What is the initial treatment for multiple myeloma?

Initial Treatment for Multiple Myeloma

For patients with newly diagnosed multiple myeloma, initial treatment should include at minimum a novel agent (immunomodulatory drug or proteasome inhibitor) combined with a steroid, with triplet therapies being the preferred option due to superior outcomes in both transplant-eligible and ineligible patients. 1

Treatment Algorithm Based on Transplant Eligibility

Transplant-Eligible Patients (<65 years)

1. Induction Therapy:

   • Preferred regimen: Bortezomib-based triplet therapy
   • Modern options include:
     • Bortezomib, lenalidomide, dexamethasone (VRd) 1
     • Daratumumab, bortezomib, lenalidomide, dexamethasone (D-VRd) - showing superior progression-free survival (84.3% vs 67.7% at 48 months) 2
   • Avoid alkylating agents during induction to prevent stem cell damage 1

2. Consolidation with ASCT:

   • High-dose melphalan 200 mg/m² followed by autologous stem cell transplantation 1
   • Use peripheral blood progenitor cells rather than bone marrow 1
   • Double ASCT may benefit patients who don't achieve complete remission after first transplant 1

3. Maintenance Therapy:

   • Lenalidomide maintenance until progression (starting dose 10 mg daily, may increase to 15 mg if tolerated) 1, 3
   • For high-risk patients: bortezomib-based maintenance is preferable 1

Transplant-Ineligible Patients (≥65 years)

1. Initial Treatment:

   • Preferred regimens (triplet therapy):
     • Bortezomib, lenalidomide, dexamethasone (VRd) 1, 4
     • Daratumumab, bortezomib, melphalan, prednisone 1
   • Alternative: Lenalidomide plus dexamethasone (Rd) for frail patients 1
   • Initial dosing should be individualized based on age, renal function, comorbidities, and frailty status 1

2. Duration of Therapy:

   • Continuous therapy is preferred over fixed-duration therapy 1
   • Lenalidomide dosing: 25 mg orally once daily on days 1-21 of 28-day cycles 3

Treatment Response Evaluation

• Assess response based on serum and urine electrophoresis
• Partial remission: ≥50% reduction of M-gradient in serum and ≥90% reduction in 24-h urine
• Complete remission: No M-component in serum/urine, <5% plasma cells in bone marrow, and negative immunofixation 1

Management of Relapsed Disease

1. First Relapse:

   • Triplet therapy is strongly recommended 1
   • Preferred options:
     • Daratumumab, lenalidomide, dexamethasone (DRd)
     • Carfilzomib, lenalidomide, dexamethasone (KRd)
     • Daratumumab, bortezomib, dexamethasone (DVd) 1
   • Consider ASCT if not received previously or if progression-free survival after first transplant was ≥18 months 1

2. Second or Higher Relapse:

   • Use combinations with at least 2 drugs that the patient is not refractory to
   • Consider quadruplet regimens, selinexor-based regimens, or bendamustine-based regimens 1

Special Considerations

Dose Adjustments for Hematologic Toxicities

• For neutropenia (ANC <1,000/mcL): Interrupt lenalidomide, resume at lower dose when ANC ≥1,000/mcL
• For thrombocytopenia (platelets <30,000/mcL): Interrupt lenalidomide, resume at lower dose when platelets ≥30,000/mcL 3

Common Adverse Events to Monitor

• Thromboembolism: Consider anticoagulant prophylaxis, especially with immunomodulatory drugs 5
• Peripheral neuropathy: Immediate dose reduction or discontinuation when paresthesia is complicated by pain or motor deficit 5
• Neutropenia and thrombocytopenia: Most common grade 3-4 adverse events with modern regimens 2

Supportive Care

• Bisphosphonates: Reduce skeletal events in patients with stage III or relapsed disease 1

Key Pitfalls to Avoid

1. Delaying treatment in symptomatic patients (CRAB features)
2. Using alkylating agents during induction in transplant-eligible patients
3. Failing to adjust doses based on age, renal function, and frailty status
4. Not monitoring for and promptly addressing peripheral neuropathy
5. Overlooking thromboprophylaxis in high-risk patients receiving immunomodulatory drugs
6. Continuing the same regimen in patients who relapse within 6 months of completing therapy

The treatment landscape for multiple myeloma has evolved significantly with the introduction of novel agents. The choice of initial therapy should be guided by transplant eligibility, with triplet regimens incorporating proteasome inhibitors and immunomodulatory drugs showing superior outcomes in both settings.