What is the recommended treatment regimen for multiple myeloma using Daratumumab (daratumumab)?

Daratumumab Treatment Regimens for Multiple Myeloma

For relapsed/refractory multiple myeloma after 1-3 prior therapies, daratumumab should be administered as part of a triplet regimen rather than monotherapy, with daratumumab/lenalidomide/dexamethasone (DRd) or daratumumab/bortezomib/dexamethasone (DVd) as Category 1 preferred options, both demonstrating superior progression-free survival compared to doublet therapy. 1, 2

Dosing Schedule

Standard Daratumumab Dosing (All Regimens)

• 16 mg/kg intravenously with the following frequency: 1, 3
  • Weeks 1-8: Weekly (days 1,8,15,22 of each 28-day cycle for cycles 1-2)
  • Weeks 9-24: Every 2 weeks (days 1,15 of cycles 3-6)
  • Week 25 onward: Every 4 weeks (day 1 of subsequent cycles) until disease progression

Split Dosing Option for First Infusion

• First dose may be split across two consecutive days to reduce infusion time and reaction risk, though this results in different pharmacokinetics on day 1 only 3

Preferred Combination Regimens by Clinical Scenario

For Lenalidomide-Sensitive or Bortezomib-Refractory Disease (First Relapse)

Daratumumab/Lenalidomide/Dexamethasone (DRd) - Category 1 Preferred 1, 2

• Lenalidomide: 25 mg orally days 1-21 of each 28-day cycle
• Dexamethasone: 40 mg weekly (20 mg for patients >75 years or BMI <18.5)
• Evidence: Median PFS 61.9 months vs 34.4 months with lenalidomide/dexamethasone alone (HR 0.56, P<0.0001) 1, 3
• Best for: Patients with only one prior line showed exceptional benefit with median PFS 27.0 vs 7.9 months (HR 0.22, P<0.0001) 1, 2

For Bortezomib-Sensitive or Lenalidomide-Refractory Disease (First Relapse)

Daratumumab/Bortezomib/Dexamethasone (DVd) - Category 1 Preferred 1, 2

• Bortezomib: 1.3 mg/m² subcutaneously on days 1,4,8,11 of each 21-day cycle (cycles 1-8)
• Dexamethasone: 20 mg on days 1,2,4,5,8,9,11,12
• Evidence: Median PFS 16.7 vs 7.1 months (HR 0.31, P<0.0001); 12-month PFS rate 60.7% vs 26.9% 1, 2
• Critical advantage: Patients with one prior line achieved median PFS 27.0 vs 7.9 months (HR 0.22, P<0.0001) 1

For Carfilzomib-Eligible Patients (After 1-3 Prior Therapies)

Daratumumab/Carfilzomib/Dexamethasone (DKd) - Category 1 Preferred 1

• Carfilzomib: 20 mg/m² IV days 1-2 of cycle 1, then 56 mg/m² IV days 8,9,15,16 of cycle 1, then 56 mg/m² days 1,2,8,9,15,16 for subsequent cycles (28-day cycles)
• Dexamethasone: 20 mg on days 1,2,8,9,15,16,22,23
• Evidence: Median PFS 28.6 vs 15.2 months (HR 0.59, P<0.0001) 1
• Alternative formulation: Isatuximab/carfilzomib/dexamethasone showed median PFS 35.7 vs 19.15 months (HR 0.53, P=0.0007) 1

For Lenalidomide-Refractory Disease After ≥2 Prior Therapies

Daratumumab/Pomalidomide/Dexamethasone (DPd) - Category 1 Preferred 1

• Pomalidomide: 4 mg orally days 1-21 of each 28-day cycle
• Dexamethasone: 40 mg weekly (20 mg for patients ≥75 years)
• Evidence: ORR 58% in heavily pretreated patients (median 3.5 prior therapies), with 65% refractory to both PI and IMiD 1
• Best for: Triple-refractory disease (lenalidomide, pomalidomide, and PI-refractory) 1

Monotherapy Indication (Heavily Pretreated Patients Only)

