Initial Treatment for Multiple Myeloma Meeting CRAB or SLiM Criteria
All patients with symptomatic multiple myeloma meeting CRAB criteria (hypercalcemia >11.5 mg/dL, renal insufficiency with creatinine >2.0 mg/dL, anemia with hemoglobin <10 g/dL, or bone lesions) require immediate treatment initiation to reduce morbidity and mortality. 1, 2
Diagnostic Confirmation Before Treatment
Before initiating therapy, confirm the diagnosis requires:
- ≥10% clonal plasma cells on bone marrow examination or biopsy-proven plasmacytoma 1, 3, 4
- Evidence of end-organ damage (CRAB criteria) attributable to the plasma cell disorder 5, 6, 2
- Complete staging workup including serum/urine protein electrophoresis, immunofixation, serum-free light chains, skeletal survey, and cytogenetics (FISH for del(17p), t(4;14), t(14;16), del(17p)) 5, 3
Treatment Algorithm Based on Transplant Eligibility
Transplant-Eligible Patients (<65 years or fit)
Induction therapy with bortezomib, lenalidomide, dexamethasone (VRd) for 3-4 cycles followed by autologous stem cell transplantation (ASCT) is the standard approach. 3, 4, 7, 8
- For high-risk cytogenetics (del(17p), t(4;14), t(14;16), t(14;20), gain 1q), consider daratumumab plus VRd (Dara-VRd) as superior induction 4, 7, 8
- Melphalan 200 mg/m² IV is the standard preparative regimen before ASCT 5
- Post-transplant maintenance: lenalidomide for standard-risk patients; bortezomib plus lenalidomide for high-risk patients 4, 7, 8
Transplant-Ineligible Patients (≥65 years or unfit)
The combination of bortezomib, melphalan, prednisone (VMP) for 8-12 cycles is a standard regimen, with superior survival compared to melphalan-prednisone alone. 5, 1, 9
Alternative regimens include:
- VRd for 8-12 cycles followed by lenalidomide maintenance 3, 4, 7
- Daratumumab, lenalidomide, dexamethasone (DRd) until progression 4, 7, 8
- Melphalan-prednisone-thalidomide (MPT) as an alternative option 5, 1
The evidence strongly favors novel agent combinations over traditional melphalan-prednisone alone, with VMP showing statistically significant improvements in progression-free survival (18.3 vs 14 months, HR 0.61, p<0.00001) and overall survival (HR 0.65, p=0.00084) 9.
Special Clinical Situations
Renal Impairment (Creatinine >2.0 mg/dL or CrCl <40 mL/min)
- Bortezomib-based regimens are preferred as they can be safely administered without dose adjustment 1, 2
- Avoid NSAIDs and maintain aggressive hydration with normal saline 1, 2
- Lenalidomide requires dose reduction based on creatinine clearance 3, 4
Hypercalcemia (>11.5 mg/dL)
- Aggressive hydration with normal saline is first-line management 1, 2
- Bisphosphonates (zoledronic acid or pamidronate) for severe hypercalcemia and ongoing bone disease management 1, 2
- Initiate anti-myeloma therapy promptly as definitive treatment 6, 2
Bone Disease
- Long-term bisphosphonates (zoledronic acid or pamidronate) reduce skeletal-related events and should be administered to all patients with bone lesions 2
- Consider radiation therapy for symptomatic focal lesions or impending pathologic fractures 5
Critical Pitfalls to Avoid
Do not delay treatment in patients with clear CRAB criteria, as this leads to increased morbidity and mortality 1, 2. The distinction between smoldering (asymptomatic) myeloma and symptomatic myeloma is critical—immediate treatment is not recommended for asymptomatic/smoldering myeloma patients who lack CRAB criteria 5, 2.
Do not use classical VAD regimen (vincristine, adriamycin, dexamethasone) as it is inferior to modern combinations and causes stem cell damage 5, 3. Dexamethasone-based induction without alkylating agents is preferred to preserve stem cell collection potential 5.
For elderly patients, avoid multiagent chemotherapy regimens that have been proven inferior to novel agent combinations 5.