Multiple Myeloma Treatment
Initial Treatment for Transplant-Eligible Patients (≤65-75 years)
For newly diagnosed multiple myeloma patients eligible for transplant, the standard of care is VRd (bortezomib, lenalidomide, dexamethasone) for 3-4 cycles, followed by autologous stem cell transplantation with high-dose melphalan (200 mg/m²), and lenalidomide maintenance until progression. 1, 2
Induction Therapy
- VRd is the preferred triplet regimen, achieving 58% VGPR or better and 52% complete response rates 1
- For high-risk cytogenetics (del(17p), t(4;14), t(14;16), t(14;20), gain 1q), add daratumumab to VRd (Dara-VRd) to improve outcomes 1, 3, 4
- Alternative triplet regimens include VTD (bortezomib-thalidomide-dexamethasone) or VCD (bortezomib-cyclophosphamide-dexamethasone), though these are less preferred 5, 2
Stem Cell Transplantation
- High-dose melphalan 200 mg/m² followed by autologous stem cell transplantation remains standard after induction 1, 2, 3
- Harvest peripheral blood stem cells before prolonged lenalidomide exposure to ensure adequate collection 5
- Avoid prolonged induction beyond 4-6 cycles as this impairs stem cell collection 1
- Selected standard-risk patients may delay transplant until first relapse after collecting stem cells 3, 4
Maintenance Therapy
- Lenalidomide maintenance until progression increases progression-free survival and possibly overall survival in standard-risk patients 5, 1, 2
- For high-risk disease, bortezomib plus lenalidomide maintenance is superior to lenalidomide alone 1, 3, 4
Initial Treatment for Transplant-Ineligible Patients (>65-75 years or unfit)
For transplant-ineligible patients with standard-risk disease, DRd (daratumumab, lenalidomide, dexamethasone) continued until progression is the preferred regimen. 1, 6, 4
Standard-Risk Disease
- DRd (daratumumab-lenalidomide-dexamethasone) until progression is the current preferred option for older adults 1, 6, 4
- Lenalidomide/low-dose dexamethasone (Rd) continuously is an alternative category 1 option, particularly for frail or elderly patients, with superior overall survival compared to high-dose dexamethasone 5, 1
- VMP (bortezomib-melphalan-prednisone) or MPT (melphalan-prednisone-thalidomide) are alternative standards, though less commonly used in North America 5, 7
High-Risk Disease
- VRd for 8-12 cycles followed by bortezomib-based maintenance until progression 1, 3
- Daratumumab-VRd is an alternative for high-risk patients who can tolerate triplet therapy 5, 4
Frail or Elderly Patients (>75 years)
- Reduce dexamethasone to 20 mg/week instead of 40 mg/week 1, 7
- Consider doublet regimens (bortezomib-dexamethasone or lenalidomide-dexamethasone) rather than triplet therapy based on geriatric assessment 5, 1
Risk Stratification (Essential Before Treatment)
Perform cytogenetic analysis by FISH on bone marrow samples to identify high-risk features before initiating therapy. 1, 7, 2
High-Risk Features
- del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del(1p), p53 mutation 1, 3, 4
- ISS stage III, high LDH, plasma cell labeling index >3%, extramedullary disease 1
Standard-Risk Features
- Hyperdiploidy, t(11;14), t(6;14) 1
Special Clinical Situations
Renal Failure
Start bortezomib-based regimens immediately without dose adjustment in patients with renal insufficiency 1, 7
- VCD (bortezomib-cyclophosphamide-dexamethasone) is particularly effective for acute renal failure 5
- Avoid delaying chemotherapy while attempting conservative measures, as this worsens outcomes 7
- Provide aggressive IV hydration with normal saline and rasburicase for tumor lysis prophylaxis in high-risk patients 7
Pre-existing Neuropathy
Use DRd instead of VRd to avoid bortezomib-related peripheral neuropathy 1
- If bortezomib is necessary, administer subcutaneously rather than intravenously to reduce neuropathy risk 5
Essential Supportive Care
Thromboprophylaxis
All patients on immunomodulatory drugs (lenalidomide, thalidomide) require thromboprophylaxis. 1, 2
- Aspirin 81-325 mg daily for standard-risk patients 5, 1
- Low-molecular weight heparin, warfarin, or direct thrombin inhibitors for high-risk patients (prior thrombosis, obesity, immobility, concurrent erythropoietin) 1
Bone Protection
Administer intravenous bisphosphonates (zoledronic acid or pamidronate) for all patients requiring therapy, continued throughout active disease. 1, 7, 2
- Zoledronic acid improves overall survival by 5.5 months independent of skeletal-related events 1
Antimicrobial Prophylaxis
Herpes zoster prophylaxis (acyclovir or valacyclovir) for patients receiving bortezomib, other proteasome inhibitors, or monoclonal antibodies (daratumumab, elotuzumab) 5, 1
Second-Line Treatment at First Relapse
Use triplet therapy over doublet therapy at first relapse, with regimens containing two novel agents plus steroids. 7, 3, 4
Lenalidomide-Sensitive or Lenalidomide-Naive
Lenalidomide-Refractory
- Daratumumab-bortezomib-dexamethasone (DVd) 4
- Carfilzomib-dexamethasone (Kd) 3
- For t(11;14) patients: venetoclax-bortezomib-dexamethasone (VenVd) 7
Triple-Class Refractory (IMiD, proteasome inhibitor, anti-CD38 refractory)
- Selinexor-dexamethasone 7
- Belantamab mafodotin monotherapy 7
- CAR-T cell therapy (idecabtagene vicleucel or ciltacabtagene autoleucel) 4
- Bispecific antibodies (teclistamab, elranatamab, talquetamab) 4
Critical Pitfalls to Avoid
- Never use carfilzomib-lenalidomide-dexamethasone (KRd) as initial therapy due to higher risk of serious cardiac, renal, and pulmonary toxicity compared to VRd 1
- Do not prolong induction beyond 4-6 cycles in transplant-eligible patients, as this impairs stem cell collection 1
- Avoid high-dose dexamethasone (40 mg four times weekly) in elderly patients; use low-dose dexamethasone (20-40 mg weekly) instead 5, 1
- Do not use melphalan-containing regimens in transplant-eligible patients as this may compromise future stem cell collection 5