What is the role of Daratumumab (daratumumab) in multiple myeloma treatment?

Daratumumab in Multiple Myeloma Treatment

Daratumumab is a CD38-targeting monoclonal antibody that has become a cornerstone therapy for multiple myeloma, with Category 1 evidence supporting its use in combination regimens for both relapsed/refractory disease and newly diagnosed patients. 1

Mechanism of Action

Daratumumab is a human IgG1κ monoclonal antibody that binds to CD38, a transmembrane glycoprotein highly expressed on myeloma cells. 2 It induces tumor cell death through multiple mechanisms:

• Direct cytotoxicity: Fc-mediated cross-linking induces apoptosis 2
• Immune-mediated killing: Complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP) 2, 3
• Immunomodulation: Reduces CD38+ myeloid-derived suppressor cells, regulatory T cells, and regulatory B cells 2

Clinical Indications and Evidence

Relapsed/Refractory Multiple Myeloma - First-Line Combinations

For patients with one or more prior therapies, daratumumab-based triplet regimens are Category 1 preferred options:

Daratumumab/Lenalidomide/Dexamethasone (DRd)

• The POLLUX trial demonstrated dramatic improvements: median PFS 16.7 vs 7.1 months (HR 0.31, P<0.0001) with extended follow-up at 3.5 years 1
• Patients with only one prior line showed exceptional benefit: median PFS 27.0 vs 7.9 months (HR 0.22, P<0.0001) 1
• Response rates were superior: ORR 92.9% vs 76.4% (P<0.001), with complete response rates of 43.1% vs 19.2% 4
• MRD-negative rates: 22.4% vs 4.6% (P<0.001), which correlated with improved outcomes 4
• This is a Category 1 preferred regimen per NCCN guidelines 1

Daratumumab/Bortezomib/Dexamethasone (DVd)

• Phase III data showed marked efficacy: 12-month PFS rate 60.7% vs 26.9% (HR 0.39, P<0.001) 5
• With 40-month follow-up: median PFS 16.7 vs 7.1 months (HR 0.31, P<0.0001) 1
• Greatest benefit in first relapse: median PFS 27.0 vs 7.9 months (HR 0.22, P<0.0001) 1
• Response rates: ORR 82.9% vs 63.2% (P<0.001); VGPR or better 59.2% vs 29.1% (P<0.001) 1, 5
• This is a Category 1 preferred regimen per NCCN guidelines 1

Heavily Pretreated Relapsed/Refractory Disease

For patients who received ≥3 prior lines including a proteasome inhibitor and immunomodulatory agent:

• Daratumumab monotherapy was FDA-approved based on phase I/II data showing ORR 29.2%, median response duration 7.4 months, and 1-year OS rate 65% 1
• This represents a Category 2A option for heavily pretreated patients 1

Newly Diagnosed Multiple Myeloma (Transplant-Ineligible)

Daratumumab/Bortezomib/Melphalan/Prednisone (D-VMP):

• The ALCYONE trial demonstrated: 18-month PFS rate 71.6% vs 50.2% (HR 0.50, P<0.001) 1
• Response rates: ORR 90.9% vs 73.9% (P<0.001); CR or better 42.6% vs 24.4% (P<0.001) 1
• MRD-negative rates: 22.3% vs 6.2% (P<0.001) 1
• This is a Category 1 option per NCCN guidelines 1

Newly Diagnosed Multiple Myeloma (Transplant-Eligible)

Daratumumab/Bortezomib/Lenalidomide/Dexamethasone (D-VRd):

• The PERSEUS trial showed superior outcomes: 48-month PFS 84.3% vs 67.7% (HR 0.42, P<0.001) 6
• Complete response rates: 87.9% vs 70.1% (P<0.001) 6
• MRD-negative rates: 75.2% vs 47.5% (P<0.001) 6

Safety Profile and Management

Common Adverse Events

Hematologic toxicities are the most frequent grade 3/4 events:

• Neutropenia: 51.9% with DRd vs 37.0% without daratumumab 1
• Thrombocytopenia: 12.7-45.3% depending on combination regimen 1
• Anemia: 12.4-14.4% 1

Infusion-Related Reactions

Infusion reactions occur predominantly during first infusion:

• Incidence: 45.3-47.7% of patients, mostly grade 1-2 1, 5
• Grade 3 reactions: 8.6% of patients 5
• Timing: 98.2% occur during first infusion 5
• Management: Premedication with corticosteroids, antihistamines, and antipyretics is standard 2
• Discontinuation: Rare, with <2% discontinuing due to infusion reactions 1

Infections

Increased infection risk, particularly in elderly patients:

• Grade 3/4 infections: 23.1% with D-VMP vs 14.7% without daratumumab 1
• Pneumonia and sepsis occur more frequently in patients ≥65 years 2

Special Populations

Elderly Patients

• No overall difference in effectiveness between patients <65 years and ≥65 years 2
• Higher incidence of serious adverse reactions in older patients, particularly pneumonia 2
• Fatal adverse reactions: 14% in patients ≥65 years vs 6% in younger patients in the CANDOR trial 2

Pregnancy and Contraception

• Daratumumab can cause fetal harm 2
• Females of reproductive potential must use effective contraception during treatment and for 3 months after the last dose 2

Clinical Positioning

The current treatment algorithm prioritizes daratumumab-based combinations:

1. First relapse (lenalidomide-sensitive): DRd is preferred (Category 1) 1
2. First relapse (bortezomib-sensitive): DVd is preferred (Category 1) 1
3. Newly diagnosed (transplant-ineligible): D-VMP is a Category 1 option 1
4. Newly diagnosed (transplant-eligible): D-VRd shows superior outcomes 6
5. Heavily pretreated (≥3 prior lines): Daratumumab monotherapy or in combination with pomalidomide/dexamethasone 1

The ESMO guidelines note that daratumumab combinations "may be considered in the near future as standards of care" for first relapse and beyond, reflecting the evolution from initial approval to current standard practice 1