What is the recommended treatment regimen for an elderly patient with multiple myeloma, considering their age and potential comorbidities?

Treatment Regimen for Elderly Multiple Myeloma Patients

Recommended Initial Therapy

For elderly patients with newly diagnosed multiple myeloma who are transplant-ineligible, the preferred initial treatment is a triplet regimen consisting of bortezomib, lenalidomide, and dexamethasone (VRd), with consideration for adding isatuximab in select cases. 1

Standard Triplet Regimen: VRd

• Bortezomib 1.3 mg/m² subcutaneously on days 1,8, and 15 of each 28-day cycle for 8-12 cycles 1, 2
• Lenalidomide 25 mg orally on days 1-21 of each cycle, continued until progression 1, 2
• Dexamethasone dosing must be reduced in elderly patients: 20 mg once weekly for patients >75 years (not the standard 40 mg weekly used in younger patients) 1
• Further dose reduction to 8-20 mg weekly should be considered for frail patients, with subsequent titration based on response and tolerability 1

Enhanced Quadruplet Regimen: Isatuximab-VRd

For patients who can tolerate more intensive therapy, adding isatuximab to VRd significantly improves outcomes, with 60-month progression-free survival of 63.2% versus 45.2% with VRd alone (HR 0.60, P<0.001). 3

• Isatuximab 10 mg/kg intravenously: days 1,8,15,22 of cycle 1; then days 1 and 15 of cycles 2-18 4, 3
• Combined with standard VRd dosing as above 3
• This regimen achieved 74.7% complete response rate versus 64.1% with VRd alone 3

Alternative Approach with Limited Dexamethasone

A novel strategy using isatuximab with weekly bortezomib, lenalidomide, and dexamethasone limited to only the first 2 cycles demonstrated 37% MRD-negative complete response in elderly patients (median age 77 years). 4

• Dexamethasone 20 mg orally on days 1,8,15,22 limited to cycles 1-2 only 4
• This approach reduces infection risk while maintaining efficacy in older patients 4

Critical Dosing Modifications for Elderly Patients

Age-Based Adjustments

• Patients >75 years: dexamethasone 20 mg weekly (not 40 mg) 1
• Frail patients: consider starting dexamethasone at 8-20 mg weekly 1
• Bortezomib requires no dose adjustment for age alone 5

Renal Impairment

• Lenalidomide requires dose reduction based on creatinine clearance as per FIRST trial protocols 1
• Bortezomib can be administered without dose adjustment in renal impairment, including dialysis patients (give after dialysis) 6, 5
• For acute renal insufficiency, consider starting with bortezomib/cyclophosphamide/dexamethasone, then switching to VRd after renal function improves 1

Hepatic Impairment

• No dose adjustment needed for mild hepatic impairment 5
• Reduce starting dose for moderate (bilirubin 1.5-3x ULN) or severe (bilirubin >3x ULN) hepatic impairment 5

Essential Supportive Care

Mandatory Prophylaxis

• Herpes zoster prophylaxis (acyclovir) is mandatory with bortezomib or isatuximab 1, 6
• Thromboprophylaxis with full-dose aspirin when using lenalidomide-based regimens 1
• Therapeutic anticoagulation for patients at high risk for thrombosis 1

Administration Route

• Subcutaneous bortezomib is strongly preferred over intravenous to reduce peripheral neuropathy risk 1

Treatment Duration and Maintenance

Induction Phase

• VRd for 8-12 cycles in transplant-ineligible patients 1, 2
• Isatuximab-VRd: isatuximab for 18 cycles, with lenalidomide continued until progression 4, 3

Maintenance Therapy

• Lenalidomide maintenance continued until progression is recommended for standard-risk patients 1, 2
• For high-risk cytogenetics (del 17p, t(4;14), t(14;16), t(14;20), gain 1q), consider bortezomib-based maintenance 2, 7, 8

Regimen Selection Algorithm

For fit elderly patients (age 65-75, minimal comorbidities):

• First choice: Isatuximab-VRd for maximum disease control 3
• Alternative: Standard VRd if isatuximab unavailable 1, 2

For frail elderly patients (age >75, multiple comorbidities, ECOG 2-3):

• Consider VRd with reduced dexamethasone (20 mg weekly or lower) 1
• Alternative: Isatuximab-VRd with dexamethasone limited to 2 cycles only 4
• If triplet intolerable: doublet therapy with lenalidomide-dexamethasone or bortezomib-dexamethasone 1

For patients with acute renal failure:

• Start with bortezomib/cyclophosphamide/dexamethasone 1
• Switch to VRd after renal function improves 1

Common Pitfalls to Avoid

• Do not use standard dexamethasone dosing (40 mg weekly) in patients >75 years - this significantly increases toxicity and mortality 1
• Do not use melphalan-containing regimens (MPT, VMP) in potentially transplant-eligible patients - these are stem cell toxic 1
• Avoid high-dose dexamethasone in very elderly patients (>80 years) even if they appear fit 1
• Do not forget lenalidomide dose adjustment for renal impairment - failure to adjust increases toxicity without improving efficacy 1

Monitoring and Response Assessment

• Assess response after every 2 cycles with serum protein electrophoresis, immunofixation, and free light chains 6
• Monitor for peripheral neuropathy closely with bortezomib - switch to subcutaneous route if not already using 1
• Watch for hypoglycemia/hyperglycemia in diabetic patients receiving bortezomib 5

Sequencing After Anti-CD38 Exposure

If the patient has prior daratumumab exposure and progresses, isatuximab-based regimens may still provide benefit, though efficacy is reduced. 9

• Two of five patients with prior daratumumab achieved responses (PR or MR-SD) with subsequent isatuximab-pomalidomide-dexamethasone 9
• Best responses occurred in patients who had achieved VGPR with prior daratumumab 9
• Consider alternative mechanisms of action (carfilzomib-based, pomalidomide-based) if daratumumab-refractory 1