Does daratumumab (Darzalex) treat multiple myeloma?

Does Daratumumab Treat Multiple Myeloma?

Yes, daratumumab (Darzalex) is FDA-approved and highly effective for treating multiple myeloma in both newly diagnosed and relapsed/refractory settings, with proven improvements in progression-free survival and overall survival across multiple clinical scenarios. 1

FDA-Approved Indications

Daratumumab is approved for adult patients with multiple myeloma in the following settings 1:

Newly Diagnosed Disease:

• In combination with lenalidomide and dexamethasone (DRd) for transplant-ineligible patients 1
• In combination with bortezomib, melphalan, and prednisone (D-VMP) for transplant-ineligible patients 1
• In combination with bortezomib, thalidomide, and dexamethasone (Dara-VTd) for transplant-eligible patients 1

Relapsed/Refractory Disease:

• In combination with lenalidomide and dexamethasone after ≥1 prior therapy 1
• In combination with bortezomib and dexamethasone (DVd) after ≥1 prior therapy 1
• In combination with carfilzomib and dexamethasone (DKd) after 1-3 prior lines 1
• In combination with pomalidomide and dexamethasone (DPd) after ≥2 prior therapies including lenalidomide and a proteasome inhibitor 1
• As monotherapy after ≥3 prior lines including a proteasome inhibitor and immunomodulatory agent, or in double-refractory patients 1

Treatment Algorithm by Clinical Setting

First-Line Therapy: Transplant-Ineligible Patients

Standard-Risk Disease:

• DRd (daratumumab-lenalidomide-dexamethasone) continued until progression is the preferred first option, demonstrating superior progression-free survival compared to Rd alone (70.6% vs 55.6% at 30 months) 2
• D-VMP (daratumumab-bortezomib-melphalan-prednisone) is an alternative first option, showing 18-month PFS of 71.6% vs 50.2% with VMP alone 2
• VRd (bortezomib-lenalidomide-dexamethasone) for 8-12 cycles followed by lenalidomide maintenance is acceptable if daratumumab-based regimens are unavailable 2

High-Risk Disease:

• VRd for 8-12 cycles followed by bortezomib-based maintenance is preferred over daratumumab-based regimens, as meta-analysis failed to demonstrate clear PFS benefit from daratumumab addition in newly diagnosed high-risk cytogenetics 2, 3

First-Line Therapy: Transplant-Eligible Patients

• Dara-VTd (daratumumab-bortezomib-thalidomide-dexamethasone) for 3-4 cycles pre-transplant is the preferred first option, showing improved stringent complete response rates and PFS compared to VTd alone 2
• VRd for 3-4 cycles is the standard alternative if daratumumab is not available 2
• For high-risk patients (especially double-hit or triple-hit myeloma), Dara-VRd (daratumumab added to VRd) is recommended, demonstrating better and deeper responses than VRd 2

First Relapse: Lenalidomide-Sensitive Patients

DRd is the primary treatment choice for first relapse in lenalidomide-sensitive patients, providing median progression-free survival of 45 months and representing the best reduction in risk of progression. 2, 4

• DRd is preferred based on superior efficacy in non-randomized comparisons and availability as subcutaneous formulation reducing infusion-related reactions 2
• KRd (carfilzomib-lenalidomide-dexamethasone) is the preferred alternative if daratumumab was previously used or is unavailable 2, 4
• IRd (ixazomib-lenalidomide-dexamethasone) is reasonable for frail patients or those with indolent relapse, offering an all-oral convenient regimen 2, 4

First Relapse: Lenalidomide-Refractory Patients

DVd (daratumumab-bortezomib-dexamethasone) is the preferred choice based on non-randomized efficacy comparisons. 2

• Alternative options include DPd (daratumumab-pomalidomide-dexamethasone), KPd (carfilzomib-pomalidomide-dexamethasone), or DKd (daratumumab-carfilzomib-dexamethasone) 2
• For patients previously treated with daratumumab, KPd is preferred 2

Second or Later Relapse

• Use triplet regimens containing at least two drug classes the patient is not refractory to 2, 4
• Consider quadruplet regimens by adding a monoclonal antibody to existing triplets 2
• Real-world data shows dara-Pd (median time to next treatment 15.3 months) and dara-Kd (13.2 months) are superior to dara-Vd (6.9 months) in this setting 5

Mechanism of Action and Clinical Significance

Daratumumab is a CD38-targeting monoclonal antibody that kills myeloma cells through multiple mechanisms 2, 6:

• Antibody-dependent cellular cytotoxicity (ADCC) 6
• Complement-dependent cytotoxicity (CDC) 6
• Antibody-dependent cellular phagocytosis (ADCP) 6
• Direct apoptosis 6
• Immunomodulation 6

Critical Pitfalls to Avoid

Laboratory Interference:

• Daratumumab interferes with blood bank cross-matching; obtain comprehensive red cell antigen screen before initiating therapy and transfuse Kell-negative blood after dithiothreitol treatment 2
• It interferes with serum protein electrophoresis and immunofixation interpretation if the patient produces IgG kappa 2
• Mass spectrometry reliably distinguishes daratumumab peak from myeloma protein 2

Treatment Selection Errors:

• Do not use lenalidomide-based regimens in patients progressing on lenalidomide maintenance; switch to proteasome inhibitor with monoclonal antibody instead 4
• Do not use single or doublet therapy when triplet combinations are tolerated, as triplets consistently demonstrate superior outcomes 4
• Real-world evidence suggests dara-Vd may not be suitable as a control arm for phase 3 studies due to inferior time to next treatment compared to dara-Kd and dara-Pd 5

Infusion Management:

• Infusion-related reactions occur in approximately 28% of patients, predominantly during first infusion 2
• Subcutaneous formulation reduces infusion time and infusion-related side effects 2

Supportive Care Requirements

All patients receiving daratumumab-containing regimens require 4:

• Thromboprophylaxis with full-dose aspirin or therapeutic anticoagulation when combined with immunomodulatory drugs 4
• Herpes zoster prophylaxis 2
• Pneumocystis jiroveci prophylaxis 2

Evidence Quality and Cytogenetic Subgroups

Meta-analysis of 2,340 newly diagnosed and 673 relapsed/refractory patients demonstrates 3:

• Clear benefit in standard-risk newly diagnosed MM (HR 0.43; P<0.05) 3
• Clear benefit in both standard-risk (HR 0.28; P<0.05) and high-risk (HR 0.48; P<0.05) relapsed/refractory disease 3
• No clear benefit in newly diagnosed high-risk MM, though data from ongoing GRIFFIN and MASTER trials may clarify this 3