What is the treatment for multiple myeloma?

Treatment of Multiple Myeloma

Initial Treatment for Newly Diagnosed Disease

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

Transplant-Eligible Patients

Induction Phase:

• Administer 4-6 cycles of VRd (bortezomib, lenalidomide, dexamethasone) as the preferred triplet regimen 1, 3
• For high-risk cytogenetics [del(17p), t(4;14), t(14;16), t(14;20)], consider quadruplet therapy with daratumumab added to VRd (DVTd) 4
• Proceed to stem cell collection after induction 1

Consolidation:

• High-dose melphalan (200 mg/m²) with ASCT using peripheral blood progenitor cells as the preferred stem cell source 1, 2
• ASCT provides median progression-free survival of 50 months versus 36 months with delayed transplant 5

Maintenance:

• Standard-risk patients: continuous lenalidomide until disease progression (median PFS 41 months) 1, 2
• High-risk cytogenetics: bortezomib-based maintenance therapy preferred over lenalidomide alone, as bortezomib partially overcomes adverse effects of t(4;14) and del(17p) 1, 6

Transplant-Ineligible Patients

For transplant-ineligible patients with standard-risk disease, daratumumab-lenalidomide-dexamethasone (DRd) continued until progression is the preferred regimen. 1, 4

• Standard-risk: DRd provides 92.9% overall response rate and median PFS of 61.9 months 7
• High-risk cytogenetics: VRd or dose-adjusted VRd with bortezomib-based maintenance 4
• Elderly patients (>75 years): reduce dexamethasone to 20 mg weekly, with further reduction to 8-20 mg weekly for frail patients 1
• Continuous therapy is superior to fixed-duration therapy for both progression-free and overall survival 1

Treatment of Relapsed/Refractory Disease

For first relapse, triplet therapy with daratumumab-lenalidomide-dexamethasone (DRd) is the preferred option based on superior efficacy across all cytogenetic risk groups. 5, 1

First Relapse Algorithm

Lenalidomide-sensitive (relapse >12 months after lenalidomide):

• DRd: provides 91.3% overall response rate and median PFS of 45.0 months 7
• Alternative: carfilzomib-lenalidomide-dexamethasone (KRd) 5

Lenalidomide-refractory:

• Daratumumab-bortezomib-dexamethasone (DVd) 5, 1
• Alternative: carfilzomib-based regimens with dexamethasone 5

Proteasome inhibitor-refractory:

• DRd remains preferred if lenalidomide-sensitive 5
• Elotuzumab-lenalidomide-dexamethasone (ERd) for daratumumab-refractory patients 5

ASCT consideration:

• Offer salvage ASCT if not previously transplanted or if PFS after first transplant was ≥18 months 5

Second or Subsequent Relapse

Treatment selection depends on prior therapy exposure and refractoriness pattern: 5

Dual-refractory (lenalidomide + proteasome inhibitor):

• Daratumumab-pomalidomide-dexamethasone (DPd) 5
• Carfilzomib-pomalidomide-dexamethasone (KPd) 5

Triple-refractory (lenalidomide + bortezomib/ixazomib + daratumumab):

• Alkylator-based regimens (cyclophosphamide combinations) 5
• Proteasome inhibitor with panobinostat 5

Aggressive Disease: Secondary Plasma Cell Leukemia or Extramedullary Disease

Fit patients should receive VDT-PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide) for 2 cycles followed by ASCT consolidation. 5

Frail patients:

• Daratumumab-based regimens (DRd, DVd, DPd) 5
• Anthracycline-containing regimens: bortezomib-doxorubicin-dexamethasone or lenalidomide-doxorubicin-dexamethasone 5
• Bendamustine-based therapy 5

Essential Supportive Care Measures

All patients require comprehensive supportive care to prevent treatment-related complications: 5

• Thromboprophylaxis: full-dose aspirin or therapeutic anticoagulation for all patients on immunomodulatory drugs (lenalidomide, pomalidomide, thalidomide) 1, 6
• Herpes zoster prophylaxis: acyclovir or valacyclovir for all patients on proteasome inhibitors 5, 1, 6
• Pneumocystis jiroveci prophylaxis: for patients receiving high-dose glucocorticosteroids 5
• Bone protection: bisphosphonates with calcium and vitamin D supplementation 5, 1
• Neuropathy prevention: subcutaneous bortezomib preferred over intravenous to reduce peripheral neuropathy risk 1, 6
• Renal dosing: reduce lenalidomide dose based on creatinine clearance in patients with renal impairment 1
• Immunizations: seasonal influenza and pneumococcal vaccines 5

Response Monitoring

Assess response with each treatment cycle using serum and urine protein electrophoresis and serum free light chains. 1, 6

• Once best response achieved or on maintenance: assess at minimum every 3 months 6
• Complete response requires <5% plasma cells in bone marrow and negative immunofixation 2
• Minimal residual disease (MRD) negativity at 10⁻⁵ threshold using next-generation sequencing provides prognostic value 7

Critical Pitfalls to Avoid

• Do not use lenalidomide-based regimens in patients progressing on lenalidomide maintenance—switch to proteasome inhibitor with monoclonal antibody 5
• Do not delay restaging at relapse—evaluation for disease evolution to plasma cell leukemia or extramedullary disease is critical as treatment approach differs dramatically 5
• Do not use single or doublet therapy when triplet combinations are tolerated—triplet regimens consistently demonstrate superior outcomes 5
• Do not overlook high-risk cytogenetics—these patients require intensified therapy with bortezomib-based maintenance rather than lenalidomide alone 1, 6