Monoclonal antibodies targeting CD38 are a therapeutic mainstay in multiple myeloma (MM). Although they have contributed to improved outcomes, most patients still experience disease relapse, and little is known about tumor-intrinsic mechanisms of resistance to these drugs. Antigen escape has been implicated as a mechanism of tumor-cell evasion in immunotherapy. Yet, it is unknown whether MM cells can develop permanent resistance to anti-CD38 antibodies by acquiring genomic events leading to biallelic disruption of the CD38 gene locus. Here, we analyzed whole-genome and whole-exome sequencing data from patients 701 newly diagnosed MM, 67 patients at relapse with naivety to anti-CD38 antibodies, and 50 patients collected at relapse after anti-CD38 antibodies. We report a loss of CD38 in 10 of 50 patients (20%) after CD38 therapy, 3 of whom exhibited a loss of both copies. Two of these cases showed convergent evolution in which distinct subclones independently acquired similar advantageous variants. Functional studies on missense mutations involved in biallelic CD38 events revealed that 2 variants, L153H and C275Y, decreased binding affinity and antibody-dependent cellular cytotoxicity of the commercial antibodies daratumumab and isatuximab. However, a third mutation, R140G, conferred selective resistance to daratumumab, while retaining sensitivity to isatuximab. Clinically, patients with MM are often rechallenged with CD38 antibodies after disease progression and these data suggest that next-generation sequencing may play a role in subsequent treatment selection for a subset of patients.

Clinical Cooperation Unit Molecular Hematology Oncology Department of Internal Medicine 5 Heidelberg University Hospital Heidelberg University and German Cancer Research Center Heidelberg Germany

Department of Bio Structure and Biophysics Integrated Drug Discovery Sanofi R and D Vitry sur Seine France

Department of eBiology Large Molecule Research Sanofi R and D Vitry sur Seine France

Department of Hematooncology Faculty of Medicine University Hospital Ostrava University of Ostrava Ostrava Czech Republic

Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN

Department of Medicine Mayo Clinic Phoenix AZ

Department of Medicine Mayo Clinic Rochester MN

Department of Oncology Arnie Charbonneau Cancer Institute University of Calgary Calgary AB Canada

Division of Translational Medical Oncology German Cancer Consortium Heidelberg Germany

Division of Translational Medical Oncology German Cancer Research Center Heidelberg Germany

Division of Translational Medical Oncology National Center for Tumor Diseases Heidelberg a partnership between German Cancer Research Center and Heidelberg University Hospital Heidelberg Germany

Division of Translational Precision Medicine Institute of Human Genetics Heidelberg University Heidelberg Germany

Heidelberg Myeloma Center Department of Internal Medicine 5 Medical Faculty Heidelberg University Hospital Heidelberg University Heidelberg Germany

Myeloma Division Sylvester Comprehensive Cancer Center University of Miami Miami FL

Myeloma Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY

Transplantation and Cellular Therapy Division Sylvester Comprehensive Cancer Center University of Miami Miami FL

Blood. 2025 Sep 25;146(13):1529-1530. doi: 10.1182/blood.2025029889. PubMed

Zobrazit více v PubMed

Facon T, Dimopoulos M-A, Leleu XP, et al. Isatuximab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. New England Journal of Medicine. 2024;

Facon T, Kumar S, Plesner T, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. New England Journal of Medicine. 2019;380(22):2104–2115. PubMed PMC

Leleu X, Hulin C, Lambert J, et al. Isatuximab, lenalidomide, dexamethasone and bortezomib in transplant-ineligible multiple myeloma: the randomized phase 3 BENEFIT trial. Nature Medicine. 2024:1–7.

Leypoldt LB, Tichy D, Besemer B, et al. Isatuximab, carfilzomib, lenalidomide, and dexamethasone for the treatment of high-risk newly diagnosed multiple myeloma. Journal of Clinical Oncology. 2024;42(1):26–37. PubMed PMC

Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. New England Journal of Medicine. 2024;390(4):301–313. PubMed

Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood, The Journal of the American Society of Hematology. 2020;136(8):936–945.

