What is the initial treatment approach for patients diagnosed with multiple myeloma?

Initial Treatment Approach for Multiple Myeloma

For newly diagnosed multiple myeloma, initiate treatment with bortezomib, lenalidomide, and dexamethasone (VRd) as the preferred triplet regimen for both transplant-eligible and transplant-ineligible patients, followed by risk-stratified consolidation and maintenance therapy. 1, 2, 3

Risk Stratification Before Treatment Initiation

All patients require immediate risk stratification using fluorescence in situ hybridization (FISH) to guide treatment intensity 4:

• High-risk disease: del(17p), t(14;16), t(14;20), or t(14;16) 4, 1
• Intermediate-risk disease: t(4;14), cytogenetic del(13), hypodiploidy, or plasma cell labeling index ≥3% 4, 5
• Standard-risk disease: All others, including t(11;14) and t(6;14) 4

High-risk patients have median overall survival of 3 years, intermediate-risk 4-5 years, and standard-risk 8-10 years 4.

Induction Therapy by Risk Category

Standard-Risk Patients (Transplant-Eligible)

Administer 4 cycles of VRd induction 1, 2:

• Bortezomib 1.3 mg/m² subcutaneously (preferred over IV to reduce neuropathy) on days 1,4,8,11 1, 6
• Lenalidomide 25 mg orally days 1-14 of each 21-day cycle 6
• Dexamethasone 20 mg orally on days 1,2,4,5,8,9,11,12 6

This regimen achieves 74% very good partial response (VGPR) or better and 52% complete response (CR) rates 1. Alternative acceptable regimens include cyclophosphamide-bortezomib-dexamethasone (CyBorD) or lenalidomide-dexamethasone (Rd), though response rates are lower 4.

High-Risk Patients (Transplant-Eligible)

Mandatory bortezomib-based triplet therapy with VRd for 4 cycles 4, 1. Bortezomib specifically overcomes adverse prognostic effects of t(4;14) translocation and del(17p) 4. Do not use lenalidomide-dexamethasone doublet therapy alone in high-risk patients, as bortezomib inclusion is critical for overcoming high-risk cytogenetics 4.

Transplant-Ineligible Patients

For patients ineligible for autologous stem cell transplantation, daratumumab-lenalidomide-dexamethasone (DRd) is now the preferred regimen based on superior outcomes 7, 8:

• Daratumumab 16 mg/kg IV weekly for cycles 1-2, every 2 weeks for cycles 3-6, then every 4 weeks until progression 7
• Lenalidomide 25 mg orally days 1-21 of each 28-day cycle 7
• Dexamethasone 40 mg weekly (20 mg weekly if age >75 years or BMI <18.5) 7

The MAIA trial demonstrated median progression-free survival of 61.9 months with DRd versus 34.4 months with Rd alone (44% reduction in disease progression risk), and 32% reduction in death risk 7. Overall response rate was 92.9% with DRd versus 81.3% with Rd 7.

A recent meta-analysis showed DRd superior to VRd in transplant-ineligible patients (HR 0.56; 95% CI 0.39-0.82) 8. VRd remains an acceptable alternative if daratumumab is unavailable 1, 6.

Consolidation with Autologous Stem Cell Transplantation

After 4 cycles of induction, transplant-eligible patients should proceed to high-dose melphalan 200 mg/m² with autologous stem cell transplantation using peripheral blood progenitor cells 1, 2, 3. This provides median progression-free survival of 50 months versus 36 months with delayed transplant 3.

Stem cell collection should occur after induction but before prolonged therapy (>4-6 cycles) to ensure adequate harvest 4. High-risk patients benefit most from early transplant, particularly if not achieving complete response with induction alone 4.

Maintenance Therapy (Risk-Adapted)

Standard-Risk Patients

Continue lenalidomide maintenance 10-15 mg daily until disease progression 1, 2, 3. This is supported by multiple randomized trials showing prolonged progression-free survival 4.

High-Risk Patients

Use bortezomib-based maintenance therapy rather than lenalidomide alone 4, 1, 3. Administer VRd (all three agents) for minimum 1 year post-transplant 4, 1. Bortezomib specifically overcomes high-risk cytogenetic features that lenalidomide does not adequately address 4.

Intermediate-Risk Patients

Bortezomib-based maintenance for minimum 1 year is recommended 4, 1.

Essential Supportive Care Measures

Initiate immediately with induction therapy 3:

• Thromboprophylaxis: Full-dose aspirin or therapeutic anticoagulation for all patients receiving lenalidomide, thalidomide, or pomalidomide 1, 2, 3
• Herpes zoster prophylaxis: Acyclovir or valacyclovir for all patients on proteasome inhibitors (bortezomib, carfilzomib) 3
• Pneumocystis prophylaxis: For patients receiving high-dose glucocorticosteroids 3
• Bisphosphonates: Zoledronic acid or pamidronate monthly to reduce skeletal-related events 2

Special Clinical Situations

Renal Failure at Presentation

Immediately initiate bortezomib-dexamethasone-based regimens due to non-renal clearance and rapid response rates 4. Avoid lenalidomide or reduce dose significantly (requires dose adjustment for creatinine clearance <50 mL/min) 4. Bortezomib-dexamethasone with cyclophosphamide or doxorubicin achieves renal response in 25-40% of patients 4.

Administration Route for Bortezomib

Subcutaneous administration is strongly preferred over intravenous, as it significantly reduces peripheral neuropathy rates (8% grade 3-4 with subcutaneous vs higher with IV) while maintaining equivalent efficacy 1, 6. Weekly dosing (rather than twice-weekly) further reduces neuropathy 1.

Response Monitoring

Assess response with each treatment cycle using 2, 3:

• Serum and urine protein electrophoresis
• Serum free light chains
• Bone marrow biopsy once best response achieved

Complete response criteria: <5% plasma cells in bone marrow and negative immunofixation 4, 2, 3. Whole-body low-dose CT is preferred over conventional skeletal survey for bone assessment 1, 2.

Critical Pitfalls to Avoid

• Never use lenalidomide-dexamethasone doublet alone in high-risk patients—bortezomib inclusion is mandatory to overcome adverse cytogenetics 4, 1
• Do not delay stem cell collection beyond 4-6 cycles of induction therapy, as prolonged exposure to alkylating agents impairs harvest 4
• Do not use single or doublet therapy when triplet regimens are tolerated—triplet combinations consistently demonstrate superior outcomes 3
• Avoid nephrotoxic agents in renal failure—use bortezomib-based regimens with non-renal clearance 4
• Do not omit thromboprophylaxis with immunomodulatory drugs—thromboembolic risk is substantial 1, 2, 3