What is the recommended risk‑adapted treatment plan for a newly diagnosed multiple myeloma patient over 60 years old, including assessment of performance status, organ function, cytogenetic risk, induction therapy, criteria for autologous stem‑cell transplantation, supportive care, and relapse options?

Risk-Adapted Treatment Plan for Newly Diagnosed Multiple Myeloma in Patients Over 60 Years

For a newly diagnosed multiple myeloma patient over 60 years old, the treatment plan must be individualized based on transplant eligibility, cytogenetic risk stratification, and performance status, with transplant-eligible patients receiving VRd induction followed by ASCT and lenalidomide maintenance, while transplant-ineligible patients receive either DRd until progression for standard-risk disease or VRd × 8-12 cycles with bortezomib-based maintenance for high-risk disease. 1, 2, 3

Initial Assessment and Risk Stratification

Performance Status and Transplant Eligibility

• Assess transplant candidacy immediately based on age, performance status, organ function, and comorbidities rather than age alone 1, 4
• Patients over 60 can still be transplant-eligible if they have good performance status (ECOG 0-2) and adequate organ function 5, 6
• For frail or elderly patients (>75 years), reduce dexamethasone dose to 20 mg/week instead of 40 mg/week and consider two-drug combinations rather than triplet therapy 1

Mandatory Cytogenetic Risk Assessment

All patients must undergo FISH testing on bone marrow samples before initiating therapy to guide treatment intensity 1, 7

High-risk features requiring intensified therapy include: 5, 2, 8

• del(17p)
• t(4;14)
• t(14;16)
• t(14;20)
• 1q amplification/del(1p)
• p53 mutation
• ISS stage III
• High LDH
• Plasma cell labeling index >3%
• Extramedullary disease

Standard-risk features include: 5, 7

• Hyperdiploidy
• t(11;14)
• t(6;14)

The presence of any two high-risk factors defines double-hit myeloma; three or more defines triple-hit myeloma, both requiring aggressive treatment approaches 2, 3, 8

Treatment Algorithm for Transplant-Eligible Patients

Induction Therapy (3-4 Cycles)

Standard-risk disease: 1, 7

• VRd (bortezomib, lenalidomide, dexamethasone) is the preferred regimen, achieving 58% VGPR or better and 52% complete response rates
• Alternative: VTd (bortezomib, thalidomide, dexamethasone) with 94% response rate and 33% CR rate 7

High-risk disease: 1, 2, 3

• Dara-VRd (daratumumab plus VRd) is recommended to improve outcomes in high-risk patients
• This represents the most recent standard for high-risk disease 8

Critical pitfall: Avoid prolonged induction (>4-6 cycles) in transplant-eligible patients as this may impair stem cell collection 1

Stem Cell Collection and Transplantation

• Perform stem cell harvest after 3-4 cycles of induction therapy 1, 7
• High-dose melphalan (200 mg/m²) with ASCT remains standard of care, providing superior progression-free survival (50 months vs 36 months without transplant, HR 0.65, p<0.001) 7
• Selected standard-risk patients achieving deep responses can collect stem cells but delay ASCT until first relapse 5, 2, 3

Post-Transplant Maintenance

Standard-risk patients: 1, 4

• Lenalidomide maintenance until progression increases progression-free survival and possibly overall survival

High-risk patients: 1, 4

• Bortezomib-based maintenance (bortezomib plus lenalidomide) is required rather than lenalidomide alone, as lenalidomide maintenance shows limited benefit in high-risk disease
• Consider tandem autologous transplantation for high-risk disease 1

Treatment Algorithm for Transplant-Ineligible Patients

Standard-Risk Disease

DRd (daratumumab, lenalidomide, dexamethasone) until progression is the preferred regimen 1, 7

Alternative options: 7

• VMP (bortezomib, melphalan, prednisone) with 24% CR rate
• MPT (melphalan, prednisone, thalidomide) with 13% CR rate
• Weekly bortezomib schedules are preferred over twice-weekly dosing to reduce polyneuropathy 1

High-Risk Disease

VRd × 8-12 cycles followed by bortezomib-based maintenance until progression 1, 7

Essential Supportive Care Measures

Thromboprophylaxis (Mandatory)

• Aspirin for standard-risk patients 1, 7
• Low-molecular weight heparin, warfarin, or direct thrombin inhibitors for high-risk patients (prior thrombosis, immobility, concurrent erythropoietin, multiple myeloma therapy) 1, 7

Antimicrobial Prophylaxis

• Herpes zoster prophylaxis for all patients on proteasome inhibitors 7
• Pneumocystis jiroveci prophylaxis for patients on high-dose dexamethasone 7
• Levofloxacin during the first two cycles for all newly diagnosed patients 7

Bone Protection

Intravenous bisphosphonates (zoledronic acid or pamidronate) should be administered for all patients requiring therapy, continued throughout active disease, as zoledronic acid improves overall survival by 5.5 months independent of skeletal-related events 1, 4

Special Clinical Situations

Renal failure: 1, 7

• Start bortezomib-based regimens immediately without dose adjustment
• Bortezomib can be administered safely in severe renal impairment and dialysis

Pre-existing neuropathy: 1

• Use DRd instead of VRd to avoid bortezomib-related neuropathy

Painful bone lesions or hypercalcemia: 7

• Initiate bisphosphonates immediately
• Use local radiotherapy for prompt pain relief of localized bone lesions

Relapse Treatment Options

Most patients require a triplet regimen at relapse, with the choice varying with each successive relapse 2, 3, 8

Newer options include: 8, 9

• Pomalidomide-based regimens for lenalidomide-refractory patients (median PFS 11.2 months) 4
• CAR-T cell therapy
• Bispecific antibodies

Aggressive relapse with extramedullary plasmacytomas or plasma cell leukemia may require anthracycline-containing combination chemotherapy regimens 6

Critical Pitfalls to Avoid

• Never use KRd (carfilzomib-lenalidomide-dexamethasone) as initial therapy due to higher risk of serious cardiac, renal, and pulmonary toxicity 1
• Do not delay cytogenetic testing—risk stratification must occur before treatment initiation 1, 7
• Avoid insufficient therapy duration in high-risk patients—continuous therapy approaches are essential 5
• Do not use lenalidomide maintenance alone in high-risk patients—proteasome inhibitor-based maintenance is required 1, 4