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, regardless of transplant eligibility, followed by risk-stratified consolidation and maintenance therapy. 1, 2, 3

Risk Stratification Before Treatment Selection

All patients require immediate risk stratification using fluorescence in situ hybridization (FISH) to identify high-risk cytogenetic abnormalities including del(17p), t(4;14), t(14;16), and t(14;20), which are present in approximately 20% of patients and confer a median overall survival of only 3 years compared to 8-10 years for standard-risk disease. 4

• Standard-risk patients (60% of cases) lack high-risk FISH abnormalities and may have hyperdiploidy, t(11;14), or t(6;14). 4
• High-risk patients (20% of cases) harbor del(17p), t(14;16), t(14;20), or high-risk gene expression profiling signatures. 4
• Intermediate-risk patients (20% of cases) have t(4;14), cytogenetic del(13), or plasma cell labeling index ≥3%. 4

Induction Therapy: The VRd Regimen

Standard Dosing for Transplant-Eligible Patients

Administer 4-6 cycles of VRd before stem cell collection: 1, 2

• Bortezomib: 1.3 mg/m² subcutaneously (preferred route to reduce peripheral neuropathy) on days 1,4,8, and 11 of cycles 1-8, then days 1 and 8 of cycles 9-12 1, 5
• Lenalidomide: 25 mg orally on days 1-14 of each 21-day cycle 5
• Dexamethasone: 20 mg orally (reduced to 10 mg if age >75 years) on days 1,2,4,5,8,9,11, and 12 5

This regimen achieves very good partial response or better in 74% of patients and complete response in 52%, with a median progression-free survival of 34.4 months. 1, 5

Critical Administration Modifications

• Subcutaneous bortezomib is mandatory rather than intravenous to significantly reduce peripheral neuropathy rates from 44% to <1% grade 3-4 events. 1, 5
• Weekly bortezomib dosing (rather than twice-weekly) further reduces neuropathy while maintaining efficacy. 1
• Mandatory thromboprophylaxis with full-dose aspirin or therapeutic anticoagulation for all patients receiving lenalidomide due to 2-5% risk of thromboembolic events. 1, 3, 5

Alternative Regimens When VRd Is Not Suitable

For patients with renal failure (eGFR <30 mL/min), bortezomib-based regimens without lenalidomide are preferred due to primarily non-renal clearance and rapid response rates: 4

• Cyclophosphamide-bortezomib-dexamethasone (CyBorD) achieves 22% complete response rate and reverses renal impairment in 25-40% of cases. 4
• Bortezomib-thalidomide-dexamethasone (VTd) achieves 94% overall response rate and is a category 1 option for transplant-eligible patients. 1

Risk-Stratified Consolidation Strategy

High-Risk Patients (del 17p, t(14;16), t(14;20))

Proceed immediately to autologous stem cell transplantation (ASCT) after VRd induction, as high-risk patients benefit most from achieving complete response, and ASCT provides median progression-free survival of 50 months versus 36 months with delayed transplant. 4, 3

• High-dose melphalan 200 mg/m² with peripheral blood progenitor cells as stem cell source. 2, 3
• Bortezomib-based maintenance therapy is mandatory (not lenalidomide alone) as bortezomib overcomes adverse prognostic effects of t(4;14) and del(17p). 4, 1, 2

Standard-Risk and Intermediate-Risk Patients

Transplant-eligible patients should proceed to ASCT after achieving at least partial response (typically after 4 cycles), though immediate transplant is not mandatory if patients prefer delayed consolidation. 4

• Stem cell collection should occur after 4-6 cycles to avoid prolonged lenalidomide exposure impairing harvest. 4
• For intermediate-risk patients, include bortezomib-based maintenance for minimum 1 year. 4

Maintenance Therapy

Lenalidomide maintenance should be continued until disease progression for all transplant-eligible patients who undergo ASCT, as this represents standard of care with level 1 evidence. 2, 3

• Standard-risk patients: Lenalidomide alone until progression. 4, 2
• High-risk patients: VRd (bortezomib-lenalidomide-dexamethasone) for minimum 1 year, as high-risk disease requires intensified maintenance. 4, 1

Transplant-Ineligible Patients

For patients ineligible for ASCT due to age >75 years, ECOG performance status ≥2, or significant comorbidities: 4

Preferred Regimen: Daratumumab-Lenalidomide-Dexamethasone (DRd)

DRd is superior to VRd in transplant-ineligible patients, with median progression-free survival of 61.9 months versus 34.4 months for lenalidomide-dexamethasone alone, representing 44% reduction in risk of disease progression or death. 6, 7

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

Meta-analysis demonstrates DRd reduces risk of progression or death by 40-44% compared to VRd in transplant-ineligible patients (HR 0.56-0.60). 7

Alternative for Transplant-Ineligible Patients

VRd remains acceptable if daratumumab is unavailable, with treatment continued until progression rather than fixed duration. 4, 5

Essential Supportive Care Measures

These interventions are mandatory to prevent treatment-related complications: 3

• Herpes zoster prophylaxis with acyclovir or valacyclovir for all patients on proteasome inhibitors (bortezomib). 3
• Pneumocystis jiroveci prophylaxis for patients receiving high-dose glucocorticosteroids. 3
• Bisphosphonates (zoledronic acid or pamidronate) to reduce skeletal-related events in patients with bone disease. 2

Response Monitoring Protocol

Assess response with each treatment cycle using: 2, 3

• Serum and urine protein electrophoresis with immunofixation
• Serum free light chain levels
• Complete blood counts to monitor for cytopenias

Complete response requires <5% plasma cells in bone marrow and negative immunofixation. 2, 3

Once best response is achieved or on maintenance therapy, assess minimally every 3 months. 3

Critical Pitfalls to Avoid

• Never use lenalidomide-based regimens in patients with creatinine clearance <30 mL/min without dose adjustment, as this causes severe myelosuppression; switch to bortezomib-based therapy. 4
• Never delay stem cell collection beyond 6 cycles of lenalidomide-containing induction, as prolonged exposure impairs harvest yields. 4
• Never use lenalidomide maintenance alone in high-risk patients—these patients require bortezomib-based maintenance to overcome adverse cytogenetics. 1, 3
• Never omit thromboprophylaxis in patients receiving immunomodulatory drugs (lenalidomide, thalidomide), as thromboembolic risk reaches 5-10% without prophylaxis. 1, 3
• Never use twice-weekly intravenous bortezomib when subcutaneous weekly dosing provides equivalent efficacy with 8-fold reduction in grade 3-4 peripheral neuropathy. 1, 5