HexaBody-CD38 (GEN3014) in Relapsed/Refractory Multiple Myeloma: A Better Antibody, A Saturated Market

What was tried

Genmab ran NCT04824794, an open-label Phase 1/2 trial of GEN3014 (HexaBody-CD38) in relapsed or refractory multiple myeloma (RRMM), diffuse large B cell lymphoma (DLBCL), and acute myeloid leukemia (AML). The trial enrolled 130 patients across dose escalation and expansion. Expansion Part A treated three populations with GEN3014 monotherapy: anti-CD38 naive RRMM, anti-CD38 refractory RRMM, and R/R DLBCL. Expansion Part B treated anti-CD38 naive RRMM with subcutaneous daratumumab as an active comparator, providing a within-trial benchmark against the standard-of-care CD38 antibody. The primary completion date was June 2025. The trial was then terminated, with Genmab citing a comprehensive review of the data, the market landscape, and strategic priorities.

The biological hypothesis

CD38 is an ectoenzyme and signaling molecule expressed at high copy number on plasma cells and at variable levels on lymphoid and myeloid populations. It is the validated target of daratumumab and isatuximab, both approved in multiple lines of myeloma therapy. CD38 antibodies kill tumor cells through antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), and direct apoptotic signaling. The relative contribution of each mechanism is debated and patient-dependent.

GEN3014 was built on Genmab's HexaBody platform [1]. A single Fc-engineering change enhances Fc-Fc interactions between adjacent IgG1 molecules bound to membrane antigen, promoting hexameric ring formation that maximizes C1q docking. The result, in preclinical models, was substantially stronger CDC than daratumumab, including against tumor cells with lower surface CD38 [1]. The thesis: a CDC-amplified CD38 antibody could deepen responses in CD38-low myeloma and address daratumumab-refractory disease where antigen escape and effector function exhaustion are documented resistance mechanisms [2,3,4].

What actually happened

The trial reached primary completion in June 2025 and Genmab discontinued the program shortly after. The public termination language is unusually transparent for a portfolio decision: it explicitly invokes "data, market landscape, and strategic priorities" rather than a clean safety or futility call. No detailed efficacy readout in RRMM Part A or against the daratumumab Part B has been posted on the registry at the time of writing. The absence of a separate publication or conference presentation following primary completion is itself informative, as is the fact that Genmab retained continued investment in epcoritamab and other bispecific programs while shutting GEN3014 down.

Failure mechanism, best guess

The most likely interpretation is that GEN3014 met its mechanistic preclinical promise on CDC but did not produce a clinical efficacy delta over daratumumab large enough to justify the cost of a Phase 3 program in a saturated market.

Three forces point in the same direction.

First, the resistance landscape. Recent work shows that biallelic CD38 antigen escape is a real mechanism of daratumumab resistance in a meaningful fraction of patients [2]. An antibody that hits the same epitope more efficiently cannot rescue a tumor that no longer presents the target. Mechanisms of daratumumab resistance also include FcγR polymorphisms, complement regulator upregulation (CD55, CD59), and exhaustion of NK effector function [3]. Enhanced CDC partly addresses one of these mechanisms, but the patient population it helps is narrower than originally modeled.

Second, the competitive environment. Daratumumab is now available subcutaneously (Darzalex Faspro), reducing infusion burden and shifting payer dynamics. Isatuximab is approved across multiple lines. CD38-targeting T cell engagers (such as elranatamab and teclistamab are BCMA, but CD38 bispecifics like GBR 1342 and AMG 424 program lessons apply), BCMA-directed CAR-T and bispecifics, and GPRC5D bispecifics now occupy the next-line space. A "best-in-class" mAb improvement no longer commands a clean differentiation story when the next-generation modalities are antigen-redirected T cells.

