What are the treatment regimens for multiple myeloma, including VTD (VTD: bortezomib, thalidomide, and dexamethasone) and lenalidomide, and what are the National Comprehensive Cancer Network (NCCN) guidelines regarding daratumumab and lenalidomide pre-transplant?

Multiple Myeloma Treatment Overview and NCCN Guidelines for Daratumumab/Lenalidomide Pre-Transplant

Understanding Multiple Myeloma

Multiple myeloma is a hematologic malignancy characterized by clonal plasma cell proliferation in the bone marrow, requiring multi-agent chemotherapy regimens that combine novel agents from different drug classes to achieve optimal disease control. 1

VTD Regimen Composition

VTD consists of bortezomib (a proteasome inhibitor), thalidomide (an immunomodulatory drug), and dexamethasone (a corticosteroid). 1

• VTD achieves a complete response rate of 33% in transplant-eligible patients 1
• This three-drug combination is administered as induction therapy for 3-4 cycles before stem cell collection and autologous stem cell transplantation (ASCT) 1
• The typical dosing schedule includes bortezomib 1.3 mg/m² subcutaneously on days 1,8,15,22; thalidomide 100-200 mg orally days 1-21; and dexamethasone 20 mg on the day of and day after bortezomib 1

Lenalidomide Overview

Lenalidomide is an immunomodulatory drug (IMiD) that affects both intracellular signaling pathways and the tumor microenvironment, approved in combination with dexamethasone for newly diagnosed patients ineligible for transplant and for relapsed/refractory disease. 1, 2

• When combined with low-dose dexamethasone (Rd regimen), lenalidomide yields a complete response rate of 24% 1
• The standard dosing is lenalidomide 25 mg orally days 1-21 with dexamethasone 40 mg orally on days 1,8,15,22, repeated every 28 days 1
• Lenalidomide is also the backbone of maintenance therapy post-transplant, demonstrating nearly 2-fold improvement in progression-free survival 1

NCCN Guidelines: Daratumumab and Lenalidomide Pre-Transplant

The NCCN Guidelines designate daratumumab combined with bortezomib, lenalidomide, and dexamethasone (D-VRd) as a Category 1 preferred regimen for newly diagnosed transplant-eligible patients, based on the landmark PERSEUS trial showing superior progression-free survival. 1, 3

Key NCCN Recommendations for Transplant-Eligible Patients:

• D-VRd (daratumumab + VRd) is the preferred induction regimen with subcutaneous daratumumab formulation recommended over intravenous due to similar efficacy with fewer infusion-related reactions 4, 3
• The regimen achieves 84.3% progression-free survival at 48 months compared to 67.7% with VRd alone (hazard ratio 0.42, P<0.001) 3
• Complete response or better rates reach 87.9% with D-VRd versus 70.1% with VRd alone 3
• Minimal residual disease (MRD) negativity rates are substantially higher: 75.2% with D-VRd versus 47.5% with VRd 3

FDA-Approved Daratumumab Indications Pre-Transplant:

Daratumumab is FDA-approved in combination with bortezomib, thalidomide, and dexamethasone (D-VTd) for newly diagnosed patients eligible for ASCT, and in combination with lenalidomide and dexamethasone for newly diagnosed patients ineligible for ASCT. 5

Specific Dosing Schedule for D-VTd (Pre-Transplant):

• Induction phase: Daratumumab 16 mg/kg IV weekly for weeks 1-8 (8 doses), then every 2 weeks for weeks 9-16 (4 doses) 5
• Stop for high-dose chemotherapy and ASCT
• Consolidation phase: Daratumumab every 2 weeks for weeks 1-8 upon re-initiation post-ASCT (4 doses) 5

Alternative Daratumumab-Based Pre-Transplant Regimen:

Daratumumab combined with cyclophosphamide, bortezomib, and dexamethasone (D-CyBorD) is included as a treatment option for both transplant-eligible and transplant-ineligible patients, with particular value in acute renal insufficiency. 4

• Subcutaneous daratumumab with hyaluronidase-fihj is preferred over IV formulation 4
• Subcutaneous bortezomib is exclusively recommended rather than IV to reduce peripheral neuropathy rates 4

Critical Safety Considerations

All patients receiving proteasome inhibitors (bortezomib) or daratumumab require mandatory herpes zoster prophylaxis and thromboprophylaxis with full-dose aspirin, escalating to therapeutic anticoagulation for high-risk patients. 4

Common Toxicities with D-VRd:

• Grade 3/4 neutropenia occurs in 62.1% (versus 51.0% with VRd alone) 3
• Grade 3/4 thrombocytopenia in 29.1% (versus 17.3% with VRd) 3
• More infections occur with D-VRd, though grade 3/4 infection rates remain similar to VRd 6
• Median CD34+ cell yield is slightly lower (8.2 × 10⁶/kg versus 9.4 × 10⁶/kg), requiring more frequent plerixafor use for stem cell mobilization 6

Current Treatment Paradigm for Transplant-Eligible Patients

The standard approach involves triplet or quadruplet induction therapy (preferably D-VRd) for 4 cycles, followed by stem cell collection, high-dose melphalan (200 mg/m²) with ASCT, consolidation therapy, and lenalidomide maintenance. 1, 3

• Three-drug combinations including at least bortezomib and dexamethasone are the standard of care before ASCT 1
• Daratumumab maintenance following D-VRd induction and consolidation continues until disease progression 4, 3
• MRD negativity by next-generation sequencing predicts superior progression-free survival and is increasingly used to guide treatment decisions 1