Attal M, Richardson PG, Rajkumar SV, et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. The Lancet. 2019;394(10214):2096–2107.

Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. New England Journal of Medicine. 2016;375(14):1319–1331. PubMed

Gandhi UH, Cornell RF, Lakshman A, et al. Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia. 2019;33(9):2266–2275. PubMed PMC

Saltarella I, Desantis V, Melaccio A, et al. Mechanisms of resistance to anti-CD38 daratumumab in multiple myeloma. Cells. 2020;9(1):167. PubMed PMC

Van de Donk NW, Usmani SZ. CD38 antibodies in multiple myeloma: mechanisms of action and modes of resistance. Frontiers in immunology. 2018;9:2134. PubMed PMC

Ise M, Matsubayashi K, Tsujimura H, Kumagai K. Loss of CD38 expression in relapsed refractory multiple myeloma. Clinical Lymphoma Myeloma and Leukemia. 2016;16(5):e59–e64.

Minarik J, Novak M, Flodr P, et al. CD 38-negative relapse in multiple myeloma after daratumumab-based chemotherapy. European journal of haematology. 2017;99(2):186–189. PubMed

Mikhael J, Belhadj-Merzoug K, Hulin C, et al. A phase 2 study of isatuximab monotherapy in patients with multiple myeloma who are refractory to daratumumab. Blood cancer journal. 2021;11(5):89. PubMed PMC

Perez de Acha O, Reiman L, Jayabalan DS, et al. CD38 antibody re-treatment in daratumumab-refractory multiple myeloma after time on other therapies. Blood Advances. 2023;7(21):6430–6440. PubMed PMC

Cohen YC, Zada M, Wang S-Y, et al. Identification of resistance pathways and therapeutic targets in relapsed multiple myeloma patients through single-cell sequencing. Nature medicine. 2021;27(3):491–503.

Maura F, Boyle EM, Coffey D, et al. Genomic and immune signatures predict clinical outcome in newly diagnosed multiple myeloma treated with immunotherapy regimens. Nature cancer. 2023;4(12):1660–1674. PubMed PMC

Ziccheddu B, Giannotta C, D’Agostino M, et al. Genomic and immune determinants of resistance to daratumumab-based therapy in relapsed refractory multiple myeloma. Blood Cancer Journal. 2024;14(1):117. PubMed PMC

Lee H, Ahn S, Maity R, et al. Mechanisms of antigen escape from BCMA-or GPRC5D-targeted immunotherapies in multiple myeloma. Nature Medicine. 2023:1–12.

Papadimitriou M, Ahn S, Diamond B, et al. Timing antigenic escape in multiple myeloma treated with T-cell redirecting immunotherapies. bioRxiv. 2024:2024.05. 22.595383.

Grab AL, Kim PS, John L, et al. Pre-Clinical Assessment of SAR442257, a CD38/CD3xCD28 Trispecific T Cell Engager in Treatment of Relapsed/Refractory Multiple Myeloma. Cells. 2024;13(10):879. PubMed PMC

Grandclément C, Estoppey C, Dheilly E, et al. Development of ISB 1442, a CD38 and CD47 bispecific biparatopic antibody innate cell modulator for the treatment of multiple myeloma. Nature Communications. 2024;15(1):2054.

Mei H, Li C, Jiang H, et al. A bispecific CAR-T cell therapy targeting BCMA and CD38 in relapsed or refractory multiple myeloma. Journal of Hematology & Oncology. 2021;14:1–17. PubMed PMC

Portuguese AJ, Fang M, Tuazon SA, et al. Acquired CD38 gene deletion as a mechanism of tumor antigen escape in multiple myeloma. Blood Advances. 2023;7(23):7235–7238. PubMed PMC

Skerget S, Penaherrera D, Chari A, et al. Comprehensive molecular profiling of multiple myeloma identifies refined copy number and expression subtypes. Nature Genetics. 2024:1–12. PubMed