Third, the within-trial daratumumab arm. Including a head-to-head comparator in expansion is a deliberate choice that exposes the molecule to a binary verdict. If GEN3014 ORR and depth-of-response in anti-CD38 naive RRMM did not meaningfully exceed the daratumumab arm, the data-driven case for a Phase 3 collapsed. The framing of the termination ("data, market landscape, strategic priorities") is consistent with a result that was clinically respectable but not differentiating.

How to prevent this next time

The Bayesian framing for class-improvement antibodies is

PP(success)=∫θ​P(final success∣θ,interim data)⋅π(θ∣interim data)dθ

where success is defined as commercial differentiation, not biological superiority. Two changes would have either accelerated the kill decision or sharpened the bet.

First, a biomarker-enrichment strategy targeted at the mechanism. CDC enhancement is most meaningful in CD38-intermediate or CD38-low myeloma where daratumumab's CDC is rate-limiting. Restricting the expansion comparator cohort to patients with documented CD38 expression below a defined threshold, or to patients with a defined complement-regulator profile, would have tested the only hypothesis where GEN3014 should outperform daratumumab. Pan-RRMM expansion against daratumumab dilutes the signal to noise.

Second, an explicit number-needed-to-screen calculation and adaptive randomization. If the CDC-enhanced advantage matters only in a minority subgroup, the trial should be designed to enrich for that subgroup using adaptive randomization and predefined futility boundaries at the daratumumab-equivalence interim. A Bayesian adaptive design with a stopping rule keyed to predicted Phase 3 success probability under daratumumab subcutaneous as comparator would have either killed the program in 2023 at smaller cost or produced a differentiated registration cohort.

The single highest leverage change would have been to define the program as CDC-rescue for CD38-low or daratumumab-refractory myeloma from day one rather than as a broad daratumumab replacement.

What this means for similar programs

Class improvement antibodies face two thresholds, biological and commercial. CD38, HER2, PD-1, and CD20 are all classes where second-generation molecules with cleaner mechanisms have failed to displace incumbents because the incumbents are good enough, the next-generation modalities are antigen-redirected T cells, and the incremental margin does not justify a confirmatory Phase 3. The lesson generalizes: a HexaBody, glyco-engineered, or affinity-matured antibody now needs to demonstrate a differentiated response in a defined subgroup, ideally one where the incumbent is documented to fail. Otherwise the program is competing against subcutaneous biosimilars and T cell engagers from a position of structural disadvantage.

Open questions

What was the ORR in GEN3014 Part A versus daratumumab Part B in anti-CD38 naive RRMM. Did patients with CD38-low or daratumumab-refractory disease show differential benefit. Did the antibody achieve any depth-of-response advantage at minimal residual disease (MRD) thresholds. Will Genmab publish the comparator data in a peer-reviewed venue or only release headline numbers at a conference.

Sources

1. [1] Beurskens FJ et al. Preclinical anti-tumour activity of HexaBody-CD38, a next-generation CD38 antibody with superior complement-dependent cytotoxicity. EBioMedicine, 2023. [2] Costa LJ et al. Biallelic antigen escape is a mechanism of resistance to anti-CD38 antibodies in multiple myeloma. Blood, 2025. [3] van de Donk NWCJ. Mechanisms of resistance to daratumumab in patients with multiple myeloma. Basic & Clinical Pharmacology & Toxicology, 2024. [4] Pawlyn C et al. Identification of resistance pathways and therapeutic targets in relapsed multiple myeloma. Nature Medicine, 2021. [5] Lancman G et al. Bispecific antibodies in the treatment of multiple myeloma. Blood Cancer Journal, 2024. [6] ClinicalTrials.gov. NCT04824794. Phase 1/2 trial of GEN3014 (HexaBody-CD38) in relapsed/refractory multiple myeloma and other hematologic malignancies. Genmab. Terminated, last update 2026. [7] Open Targets Platform. CD38 (ENSG00000004468) target dossier; CD38-multiple myeloma association score 0.623 (clinical 0.98, literature 0.91). [8] openFDA FAERS. Daratumumab adverse event report aggregate, May 2026. Available from: https://clinicaltrials.gov/study/NCT04824794.