Treatment of Newly Diagnosed Multiple Myeloma in Older Adults
For older adults newly diagnosed with multiple myeloma, transplant eligibility determines the treatment pathway: transplant-eligible patients (medically fit, age up to 70-75 years) should receive VRd induction for 3-4 cycles followed by autologous stem cell transplantation and lenalidomide maintenance, while transplant-ineligible patients should receive daratumumab-lenalidomide-dexamethasone (DRd) until progression. 1, 2
Initial Assessment: Determining Transplant Eligibility
The critical first decision is transplant candidacy, which depends on physiologic age rather than chronologic age alone 3:
- Transplant-eligible criteria: Medically fit patients up to age 70-75 years without severe comorbidities, adequate performance status, and absence of significant renal failure can safely undergo autologous stem cell transplantation (ASCT) 3
- Transplant-ineligible criteria: Patients over 75 years, those with poor performance status (ECOG ≥2), significant comorbidities, or frailty are considered ineligible 3, 1
Risk stratification must be performed using FISH cytogenetics on bone marrow to identify high-risk features including del(17p), t(4;14), t(14;16), t(14;20), and 1q amplification/del(1p), as this determines treatment intensity 1, 4, 5.
Transplant-Eligible Patients: The Standard Pathway
Induction Therapy
Standard-risk disease: VRd (bortezomib, lenalidomide, dexamethasone) for 3-4 cycles achieves 58% VGPR or better and 52% complete response rates 1. This triplet regimen has become the standard induction approach 3.
High-risk disease: Add daratumumab to VRd (Dara-VRd) to improve outcomes, as this combination improves 18-month progression-free survival to 93% versus 85% with VRd alone 1, 4.
Consolidation with Transplant
Following induction, proceed with high-dose melphalan 200 mg/m² followed by autologous stem cell transplantation 3, 1. Peripheral blood progenitor cells should be used rather than bone marrow 3.
Critical pitfall to avoid: Do not prolong induction beyond 4-6 cycles in transplant-eligible patients, as this may impair stem cell collection 1.
Maintenance Therapy
Lenalidomide maintenance until progression is the standard for all transplant-eligible patients, as it increases progression-free survival and possibly overall survival 1, 6. For high-risk disease, consider adding bortezomib to lenalidomide maintenance, as lenalidomide alone shows limited benefit in high-risk cytogenetics 1.
Transplant-Ineligible Patients: Continuous Therapy Approach
First-Line Treatment Selection
Standard-risk disease: Daratumumab-lenalidomide-dexamethasone (DRd) until progression is the preferred option 1, 2, 7. The MAIA trial demonstrated that DRd achieved a median PFS of 61.9 months versus 34.4 months with lenalidomide-dexamethasone alone, representing a 44% reduction in risk of disease progression or death 2.
Alternative regimens for standard-risk disease include:
- Bortezomib-melphalan-prednisone (VMP): bortezomib 1.3 mg/m² subcutaneously days 1,8,15,22; melphalan 9 mg/m² orally days 1-4; prednisone 60 mg/m² orally days 1-4, repeated every 35 days 3, 6
- Weekly bortezomib schedules are preferred over twice-weekly dosing to reduce polyneuropathy 1
High-risk disease: VRd for 8-12 cycles followed by bortezomib-based maintenance until progression, as bortezomib partially overcomes the adverse prognosis of high-risk cytogenetics 1, 4.
Dose Modifications for Frailty
For frail or elderly patients over 75 years: Reduce dexamethasone dose to 20 mg/week instead of 40 mg/week, and consider two-drug combinations rather than triplet therapy based on geriatric assessment 1. The International Myeloma Working Group emphasizes that thalidomide or bortezomib combined with melphalan and prednisone represent standards of care for elderly, transplantation-ineligible patients 3.
Special Clinical Situations Requiring Immediate Attention
Renal Failure
Start bortezomib-based regimens immediately without dose adjustment in patients with renal insufficiency 1. Do not delay chemotherapy for extended periods while attempting conservative measures alone, as this worsens outcomes 6. Establish IV access and begin normal saline at 150-200 mL/hour to achieve urine output >100 mL/hour before initiating therapy 6.
Pre-existing Neuropathy
Use DRd instead of VRd to avoid bortezomib-related neuropathy in patients with pre-existing peripheral neuropathy 1.
High Tumor Burden
Administer aggressive hydration with normal saline and rasburicase to prevent tumor lysis syndrome in patients with high tumor burden, renal insufficiency, or elevated LDH 6. Give rasburicase 0.2 mg/kg IV as a single dose (or 3-6 mg fixed dose) in high-risk patients 6.
Essential Supportive Care Measures
All patients requiring therapy must receive comprehensive supportive care 1, 4:
Bone Protection
Intravenous bisphosphonates (zoledronic acid or pamidronate) should be administered throughout active disease, as zoledronic acid improves overall survival by 5.5 months independent of skeletal-related events 1, 6.
Thromboprophylaxis
- Standard-risk patients: Aspirin 1, 4
- High-risk patients: Low-molecular weight heparin (enoxaparin), warfarin, or direct thrombin inhibitors 1
Infection Prophylaxis
- Acyclovir for all patients on bortezomib-based regimens 4
- Consider levofloxacin during the first two cycles 4
Erythropoietin
Patients with moderate-to-severe anemia should receive erythropoietin 3.
Critical Pitfalls to Avoid
Never use carfilzomib-lenalidomide-dexamethasone (KRd) as initial therapy due to higher risk of serious cardiac, renal, and pulmonary toxicity 1
Do not delay treatment in symptomatic myeloma with CRAB criteria (hypercalcemia, renal insufficiency, anemia, bone lesions), as therapy is required immediately 3, 6
Avoid multiagent chemotherapy in elderly patients, as it has not proven superior and may be inferior to standard combinations 3
Do not use melphalan-containing regimens in transplant-eligible patients before stem cell collection, as this impairs stem cell harvest 1
Response Monitoring
Check M-protein (serum/urine electrophoresis) after 1-2 cycles initially to ensure no progression, then every other cycle during active treatment 6. The goal is achieving at least a very good partial response (VGPR), with complete response (CR) or minimal residual disease (MRD) negativity representing optimal outcomes 1, 2.