Daratumumab
Daratumumab is a human IgG1κ monoclonal antibody that specifically binds to CD38, a transmembrane glycoprotein highly expressed on malignant plasma cells in multiple myeloma, inducing tumor cell death through complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, and direct apoptosis.[1][2] It was first approved by the U.S. Food and Drug Administration in November 2015 as monotherapy for patients with multiple myeloma who had received at least three prior lines of therapy, marking it as the first CD38-targeted agent in its class.[3] Subsequent approvals expanded its use to frontline and relapsed settings, often in combination with proteasome inhibitors, immunomodulatory drugs, or corticosteroids, demonstrating improved progression-free survival and overall response rates in clinical trials such as CASTOR, POLLUX, and MAIA.[4][5] A subcutaneous formulation, daratumumab and hyaluronidase-fihj (Darzalex Faspro), was approved in 2020 for broader accessibility, reducing infusion times while maintaining efficacy.[6] Common adverse effects include infusion-related reactions, neutropenia, thrombocytopenia, and infections, necessitating premedication and monitoring, though its risk-benefit profile has established it as a cornerstone in multiple myeloma therapy.[7][5]Medical Applications
Indications and Approvals
Daratumumab received accelerated approval from the U.S. Food and Drug Administration (FDA) on November 16, 2015, as monotherapy for adult patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or who are double-refractory to both classes.[3] This was based on response rates in heavily pretreated relapsed or refractory multiple myeloma (RRMM) patients. The European Medicines Agency (EMA) granted conditional marketing authorization for the same monotherapy indication in RRMM on May 20, 2016, for patients with at least three prior therapies.[8] Subsequent FDA expansions included approval on January 31, 2019, for combination with lenalidomide and dexamethasone (D-Rd) in RRMM patients after at least one prior line of therapy.[9] On June 27, 2019, the FDA approved daratumumab with bortezomib, melphalan, and prednisone (D-VMP) for newly diagnosed multiple myeloma (NDMM) patients ineligible for autologous stem cell transplant.[9] Further, on September 26, 2019, approval extended to daratumumab with bortezomib, thalidomide, and dexamethasone (D-VTd) for NDMM patients eligible for transplant, and on September 20, 2020, to daratumumab with pomalidomide and dexamethasone for RRMM after at least two prior lines.[10] The EMA aligned with similar combination approvals, including D-Rd for RRMM after one prior line on June 28, 2019, and D-VMP for transplant-ineligible NDMM on December 18, 2018.[8] The subcutaneous formulation, daratumumab and hyaluronidase-fihj (Darzalex Faspro), was FDA-approved on May 1, 2020, initially for monotherapy and later expanded to match intravenous indications, including RRMM combinations after one or more prior lines and NDMM frontline regimens.[6] On July 30, 2024, the FDA approved Darzalex Faspro with bortezomib, lenalidomide, and dexamethasone (D-VRd) for induction and consolidation in transplant-eligible NDMM patients.[11] EMA approvals for the subcutaneous form followed, including D-VTd for transplant-eligible NDMM on January 27, 2020, and extensions to D-VRd.[12] In 2025, the European Commission approved subcutaneous daratumumab monotherapy on July 23 for adults with high-risk smoldering multiple myeloma, marking the first licensed treatment for this precursor condition, based on progression-free survival data in asymptomatic patients at high risk of progression.[13] This targets patients without active myeloma symptoms but with biomarkers indicating elevated risk, such as bone marrow plasma cell involvement exceeding 60% or serum free light chain ratio greater than 100.[8] FDA consideration for this indication received Oncologic Drugs Advisory Committee support in June 2025 but remained pending full approval as of October 2025.[14]Clinical Efficacy Evidence
In the phase 3 POLLUX trial evaluating daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) in patients with relapsed or refractory multiple myeloma (RRMM) who had received at least one prior therapy, the overall response rate (ORR) was 93% with D-Rd compared to 76% with Rd, including higher rates of very good partial response or better (81% vs. 49%).[15] D-Rd reduced the risk of progression or death by 63%, with a hazard ratio (HR) for progression-free survival (PFS) of 0.37 after a median follow-up of 13.5 months, and longer-term data confirmed sustained PFS benefits.[16] The phase 3 CASTOR trial assessed daratumumab plus bortezomib and dexamethasone (D-Vd) versus bortezomib and dexamethasone (Vd) in RRMM patients with one to three prior lines of therapy, yielding an ORR of 83% with D-Vd versus 63% with Vd, and median PFS of 18.0 months versus 7.3 months in that subgroup.