What are the medications used to treat multiple myeloma?

Multiple Myeloma Treatment Medications

Multiple myeloma is treated with disease-modifying medications, not just pain control—the standard regimens combine proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies to directly target the cancer cells and improve survival.

Core Drug Classes for Multiple Myeloma Treatment

Proteasome Inhibitors

• Bortezomib is the backbone proteasome inhibitor used in both initial and relapsed disease, administered subcutaneously to reduce peripheral neuropathy risk 1
• Carfilzomib is a second-generation proteasome inhibitor approved for relapsed disease, typically dosed at 27 mg/m² or 56 mg/m² depending on the combination regimen 1
• Ixazomib is the first oral proteasome inhibitor, approved in combination with lenalidomide and dexamethasone for patients who have received at least one prior therapy 1

Immunomodulatory Drugs (IMiDs)

• Lenalidomide is the most widely used IMiD, forming the foundation of both initial therapy and maintenance treatment until disease progression 2, 3
• Thalidomide is used in combination regimens, particularly in elderly patients with melphalan and prednisone (MPT regimen) 1
• Pomalidomide is reserved for heavily pretreated patients who have received at least two prior therapies including lenalidomide and bortezomib 1

Monoclonal Antibodies

• Daratumumab (anti-CD38 antibody) is now a preferred first-line agent in combination with lenalidomide and dexamethasone, showing superior progression-free survival compared to doublet regimens 1, 2
• Elotuzumab (anti-SLAMF7 antibody) is approved in combination with lenalidomide and dexamethasone for patients who have received one to three prior therapies 1, 4
• Isatuximab (anti-CD38 antibody) demonstrated improved outcomes when added to bortezomib, lenalidomide, and dexamethasone in transplant-ineligible patients 5

Corticosteroids

• Dexamethasone is included in virtually all multiple myeloma regimens, typically at 20-40 mg doses depending on the combination and patient age 1, 2

Alkylating Agents

• Melphalan at 200 mg/m² IV is the standard preparative regimen before autologous stem cell transplantation 1
• Cyclophosphamide is used in various combination regimens, particularly in patients with specific toxicity concerns 1

Standard Treatment Regimens by Clinical Setting

Transplant-Eligible Patients (Initial Treatment)

• VRd (bortezomib, lenalidomide, dexamethasone) is the standard three-drug induction regimen, followed by high-dose melphalan and autologous stem cell transplantation 1, 2, 3
• Lenalidomide maintenance should be continued until disease progression after transplantation, providing median progression-free survival of 41 months 2
• Adding isatuximab to VRd (Isa-VRd) showed 63.2% progression-free survival at 60 months versus 45.2% with VRd alone in transplant-ineligible patients, suggesting potential benefit 5

Transplant-Ineligible Patients (Initial Treatment)

• Daratumumab, lenalidomide, and dexamethasone (DRd) is the preferred first-line regimen based on superior efficacy compared to VRd in meta-analyses (HR 0.56 for progression or death) 1, 2, 6
• VRd remains an acceptable alternative, particularly when daratumumab is not available 2, 3
• VMP (bortezomib, melphalan, prednisone) or MPT (melphalan, prednisone, thalidomide) are options for elderly patients who cannot tolerate triplet regimens 1

First Relapse Treatment

• Daratumumab-based triplet regimens are preferred, specifically DRd (daratumumab, lenalidomide, dexamethasone) or DVd (daratumumab, bortezomib, dexamethasone) 1, 2
• KRd (carfilzomib, lenalidomide, dexamethasone) is the preferred alternative when daratumumab has been previously used 1
• For lenalidomide-refractory patients, use DVd, KPd (carfilzomib, pomalidomide, dexamethasone), or DPd (daratumumab, pomalidomide, dexamethasone) 1

Second or Later Relapse

• Pomalidomide-based combinations with monoclonal antibodies (daratumumab or isatuximab) are standard for patients who have received lenalidomide and a proteasome inhibitor 1
• Panobinostat (HDAC inhibitor) combined with bortezomib and dexamethasone is indicated for patients who received at least two prior regimens including bortezomib and an immunomodulatory drug 1
• Selinexor-based regimens and venetoclax for t(11;14) myeloma are additional options in heavily pretreated disease 1

Critical Supportive Medications

Infection Prophylaxis

• Herpes zoster prophylaxis (acyclovir or valacyclovir) is mandatory for all patients receiving proteasome inhibitors 2, 3, 7
• Pneumococcal and influenza vaccines should be administered 1

Thromboprophylaxis

• Aspirin or therapeutic anticoagulation is required for patients on immunomodulatory drug-based therapy due to increased thromboembolism risk 2, 3

Bone Protection

• Bisphosphonates with calcium and vitamin D supplementation are standard for all patients to prevent skeletal complications 1

Common Pitfalls to Avoid

Do not confuse supportive care medications with disease-modifying therapy—while pain management, bisphosphonates, and transfusions are important, the triplet combinations of proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies are what actually treat the cancer and improve survival 1, 2.

Avoid using VRd and KRd interchangeably for initial therapy—the ENDURANCE trial demonstrated no progression-free survival benefit with KRd over VRd (34.6 vs 34.4 months, HR 1.04), but KRd had significantly more toxicity including 11 treatment-related deaths versus 2 with VRd 8. VRd remains the standard backbone for transplant-eligible patients 2, 8.

Do not delay monoclonal antibody incorporation—daratumumab-based regimens should be used at first relapse rather than reserved for later lines, as they provide superior outcomes across all cytogenetic risk groups 1, 2.

Remember that lenalidomide, pomalidomide, and thalidomide require REMS program enrollment due to teratogenicity, with mandatory contraception, pregnancy testing, and restrictions on blood/sperm donation 9.