What is the best approach to treating an elderly patient with multiple myeloma, considering their age and potential comorbidities such as impaired renal function and anemia?

Treatment of Elderly Patients with Multiple Myeloma

For elderly patients with multiple myeloma who are transplant-ineligible (typically >65-70 years or with significant comorbidities), initiate triplet therapy with bortezomib, melphalan, and prednisone (VMP) or daratumumab-bortezomib-melphalan-prednisone (D-VMP) for fit patients, with dose reductions of bendamustine in those with renal impairment. 1, 2

Determining Transplant Eligibility

The critical first decision is whether the elderly patient can tolerate autologous stem cell transplantation (ASCT):

• Transplant-eligible elderly patients (age 65-75 years who are medically fit) should receive the same approach as younger patients: VRd induction (bortezomib, lenalidomide, dexamethasone) followed by high-dose melphalan 200 mg/m² with ASCT, then lenalidomide maintenance until progression 3, 1

• Transplant-ineligible patients (>70-75 years or with significant comorbidities) require age-adapted triplet regimens without transplantation 1, 2

The International Myeloma Working Group emphasizes that selected patients up to age 70-75 years who are medically fit can safely undergo ASCT at specialized centers, though benefits have not been consistently demonstrated in the elderly compared to younger patients 3

Assessing Frailty Status

Frailty assessment using geriatric factors including functional status and comorbidities should be performed to predict treatment toxicity and survival, as this produces a more thorough evaluation than age and performance status alone. 1, 4, 5

Traditional age cutoffs are insufficient because they fail to account for physiologic changes, comorbidities, decreased treatment tolerance, and socioeconomic barriers that affect elderly patients 4, 6

Treatment Regimens for Transplant-Ineligible Elderly Patients

First-Line Triplet Therapy (Fit Elderly Patients)

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, 2, 7

Alternative: Daratumumab-VMP (D-VMP) for fit elderly patients provides enhanced efficacy 1, 2

First-Line Doublet Therapy (Frail Elderly Patients)

Lenalidomide/low-dose dexamethasone (Rd):

• Lenalidomide 25 mg orally days 1-21
• Dexamethasone 40 mg orally days 1,8,15,22
• Repeated every 28 days 3, 2

At minimum, a doublet regimen with a novel agent (immunomodulatory drug or proteasome inhibitor) plus steroid should be used 1

Managing Renal Impairment

Bortezomib-based therapy is specifically recommended for elderly patients with renal impairment, as no starting dose adjustment is required. 8

• For patients requiring dialysis, administer bortezomib after the dialysis procedure 8

• Bendamustine requires dose reduction in elderly patients with renal impairment 3

• The European Myeloma Network emphasizes immediate initiation of bortezomib-based regimens in patients with renal insufficiency, preceded by appropriate tumor lysis prophylaxis 2

Managing Anemia and Cytopenias

Treatment should be initiated when symptomatic disease is present, defined by CRAB criteria including:

• Hemoglobin <10 g/dL or 2 g/dL below lower limit of normal 2
• Cytopenias related to direct bone marrow involvement by tumor cells 3

Common pitfall: Bendamustine-rituximab causes limited myelosuppression compared to purine analog-based regimens in elderly patients, but still requires monitoring 3

Essential Supportive Care Measures

All elderly myeloma patients require mandatory interventions:

• Herpes zoster prophylaxis with acyclovir or valacyclovir 1
• Thromboprophylaxis with full-dose aspirin (due to immunomodulatory drugs) 1
• Bisphosphonates to reduce skeletal-related events 1, 2, 7
• Aggressive IV hydration with normal saline at 150-200 mL/hour in patients with renal insufficiency or high tumor burden to prevent tumor lysis syndrome 2, 7

Bortezomib Administration Considerations

Administer bortezomib subcutaneously once weekly rather than twice weekly to reduce neurotoxicity risk in elderly patients. 3

• If urgent IgM reduction is needed, bortezomib can be started at twice-per-week doses for 1-2 cycles, then changed to once-weekly dosing 3

• No dose adjustment is needed for elderly patients (≥65 years), as no overall differences in safety or effectiveness were observed compared to younger patients, though greater sensitivity in some older individuals cannot be ruled out 8

Monitoring Diabetic Elderly Patients

Elderly diabetic patients on oral hypoglycemics require close monitoring of blood glucose levels during bortezomib treatment, with adjustment of antidiabetic medication doses as needed. 8

Hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics during bortezomib clinical trials 8

Treatment of Relapsed Disease in Elderly Patients

At first relapse, use triplet therapy containing two novel agents (proteasome inhibitor, immunomodulatory drug, or monoclonal antibody) plus steroids. 2

For triple-class refractory elderly patients, selinexor/dexamethasone or belantamab mafodotin monotherapy is recommended 2

Key Clinical Pitfalls to Avoid

• Do not delay chemotherapy for extended periods while attempting conservative measures alone in patients with renal involvement, as this worsens outcomes 2

• Do not use rituximab single-agent therapy in frail elderly patients with high IgM levels due to lower response rates and risk of IgM flare 3

• Do not treat asymptomatic/smoldering myeloma in elderly patients; monitor at 3-6 month intervals with laboratory tests instead 1, 2, 7

• Do not use standard melphalan 200 mg/m² conditioning in transplant-ineligible elderly patients; use oral melphalan 9 mg/m²/day for 4 days instead 7