[17] Extended follow-up at 42 months showed PFS rates of 22% with D-Vd versus 1% with Vd, alongside deeper responses including higher minimal residual disease (MRD) negativity rates.[17] For newly diagnosed multiple myeloma (NDMM) in transplant-eligible patients, the phase 3 PERSEUS trial demonstrated that daratumumab plus bortezomib, lenalidomide, and dexamethasone (D-VRd) induction followed by daratumumab plus lenalidomide (DR) maintenance improved PFS compared to VRd alone, with median PFS projected at 17 years in the D-VRd arm based on 2025 projections and sustained MRD negativity in nearly two-thirds of patients achieving over 95% 48-month PFS rates.[18] At a median follow-up of 47.5 months, D-VRd yielded higher rates of MRD negativity at 10^{-5} and 10^{-6} thresholds.[19] Subgroup analyses from trials like PERSEUS indicate daratumumab-containing regimens provide PFS benefits in patients with high-risk cytogenetic abnormalities (HRCAs, including del(17p), t(4;14), t(14;16), or gain(1q)), though outcomes may be attenuated compared to standard-risk patients; for instance, 1q gain or amplification, present in up to 40% of cases, correlates with reduced CD38 expression and potentially inferior responses despite overall HR reductions.[20] In high-risk smoldering multiple myeloma, the phase 3 AQUILA trial of subcutaneous daratumumab monotherapy versus active monitoring reported a 51% lower risk of progression to active myeloma or death after median follow-up exceeding 5 years (65 months), with continued single-agent activity observed at around 7 years but limited long-term overall survival data due to the disease's indolent nature.[21][22] Real-world studies in RRMM report ORRs of 76-93% with daratumumab-based regimens, varying by prior refractoriness and combination (e.g., 76.3% overall in relapsed settings, lower at 30% for monotherapy), with median PFS ranging from 6-28 months depending on lines of therapy and cytogenetic risk, though these outcomes reflect heterogeneous populations and shorter follow-up than pivotal trials.[23][24][25]Comparative Effectiveness
In relapsed/refractory multiple myeloma (RRMM), daratumumab plus bortezomib and dexamethasone (D-Vd) showed superior progression-free survival (PFS) over Vd alone in the phase 3 CASTOR trial, with a median PFS of 16.6 months versus 7.9 months (hazard ratio [HR] 0.39; 95% CI 0.33-0.47) and an overall survival (OS) benefit (HR 0.74; 95% CI 0.59-0.92 at 3-year follow-up).[26] Similarly, in the POLLUX trial, daratumumab plus lenalidomide and dexamethasone (D-Rd) extended median PFS to 18.4 months compared to 9.3 months with Rd alone (HR 0.44; 95% CI 0.35-0.55), though OS gains were more modest in heavily pretreated subgroups.[27] These head-to-head data indicate daratumumab adds approximately 7-9 months of PFS when combined with proteasome inhibitor or immunomodulatory drug backbones, driven by deeper responses in CD38-expressing disease, but real-world analyses suggest attenuated OS benefits in triple-class refractory settings due to subsequent therapies.[28] Meta-analyses of daratumumab combinations versus bortezomib-, lenalidomide-, or pomalidomide-based regimens confirm consistent PFS improvements (pooled HR 0.40-0.50 across RRMM trials), with matching-adjusted indirect comparisons showing daratumumab monotherapy or D-Rd outperforming pomalidomide plus low-dose dexamethasone in OS for heavily pretreated patients (HR 0.72).[29] In newly diagnosed multiple myeloma ineligible for transplant, D-Rd reduced progression risk versus bortezomib, lenalidomide, and dexamethasone (VRd) (HR 0.59 for PFS), though direct superiority in OS remains unproven without mature data.[30] Efficacy depends on baseline CD38 expression, with reduced responses in low-CD38 tumors, underscoring no universal advantage over backbone therapies in all causal pathways of disease progression.[31] Compared to bispecific antibodies (e.g., teclistamab) or CAR-T therapies (e.g., cilta-cel) in daratumumab-refractory RRMM, daratumumab regimens offer earlier-line, outpatient administration with lower toxicity but shallower responses (complete response rates 10-20% lower) and shorter PFS in triple-class exposed patients (median 6-12 months versus 18-24 months for CAR-T).[32][33] Indirect comparisons favor CAR-T for OS in refractory cases (HR 0.50-0.70 versus daratumumab historical controls), reflecting T-cell redirection's independence from CD38 targeting, though daratumumab's role persists as a less resource-intensive bridge to these modalities.| Trial/Regimen | Comparison | Median PFS (months) | PFS HR (95% CI) | OS HR (if available) |
|---|---|---|---|---|
| CASTOR (D-Vd vs Vd, RRMM) | Post-1L | 16.6 vs 7.9 | 0.39 (0.33-0.47) | 0.74 (0.59-0.92) |
| POLLUX (D-Rd vs Rd, RRMM) | Post-1L IMiD | 18.4 vs 9.3 | 0.44 (0.35-0.55) | Modest gain |
| APOLLO (D-Vd vs Vd, RRMM) | Post-Len/Pom | 11.2 vs 7.1 | 0.63 (0.50-0.79) | 0.79 (0.60-1.03) |