Poos AM, Prokoph N, Przybilla MJ, et al. Resolving therapy resistance mechanisms in multiple myeloma by multiomics subclone analysis. Blood. 2023;142(19):1633–1646. PubMed PMC

Rausch T, Zichner T, Schlattl A, Stütz AM, Benes V, Korbel JO. DELLY: structural variant discovery by integrated paired-end and split-read analysis. Bioinformatics. 2012;28(18):i333–i339. PubMed PMC

Chen X, Schulz-Trieglaff O, Shaw R, et al. Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics. 2016;32(8):1220–1222. PubMed

Wala JA, Bandopadhayay P, Greenwald NF, et al. SvABA: genome-wide detection of structural variants and indels by local assembly. Genome research. 2018;28(4):581–591. PubMed PMC

Reisinger E, Genthner L, Kerssemakers J, et al. OTP: An automatized system for managing and processing NGS data. Journal of biotechnology. 2017;261:53–62. PubMed

Rimmer A, Phan H, Mathieson I, et al. Integrating mapping-, assembly-and haplotype-based approaches for calling variants in clinical sequencing applications. Nature genetics. 2014;46(8):912–918. PubMed PMC

Danecek P, Bonfield JK, Liddle J, et al. Twelve years of SAMtools and BCFtools. Gigascience. 2021;10(2):giab008. PubMed PMC

Tarabichi M, Salcedo A, Deshwar AG, et al. A practical guide to cancer subclonal reconstruction from DNA sequencing. Nature methods. 2021;18(2):144–155. PubMed PMC

Rustad EH, Yellapantula VD, Glodzik D, et al. Revealing the impact of structural variants in multiple myeloma. Blood cancer discovery. 2020;1(3):258. PubMed PMC

Nik-Zainal S, Van Loo P, Wedge DC, et al. The life history of 21 breast cancers. Cell. 2012;149(5):994–1007. PubMed PMC

Panakkal V, Lakshman A, Shi M, et al. Utility of flow cytometry screening before MRD testing in multiple myeloma. Blood cancer journal. 2023;13(1):55. PubMed PMC

Maura F, Rajanna AR, Ziccheddu B, et al. Genomic classification and individualized prognosis in multiple myeloma. Journal of Clinical Oncology. 2024;42(11):1229–1240. PubMed PMC

Maura F, Bolli N, Angelopoulos N, et al. Genomic landscape and chronological reconstruction of driver events in multiple myeloma. Nature communications. 2019;10(1):3835.

Landau HJ, Yellapantula V, Diamond BT, et al. Accelerated single cell seeding in relapsed multiple myeloma. Nature communications. 2020;11(1):3617.

Cirrincione AM, Poos AM, Ziccheddu B, et al. The biological and clinical impact of deletions before and after large chromosomal gains in multiple myeloma. Blood. 2024;144(7):771–783. PubMed PMC

Derrien J, Gastineau S, Frigout A, et al. Acquired resistance to a GPRC5D-directed T-cell engager in multiple myeloma is mediated by genetic or epigenetic target inactivation. Nature Cancer. 2023;4(11):1536–1543. PubMed

Truger MS, Duell J, Zhou X, et al. Single-and double-hit events in genes encoding immune targets before and after T cell–engaging antibody therapy in MM. Blood advances. 2021;5(19):3794–3798. PubMed PMC

Lee HT, Kim Y, Park UB, Jeong TJ, Lee SH, Heo Y-S. Crystal structure of CD38 in complex with daratumumab, a first-in-class anti-CD38 antibody drug for treating multiple myeloma. Biochemical and Biophysical Research Communications. 2021;536:26–31. PubMed

Martin TG, Corzo K, Chiron M, et al. Therapeutic opportunities with pharmacological inhibition of CD38 with isatuximab. Cells. 2019;8(12):1522. PubMed PMC

Badros AZ, Foster L, Anderson LD Jr, et al. Daratumumab with lenalidomide as maintenance after transplant in newly diagnosed multiple myeloma: the AURIGA study. Blood Journal. 2024:blood. 2024025746.