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

Initial Treatment for Multiple Myeloma

For transplant-eligible patients with newly diagnosed multiple myeloma, initiate induction therapy with bortezomib, lenalidomide, and dexamethasone (VRd) for 4-6 cycles, followed by autologous stem cell transplantation and lenalidomide maintenance until progression. 1, 2, 3

Risk Stratification Before Treatment Selection

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

• High-risk features: del(17p), t(4;14), t(14;16), t(14;20), or high-risk gene expression profiling signature—these patients have median overall survival of 3 years without optimized therapy 4
• Intermediate-risk features: t(4;14) or cytogenetic del(13)—median overall survival 4-5 years 4
• Standard-risk features: All others including t(11;14), t(6;14), or normal cytogenetics—median overall survival 8-10 years 4

Transplant-Eligible Patients

Standard-Risk and Intermediate-Risk Disease

Induction regimen (4-6 cycles before stem cell collection) 1, 2:

• VRd (preferred): Bortezomib 1.3 mg/m² subcutaneously on days 1,4,8,11 + lenalidomide 25 mg orally days 1-14 + dexamethasone 20 mg on days 1,2,4,5,8,9,11,12 of 21-day cycles 5
• This achieves 74% very good partial response or better and 52% complete response rates 1
• Alternative: VTd (bortezomib-thalidomide-dexamethasone) achieves 94% overall response rate but is less commonly used 1

Consolidation 1, 2:

• High-dose melphalan 200 mg/m² with autologous stem cell transplantation using peripheral blood progenitor cells 2, 3
• This provides median progression-free survival of 50 months versus 36 months with delayed transplant 3

Maintenance therapy 1, 2:

• Lenalidomide continued until progression for standard-risk patients 1, 2
• For intermediate-risk patients, include bortezomib-based maintenance for minimum 1 year 4, 1

High-Risk Disease

Induction regimen (4 cycles) 4, 1:

• VRd is mandatory (not optional)—bortezomib specifically overcomes adverse prognostic effects of t(4;14) and del(17p) 4
• The goal is complete response, not just very good partial response, as high-risk patients benefit most from deeper responses 4

Consolidation 1:

• Autologous stem cell transplantation is especially important if complete response not achieved after induction 1

Maintenance therapy 4, 1:

• VRd (bortezomib-lenalidomide-dexamethasone) for minimum 1 year, not lenalidomide alone 4, 1
• Bortezomib-based maintenance overcomes high-risk cytogenetics better than lenalidomide monotherapy 1

Transplant-Ineligible Patients

Standard-Risk Disease

Preferred regimen 6:

• Daratumumab-lenalidomide-dexamethasone (DRd): Daratumumab 16 mg/kg IV weekly for cycles 1-2, every 2 weeks for cycles 3-6, then every 4 weeks + lenalidomide 25 mg days 1-21 of 28-day cycles + dexamethasone 40 mg weekly (20 mg if age >75 years) 6
• Continue until progression or unacceptable toxicity 6
• This achieves median progression-free survival of 61.9 months versus 34.4 months with lenalidomide-dexamethasone alone, representing 44% reduction in progression risk 6
• Overall response rate is 92.9% with 47.6% achieving complete response or better 6

Alternative regimen 1, 5:

• VRd: Same dosing as transplant-eligible patients but continued longer (12 cycles of 21 days) 5
• Median progression-free survival 34.4 months 5
• Recent meta-analysis shows DRd superior to VRd with hazard ratio 0.60 for progression or death 7

High-Risk Disease

Preferred approach 4:

• Bortezomib-containing triplet regimen such as cyclophosphamide-bortezomib-dexamethasone (CyBorD) or VRd 4
• Bortezomib is non-negotiable for high-risk patients due to ability to overcome t(4;14) translocation effects 4
• Consider adding daratumumab to VRd based on emerging evidence, though this is not yet standard 8

Special Clinical Situations

Renal Failure at Presentation

Immediate management 4:

• Start bortezomib-dexamethasone based regimen immediately—bortezomib has primarily non-renal clearance and produces rapid responses 4
• Avoid lenalidomide until renal function improves (requires dose adjustment if creatinine clearance <60 mL/min) 4
• Add cyclophosphamide, thalidomide, or doxorubicin to bortezomib-dexamethasone for faster response 4
• Maintain euvolemia and avoid nephrotoxic drugs 4
• Bortezomib-based regimens reverse renal impairment in 25-40% of patients 4

Route of Administration Considerations

Bortezomib administration 1:

• Subcutaneous route is preferred over intravenous—significantly reduces peripheral neuropathy while maintaining efficacy 1
• Weekly dosing (rather than twice weekly) further reduces neuropathy risk 1

Essential Supportive Care

Thromboprophylaxis 1, 2, 3:

• Mandatory for all patients receiving immunomodulatory drugs (lenalidomide, thalidomide) 1, 2
• Use full-dose aspirin or therapeutic anticoagulation 3

Infection prophylaxis 3:

• Herpes zoster prophylaxis with acyclovir or valacyclovir for all patients on proteasome inhibitors 3
• Pneumocystis jiroveci prophylaxis for patients receiving high-dose glucocorticosteroids 3

Bone protection 2:

• Bisphosphonates to reduce skeletal-related events 2

Response Monitoring

Assessment schedule 2, 3:

• Evaluate response with each treatment cycle using serum and urine protein electrophoresis and serum free light chains 2, 3
• Once best response achieved or on maintenance, assess minimum every 3 months 3
• Complete response requires <5% plasma cells in bone marrow and negative immunofixation 2, 3
• Whole-body low-dose CT preferred over conventional skeletal survey for bone assessment 2

Critical Pitfalls to Avoid

Do not use lenalidomide-based regimens in high-risk patients without bortezomib—this is inadequate therapy and bortezomib specifically overcomes high-risk cytogenetic features 4, 3

Do not delay treatment in patients with renal failure—start bortezomib-based therapy immediately as rapid response is critical for renal recovery 4

Do not use intravenous bortezomib when subcutaneous is available—peripheral neuropathy rates are significantly higher with IV administration 1

Do not omit thromboprophylaxis in patients on immunomodulatory drugs—thrombotic events are a major complication 1, 2, 3

Do not continue same induction regimen beyond 4-6 cycles in transplant-eligible patients—this delays stem cell collection and may impair harvest 4, 1