Abstract
Daratumumab is approved for patients with multiple myeloma (MM) and high-risk smoldering MM (HR-SMM). However, HR-SMM is often as genomically complex as MM, suggesting it may be too advanced for single-agent intervention. We report on a Phase II trial of single-agent daratumumab in patients with earlier-stage disease, including high-risk monoclonal gammopathy of undetermined significance and low-risk SMM, to test if earlier treatment can induce deep responses and prevent progression to MM (D-PRISM/NCT03236428, n = 41). As primary outcome, the rate of Very Good Partial Response or better is 17% (95% CI: 7–32), which is comparable to what was observed in HR-SMM and does not meet the study’s primary endpoint. The overall response rate is 54%, with two patients developing MM and 51% biochemical progression. Grade 3 or higher toxicities include hypertension (7%), diarrhea (2%), flu-like symptoms (2%), and headache (2%). Genomic and immune variables associated with biochemical progression are identified in exploratory analyses leveraging whole-genome and single-cell RNA-sequencing. This study demonstrates that, although less effective than expected, daratumumab is safe and can induce deep responses in certain early-stage patients, highlighting the importance of adopting genomic and immune profiling to improve patient selection and maximize the benefit/risk ratio in trials of early intervention.
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Data availability
Data generated for this study were deposited in a controlled-access repository (dbGaP) in accordance with privacy requirements set forth in the informed consent forms signed by study participants. Access to this dataset can be obtained by registering the investigator’s institution in eRA Commons, establishing an eRA Commons account for the investigator and submitting a Data Access Request through the dbGaP Authorized Access website; following authorization by the requesting institution’s signing official and review by NIH staff, the request may be approved for data download. Raw and processed single-cell RNA-sequencing data are deposited in dbGaP (phs004127.v1.p1, https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs004127.v1.p1). Raw WGS data used for cytogenetic classification are also deposited in dbGaP (phs003846.v1.p1, https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs003846.v1.p1)33. Outcome and toxicity data for all patients in the trial are provided in Supplementary Data 1 and the study protocol is provided in the Supplementary Information file. Source data are provided with this paper.
Code availability
R code used to conduct scRNAseq analyses has been deposited to Github (https://github.com/ghobriallab/Nat_Comm_2026_D-PRISM_STUDY) and accessioned on Zenodo58.
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Acknowledgements
The authors thank the patients and their families for participating in this study. Anna V. Justis, Ph.D., a medical writer employed by Dana-Farber Cancer Institute, edited this manuscript. Johnson and Johnson provided support for the clinical trial. This funder reviewed the final manuscript and approved its publication; they were not involved in the conceptualization, design, or conduct of the trial or preparation of the manuscript. Funding was also provided by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, Cancer Research UK, and the NIH (R35CA263817 awarded to I.M.G.).
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O.N. and I.M.G. conceptualized the study. O.N., M.K., J.V.M., A.J.Y., J.A.Z., A.K., C.D., C.R., F.A., M.M., A.B., J.R., E.K.O’D., J.P.L., and P.G.R. conducted the clinical trial. F.C., E.D.L., A.K.D., and M.R. conducted laboratory analyses and collected data. S.M., J.P., R.S-P., and T.H.M., collected clinical data and participated in data curation. J.P. supervised data curation. A.S. supervised clinical trial conduct and data collection. I.M.G. acquired funding for this study. M.P.A., R.A.R., T.W., F.C., J-B.A., J.T., L.T., L.P., and R.S-P. conducted formal analyses, and G.G. and R.S-P. supervised analyses. M.P.A., O.N., and R.S-P. wrote the original draft of this manuscript. All authors reviewed and approved the final version for publication. O.N., G.G., R.S-P., and I.M.G. supervised this study.
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O.N. reports research support from Takeda and Janssen; advisory board participation for Bristol-Myers Squibb, Janssen, Sanofi, Takeda, Kite and GPCR therapeutics; and honorarium from Pfizer. M.B. reports consultancy for Janssen, BMS, Takeda, Epizyme, Karyopharm, Menarini Biosystems, and Adaptive Biotechnology. A.J.Y reports consulting for AbbVie, Adaptive Biotechnologies, Amgen, BMS, Celgene, GSK, Johnson & Johnson, Karyopharm, Oncopeptides, Pfizer, Prothena, Regeneron, Sanofi, Sebia, Takeda. Research funding to institution from Amgen, BMS, GSK, Johnson & Johnson, Sanofi. P.G.R. is a consultant for Celgene/Bristol-Myers Squibb, GlaxoSmithKline, Karyopharm, Oncopeptides, Regeneron, and Sanofi, and has received research support from Oncopeptides. T.H.M. reports consulting for Sanofi. G.G. is a consultant, current equity holder, and co-founder for Scorpion Therapeutics and Predicta Biosciences, is receiving research funds from IBM, Pharmacyclics, and is a holder of patents and royalties for SignatureAnalyzer-GPU (US 2021/0358574, published), MSMuTect and MSMutSig (US 11,608,533, issued), MSIDetect (US 2023/0332246, published), and POLYSOLVER (US 11,725,237, issued). None of these patents are related to this work. R.S-P. is a consultant, private equity holder, and co-founder of Predicta Biosciences. I.M.G. has consulted for Bristol-Myers Squibb, AstraZeneca, Amgen, BioSkryb, Clinical Care Options, Curio Science, Sanofi, Janssen, Pfizer, Menarini Silicone Biosystems, Aptitude Health, GlaxoSmithKline, AbbVie, Adaptive Biotechnologies, Window Therapeutics, and Regeneron. She has received honoraria or speaker fees from Vor Biopharma, Janssen, MJH Life Sciences, Novartis, Takeda, Amgen, Regeneron, Curio Science, Standard Biotools, and Physicians’ Education Resource. She is a founder and board member of and holds private equity in Predicta Biosciences. Her spouse is the chief medical officer of and holds private equity in Disc Medicine. All other authors declare no conflicts of interest.
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Nadeem, O., Aranha, M.P., Redd, R.A. et al. Daratumumab in high-risk MGUS and low-risk smoldering myeloma: results of the Phase II D-PRISM study. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71483-z
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DOI: https://doi.org/10.1038/s41467-026-71483-z
