Initial Treatment for Multiple Myeloma
The initial treatment for multiple myeloma should be bortezomib, lenalidomide, and dexamethasone (VRd) as a triplet induction regimen, regardless of transplant eligibility. 1, 2
Risk Stratification Before Treatment
Before initiating therapy, all patients require comprehensive staging including:
- Bone marrow examination with FISH for cytogenetic abnormalities to identify high-risk features including del(17p), t(4;14), t(14;16), t(14;20), gain 1q, or p53 mutation 2, 3
- Serum and urine protein electrophoresis with serum free light chains for baseline disease burden assessment 2
- Whole-body low-dose CT scan (preferred over conventional skeletal survey) for bone disease evaluation 1, 2
- Frailty assessment and comorbidity evaluation to determine transplant eligibility 1, 2
High-risk cytogenetics includes del(17p), t(4;14), t(14;16), t(14;20), gain 1q, or p53 mutation; presence of two or more high-risk factors constitutes double-hit myeloma, and three or more constitutes triple-hit myeloma 3, 4.
Induction Therapy
Standard Regimen: VRd (Bortezomib, Lenalidomide, Dexamethasone)
VRd is the preferred induction regimen for both transplant-eligible and transplant-ineligible patients with standard-risk and intermediate-risk disease. 1, 5
Dosing schedule (21-day cycles): 6
- Bortezomib 1.3 mg/m² subcutaneously on days 1,8,15
- Lenalidomide 25 mg orally on days 1-14
- Dexamethasone 20 mg on day of and day after bortezomib (or 40 mg on days 1,8,15,22)
Duration:
- Transplant-eligible patients: 3-4 cycles before proceeding to autologous stem cell transplantation (ASCT) 3, 4
- Transplant-ineligible patients: 8-12 cycles followed by maintenance therapy 3, 4
VRd delivers exceptional response rates: 97.1% overall response rate after induction, with 89.9% achieving very good partial response (VGPR) or better after transplantation 7. The median progression-free survival with VRd is 65 months for the entire cohort, 76.5 months for standard-risk patients, and 40.3 months for high-risk patients 7.
High-Risk Disease Modification
For high-risk patients (del 17p, t(14;16), t(14;20), or other high-risk cytogenetics), consider daratumumab, bortezomib, lenalidomide, and dexamethasone (Dara-VRd) as an alternative to VRd. 1, 3, 4
This four-drug combination provides enhanced disease control in high-risk populations, though VRd remains acceptable 3, 4.
Why VRd Over Other Regimens
The ENDURANCE trial definitively demonstrated that carfilzomib, lenalidomide, and dexamethasone (KRd) did not improve progression-free survival compared to VRd (34.6 months vs 34.4 months, HR 1.04, p=0.74) but had significantly more toxicity, including higher rates of treatment-related deaths (2% vs <1%) 5. This establishes VRd as the standard of care for induction therapy in standard-risk and intermediate-risk newly diagnosed multiple myeloma. 5
Consolidation with Autologous Stem Cell Transplantation
Following induction, transplant-eligible patients should proceed to high-dose melphalan (200 mg/m²) with autologous stem cell transplantation. 1
- Peripheral blood progenitor cells are preferred over bone marrow as the stem cell source 1
- Selected standard-risk patients may collect stem cells, receive additional cycles of induction therapy, and delay transplant until first relapse 3, 4
Maintenance Therapy
Standard-Risk Patients
Lenalidomide maintenance should be continued until disease progression after ASCT or completion of induction in transplant-ineligible patients 1, 2, 3, 4.
This approach provides median progression-free survival of 41 months and represents the standard of care for standard-risk disease 8.
High-Risk Patients
For high-risk patients, bortezomib-based maintenance therapy is preferred over lenalidomide alone. 1, 2, 3, 4
Bortezomib plus lenalidomide maintenance is specifically recommended for high-risk myeloma to improve outcomes 3.
Essential Supportive Care Measures
Thromboprophylaxis (Critical)
All patients receiving lenalidomide-based therapy require thromboprophylaxis with full-dose aspirin or therapeutic anticoagulation. 1, 8, 2
This is mandatory given the significantly elevated thrombotic risk with immunomodulatory drugs 1, 8.
Additional Supportive Measures
- Herpes zoster prophylaxis for all patients treated with proteasome inhibitors (bortezomib) 8, 2
- Bisphosphonates to reduce skeletal-related events 1, 8
- Subcutaneous bortezomib administration is strongly preferred over intravenous to significantly reduce peripheral neuropathy risk 8, 2
Response Monitoring
Response should be assessed with each treatment cycle using serum and urine protein electrophoresis and serum free light chains. 8, 2
- Complete response requires <5% plasma cells in bone marrow and negative immunofixation 1, 8
- Once best response is attained or on maintenance therapy, assessment may occur every 3 months 2
- Whole-body low-dose CT is preferred over conventional skeletal survey for bone assessment 1, 8
Common Pitfalls to Avoid
Do not use high-dose dexamethasone (40 mg daily) continuously as this increases toxicity without improving outcomes; lower doses (20 mg on bortezomib days) are preferred in the VRd regimen 6.
Do not administer bortezomib intravenously when subcutaneous administration is available, as subcutaneous delivery significantly reduces peripheral neuropathy rates 8, 2.
Do not omit thromboprophylaxis in patients receiving lenalidomide, as thromboembolic events occur in 2-5% of patients even with prophylaxis 5.
Do not use venetoclax-based regimens as initial therapy for t(11;14) myeloma; these are reserved for relapsed/refractory disease, with standard VRd induction being appropriate for newly diagnosed t(11;14) patients 8.