autologous stem cell transplantation (ASCT) and continuous lenalidomide maintenance until progression is the standard of care, while for transplant-ineligible patients, triplet therapy with daratumumab-lenalidomide-dexamethasone (DRd) or VRd with dose modifications provides superior outcomes. 1, 2
Initial Treatment for Newly Diagnosed Disease
Transplant-Eligible Patients (Age <70, Good Performance Status)
Induction therapy should consist of 4-6 cycles of VRd (bortezomib, lenalidomide, dexamethasone) as the preferred triplet regimen. 1 This approach provides the foundation for subsequent high-dose therapy.
Following induction, high-dose melphalan 200 mg/m² with ASCT using peripheral blood progenitor cells (not bone marrow) is the standard treatment. 1, 3 The ASCT provides median progression-free survival of 50 months versus 36 months with delayed transplant, representing a clinically meaningful benefit. 1
After ASCT, continuous lenalidomide maintenance until disease progression is strongly recommended, providing median progression-free survival of 41 months. 2 This maintenance strategy improves both progression-free and overall survival. 2
Transplant-Ineligible Patients (Age >70, Poor Performance Status, Significant Comorbidities)
VRd remains the preferred triplet regimen with dose modifications: dexamethasone reduced to 20 mg weekly for patients >75 years, with further reduction to 8-20 mg weekly for frail patients. 2 This dose adjustment balances efficacy with tolerability in vulnerable populations.
Alternatively, daratumumab-lenalidomide-dexamethasone (DRd) is highly effective, demonstrating 92.9% overall response rate and median PFS of 61.9 months versus 34.4 months with lenalidomide-dexamethasone alone. 4 The FDA label data shows a 44% reduction in risk of disease progression or death with DRd. 4
Continuous therapy is superior to fixed-duration therapy in transplant-ineligible patients, improving both progression-free survival and overall survival. 2
Treatment of Relapsed/Refractory Disease
First Relapse Strategy
For lenalidomide-sensitive patients (relapse >1 year after stopping lenalidomide), daratumumab-lenalidomide-dexamethasone (DRd) is the preferred option based on superior efficacy across all cytogenetic risk groups, providing 91.3% overall response rate and median PFS of 45.0 months. 1, 3 This represents the strongest evidence-based choice for first relapse.
For lenalidomide-refractory patients (progression during or within 1 year of lenalidomide), daratumumab-bortezomib-dexamethasone (DVd) is the preferred regimen. 1, 3 This switches the backbone from immunomodulatory drug to proteasome inhibitor while maintaining monoclonal antibody therapy.
Alternative options for lenalidomide-refractory disease include carfilzomib-pomalidomide-dexamethasone (KPd), which is preferred if the patient has been previously treated with daratumumab. 3
Salvage ASCT should be considered at first relapse for transplant-eligible patients who either never received transplant or had progression-free survival ≥18 months after first ASCT. 3 Patients with PFS <18 months after first ASCT have median OS <6 months with repeat transplant, making this approach futile. 3
Second or Higher Relapse
For double-refractory patients (refractory to both proteasome inhibitor and immunomodulatory drug), pomalidomide combinations with monoclonal antibodies or cyclophosphamide are reasonable options. 3
Triplet regimens containing at least 2 new drugs that the patient is not refractory to should be prioritized. 3 This maintains treatment intensity while avoiding known resistance mechanisms.
High-Risk Cytogenetics Management
Patients with del(17p), t(4;14), or t(14;16) require intensified therapy with bortezomib-based maintenance rather than lenalidomide alone, as bortezomib partially overcomes the adverse effects of these high-risk features. 2, 3 Combined therapy with second-generation proteasome inhibitors, monoclonal antibodies, and immunomodulatory drugs improves outcomes in del(17p) patients. 3
Essential Supportive Care Measures
All patients on immunomodulatory drugs (lenalidomide, pomalidomide, thalidomide) require thromboprophylaxis with full-dose aspirin or therapeutic anticoagulation. 1
Herpes zoster prophylaxis with acyclovir or valacyclovir is mandatory for all patients on proteasome inhibitors. 1
Pneumocystis jiroveci prophylaxis is required for patients receiving high-dose glucocorticosteroids. 1
Long-term bisphosphonates (oral or intravenous) reduce skeletal events and should be administered to patients with stage III or relapsed disease. 3
Subcutaneous bortezomib is preferred over intravenous administration to prevent peripheral neuropathy. 2
Response Monitoring
Assessment should occur with each treatment cycle using serum and urine protein electrophoresis and serum free light chains. 1, 2 Once best response is achieved or on maintenance, assess at minimum every 3 months. 1
Complete response requires <5% plasma cells in bone marrow and negative immunofixation. 1 Minimal residual disease negativity at 10⁻⁵ threshold provides additional prognostic information. 4
Critical Pitfalls to Avoid
Do not use lenalidomide-based regimens in patients progressing on lenalidomide maintenance—switch to proteasome inhibitor with monoclonal antibody. 1 This avoids treating through established resistance.
Do not delay restaging at relapse—evaluation for disease evolution to plasma cell leukemia or extramedullary disease is critical as treatment approach differs dramatically. 1
Do not use single or doublet therapy when triplet combinations are tolerated—triplet regimens consistently demonstrate superior outcomes. 1, 3 All three best-treatment options for relapsed disease are triple-combination regimens with lenalidomide and dexamethasone (combined with daratumumab, carfilzomib, or elotuzumab). 3
Do not overlook high-risk cytogenetics—these patients require intensified therapy and cannot be treated with standard-risk approaches. 1
Do not use melphalan-containing regimens in transplant-eligible patients before stem cell collection, as this compromises stem cell harvest. 3