Daratumumab Monotherapy - Reserved for specific circumstances 1, 2, 4

• Indication: Patients with ≥3 prior therapies including PI and IMiD, or double-refractory to both 1, 5
• Dosing: Same schedule as combination therapy (16 mg/kg) 1
• Evidence: ORR 29.2%, median response duration 7.4 months 2
• Real-world data: ORR 37%, median PFS 7.2 months, median OS 7.8 months 4
• Critical limitation: Inferior to combination regimens; use only when combination therapy is not feasible 1, 2

Newly Diagnosed Multiple Myeloma (Transplant-Ineligible)

Daratumumab/Lenalidomide/Dexamethasone (DRd) - Category 1 3

• Same dosing as relapsed setting
• Evidence: Median PFS 61.9 vs 34.4 months (HR 0.56, P<0.0001); 32% reduction in death risk (HR 0.68, P=0.0013) 3
• Treatment duration: Continue until disease progression or unacceptable toxicity 3

Critical Safety Management

Infusion-Related Reactions (IRRs)

• Incidence: 45.3-56% during first infusion, 2% during second, 2% during subsequent infusions 1, 6
• Severity: Mostly grade 1-2; grade 3 in 8.6% 1
• Symptoms: Respiratory (cough, dyspnea, throat irritation, nasal congestion) most common 6
• Premedication strategy: Montelukast reduced first-infusion IRR rate from 59% to 38% in one cohort 6
• Management: Standard premedication with antihistamines, acetaminophen, and corticosteroids 3, 7

Hematologic Toxicity

• Neutropenia: 51.9% (grade 3-4) with DRd vs 37.0% without daratumumab 1, 2
• Thrombocytopenia: 12.7-45.3% depending on combination regimen 1, 2
• Anemia: 12.4-14.4% (grade 3-4) 1
• Monitoring: Complete blood counts before each dose 3

Infection Risk

• Incidence: Grade 3-4 infections in 23.1% with daratumumab combinations vs 14.7% without 2
• Prophylaxis: Consider herpes zoster prophylaxis (per NCCN guidelines for proteasome inhibitor-based regimens) 8
• Elderly patients: Increased infection risk requires heightened monitoring 2

Blood Bank Interference

• Critical issue: Daratumumab binds CD38 on red blood cells, causing positive indirect antiglobulin tests 5, 7
• Management: Type and screen patients before starting therapy; notify blood bank of daratumumab use 7
• Duration: Interference may persist for up to 6 months after last dose 7

Common Pitfalls and How to Avoid Them

Pitfall 1: Using Monotherapy When Combination Therapy Is Appropriate

• Error: Prescribing daratumumab monotherapy for patients with 1-3 prior therapies
• Correction: Always use triplet combinations (DRd, DVd, or DKd) for patients with 1-3 prior therapies; monotherapy is only for heavily pretreated patients (≥3 prior lines) when combinations are not feasible 1, 2

Pitfall 2: Inadequate First Infusion Time Management

• Error: Scheduling insufficient time for first infusion (IRRs occur in >50% of patients)
• Correction: Allocate 7+ hours for first infusion; consider split dosing over two consecutive days to reduce infusion time and reaction risk 3, 6

Pitfall 3: Wrong Regimen Selection Based on Prior Therapy

• Error: Using lenalidomide-containing regimen (DRd) in lenalidomide-refractory patients
• Correction: For lenalidomide-refractory disease, use DVd (if bortezomib-sensitive), DKd (if carfilzomib-eligible), or DPd (if pomalidomide-appropriate) 1

Pitfall 4: Failing to Notify Blood Bank

• Error: Not informing blood bank before starting daratumumab, causing delays in transfusion compatibility testing
• Correction: Type and screen before first dose; document daratumumab use in medical record; notify blood bank of ongoing therapy 5, 7

Pitfall 5: Discontinuing Too Early After First Relapse

• Error: Stopping daratumumab-based therapy prematurely in responding patients
• Correction: Continue treatment until disease progression or unacceptable toxicity; patients achieving PR or better after 6 months have significantly longer PFS (29.5 vs 3.6 months, P=0.0001) and OS (30.6 vs 3.9 months, P=0.0001) 4