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

Initial Treatment for Multiple Myeloma

All patients with newly diagnosed symptomatic multiple myeloma should receive induction therapy with bortezomib, lenalidomide, and dexamethasone (VRd), which is the preferred triplet regimen regardless of transplant eligibility. 1, 2, 3

Risk Stratification Before Treatment

Before initiating therapy, perform comprehensive risk stratification to guide treatment intensity and maintenance strategies 4:

• Obtain FISH testing for cytogenetic abnormalities including del(17p), t(4;14), t(14;16), t(14;20), and del(13q) 4
• Measure serum β2-microglobulin, albumin, and LDH for International Staging System (ISS) classification 4
• Assess plasma cell proliferation rate and presence of extramedullary disease 4

High-risk features include: del(17p), t(4;14), t(14;16), t(14;20), ISS stage III, elevated LDH, or plasma cell labeling index ≥3% 4. These patients have median overall survival of 3 years compared to 8-10 years for standard-risk patients 4.

Transplant-Eligible Patients

Induction Therapy (4 cycles)

Administer VRd (bortezomib-lenalidomide-dexamethasone) for 4 cycles before stem cell collection 4, 1, 2:

• Bortezomib: 1.3 mg/m² subcutaneously (preferred over IV to reduce neuropathy) on days 1,4,8,11 of 21-day cycles 1, 3
• Lenalidomide: 25 mg orally days 1-14 of 21-day cycles 1, 2
• Dexamethasone: 40 mg weekly (20 mg if >75 years) 1, 2

This regimen achieves 58% very good partial response (VGPR) or better after induction, with 52% achieving complete response (CR) or near-CR 1. Do not exceed 4-6 cycles before stem cell collection to avoid compromising stem cell harvest 4.

Alternative for High-Risk Patients

For patients with del(17p), t(4;14), t(14;16), or t(14;20), VRd remains the preferred induction as bortezomib overcomes adverse prognostic effects of these high-risk cytogenetic features, particularly t(4;14) 4. The 2013 Mayo guidelines specifically recommend VRd over other regimens for high-risk disease to maximize complete response rates 4.

Consolidation with Autologous Stem Cell Transplantation

Proceed to high-dose melphalan (200 mg/m²) with autologous stem cell transplantation after induction 1, 2, 5:

• Transplantation extends median progression-free survival to 50 months versus 36 months with RVD alone (HR 0.65, p<0.001) 5
• Complete response rates increase from 48% to 59% with transplantation 5
• High-risk patients benefit most from transplantation, especially if not achieving CR with induction alone 4

Maintenance Therapy

Continue lenalidomide maintenance until disease progression for all transplant-eligible patients 1, 2, 3:

• Standard-risk patients: Lenalidomide alone 4, 1
• High-risk patients: VRd (bortezomib-lenalidomide-dexamethasone) for minimum 1 year, then consider continuing lenalidomide 4, 1. The European guidelines specifically recommend bortezomib-based maintenance over lenalidomide alone for high-risk cytogenetics 1.

Transplant-Ineligible Patients

First-Line Therapy

Daratumumab-lenalidomide-dexamethasone (DRd) is now the preferred regimen for transplant-ineligible patients based on superior outcomes 6, 7:

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

The MAIA trial demonstrated median progression-free survival of 61.9 months with DRd versus 34.4 months with lenalidomide-dexamethasone alone (HR 0.56, p<0.0001), representing a 44% reduction in disease progression or death 6. Overall survival also improved with 32% reduction in death risk (HR 0.68, p=0.0013) 6.

Continue treatment until disease progression rather than fixed-duration therapy 3.

Alternative Regimen

If daratumumab is unavailable, VRd remains an acceptable alternative for transplant-ineligible patients 1, 2, 3. Recent meta-analysis shows DRd has lower risk of progression versus VRd (HR 0.60,95% CI 0.46-0.77) 7.

Special Clinical Situations

Renal Failure

Initiate bortezomib-dexamethasone immediately for patients presenting with renal failure 4:

• Bortezomib has primarily non-renal clearance allowing rapid responses 4
• Add cyclophosphamide, doxorubicin, or thalidomide as third agent (avoid lenalidomide until renal function improves) 4
• Bortezomib-based regimens reverse renal impairment in 25-40% of patients 4
• Avoid nephrotoxic agents and maintain euvolemia 4

Intermediate-Risk Disease

Use bortezomib-containing regimens (VRd or cyclophosphamide-bortezomib-dexamethasone) for intermediate-risk patients with t(4;14) or cytogenetic del(13q) 4. Continue bortezomib-based maintenance for minimum 1 year 4.

Essential Supportive Care

Implement these measures at treatment initiation 3:

• Thromboprophylaxis: Full-dose aspirin or therapeutic anticoagulation for all patients receiving immunomodulatory drugs (lenalidomide, thalidomide) 1, 2, 3
• Herpes zoster prophylaxis: Antiviral prophylaxis for all patients receiving proteasome inhibitors 3
• Bisphosphonates: Initiate for bone disease management 4
• Subcutaneous bortezomib: Preferred route to reduce peripheral neuropathy risk by approximately 50% compared to IV administration 1, 3

Response Monitoring

Assess response with each treatment cycle using serum and urine protein electrophoresis 4, 3:

• Complete response requires <5% plasma cells in bone marrow and negative immunofixation 4, 3
• Whole-body low-dose CT is preferred over conventional skeletal survey for bone assessment 1, 2
• Once best response achieved or on maintenance, assess minimally every 3 months 3

Critical Pitfalls to Avoid

Do not use lenalidomide-based regimens as monotherapy for high-risk cytogenetics - these patients require bortezomib-containing regimens to overcome adverse prognostic features 4. The older 2009 Mayo guidelines showed comparable outcomes between lenalidomide-dex and bortezomib-dex for standard-risk disease, but subsequent evidence clearly demonstrates bortezomib's superiority for high-risk features 4.

Do not delay stem cell collection beyond 4-6 cycles of induction in transplant-eligible patients, as prolonged exposure to alkylating agents or lenalidomide may compromise harvest 4.

Do not use IV bortezomib when subcutaneous administration is available - the subcutaneous route significantly reduces neuropathy while maintaining equivalent efficacy 1, 3.