Genomic and immune determinants of resistance to daratumumab-based therapy in relapsed refractory multiple myeloma.
Journal
Blood cancer journal
ISSN: 2044-5385
Titre abrégé: Blood Cancer J
Pays: United States
ID NLM: 101568469
Informations de publication
Date de publication:
19 Jul 2024
19 Jul 2024
Historique:
received:
13
02
2024
accepted:
08
07
2024
revised:
01
07
2024
medline:
20
7
2024
pubmed:
20
7
2024
entrez:
19
7
2024
Statut:
epublish
Résumé
Targeted immunotherapy combinations, including the anti-CD38 monoclonal antibody (MoAb) daratumumab, have shown promising results in patients with relapsed/refractory multiple myeloma (RRMM), leading to a considerable increase in progression-free survival. However, a large fraction of patients inevitably relapse. To understand this, we investigated 32 relapsed MM patients treated with daratumumab, lenalidomide, and dexamethasone (Dara-Rd; NCT03848676). We conducted an integrated analysis using whole-genome sequencing (WGS) and flow cytometry in patients with RRMM. WGS before and after treatment pinpointed genomic drivers associated with early progression, including RPL5 loss, APOBEC mutagenesis, and gain of function structural variants involving MYC and chromothripsis. Flow cytometry on 202 blood samples, collected every 3 months until progression for 31 patients, revealed distinct immune changes significantly impacting clinical outcomes. Progressing patients exhibited significant depletion of CD38-positive NK cells, persistence of T-cell exhaustion, and reduced depletion of regulatory T cells over time. These findings underscore the influence of immune composition and daratumumab-induced immune changes in promoting MM resistance. Integrating genomics and flow cytometry unveiled associations between adverse genomic features and immune patterns. Overall, this study sheds light on the intricate interplay between genomic complexity and the immune microenvironment driving resistance to Dara-Rd in patients with RRMM.
Identifiants
pubmed: 39030183
doi: 10.1038/s41408-024-01096-6
pii: 10.1038/s41408-024-01096-6
doi:
Substances chimiques
daratumumab
4Z63YK6E0E
Antibodies, Monoclonal
0
Dexamethasone
7S5I7G3JQL
Lenalidomide
F0P408N6V4
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
117Subventions
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : P30 CA 240139
Organisme : Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)
ID : AIRC IG 20541
Organisme : Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)
ID : AIRC IG 20541
Informations de copyright
© 2024. The Author(s).
Références
Shah UA, Mailankody S. Emerging immunotherapies in multiple myeloma. BMJ. 2020;370:m3176.
pubmed: 32958461
doi: 10.1136/bmj.m3176
van de Donk N, Usmani SZ. CD38 antibodies in multiple myeloma: mechanisms of action and modes of resistance. Front Immunol. 2018;9:2134.
pubmed: 30294326
pmcid: 6158369
doi: 10.3389/fimmu.2018.02134
Costa LJ, Chhabra S, Medvedova E, Dholaria BR, Schmidt TM, Godby KN, et al. Daratumumab, carfilzomib, lenalidomide, and dexamethasone with minimal residual disease response-adapted therapy in newly diagnosed multiple myeloma. J Clin Oncol. 2021;40:2901–12.
Dimopoulos MA, Terpos E, Boccadoro M, Delimpasi S, Beksac M, Katodritou E, et al. Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22:801–12.
pubmed: 34087126
doi: 10.1016/S1470-2045(21)00128-5
Facon T, Kumar S, Plesner T, Orlowski RZ, Moreau P, Bahlis N, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. New Engl J Med. 2019;380:2104–15.
pubmed: 31141632
doi: 10.1056/NEJMoa1817249
Landgren O, Hultcrantz M, Diamond B, Lesokhin AM, Mailankody S, Hassoun H, et al. Safety and effectiveness of weekly carfilzomib, lenalidomide, dexamethasone, and daratumumab combination therapy for patients with newly diagnosed multiple myeloma: the MANHATTAN nonrandomized clinical trial. JAMA Oncol. 2021;7:862–8.
pubmed: 33856405
pmcid: 8050789
doi: 10.1001/jamaoncol.2021.0611
Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. New Engl J Med. 2018;378:518–28.
pubmed: 29231133
doi: 10.1056/NEJMoa1714678
Rajkumar SV. Multiple myeloma: 2022 update on diagnosis, risk stratification, and management. Am J Hematol. 2022;97:1086–107.
pubmed: 35560063
pmcid: 9387011
doi: 10.1002/ajh.26590
Voorhees PM, Kaufman JL, Laubach J, Sborov DW, Reeves B, Rodriguez C, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;136:936–45.
pubmed: 32325490
pmcid: 7441167
doi: 10.1182/blood.2020005288
Krejcik J, Casneuf T, Nijhof IS, Verbist B, Bald J, Plesner T, et al. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood. 2016;128:384–94.
pubmed: 27222480
pmcid: 4957162
doi: 10.1182/blood-2015-12-687749
Saltarella I, Desantis V, Melaccio A, Solimando AG, Lamanuzzi A, Ria R, et al. Mechanisms of resistance to anti-CD38 daratumumab in multiple myeloma. Cells. 2020;9:167.
pubmed: 31936617
pmcid: 7017193
doi: 10.3390/cells9010167
van de Donk NW, Janmaat ML, Mutis T, Lammerts van Bueren JJ, Ahmadi T, Sasser AK, et al. Monoclonal antibodies targeting CD38 in hematological malignancies and beyond. Immunol Rev. 2016;270:95–112.
pubmed: 26864107
pmcid: 4755228
doi: 10.1111/imr.12389
Cohen YC, Zada M, Wang SY, Bornstein C, David E, Moshe A, et al. Identification of resistance pathways and therapeutic targets in relapsed multiple myeloma patients through single-cell sequencing. Nat Med. 2021;27:491–503.
pubmed: 33619369
pmcid: 7612793
doi: 10.1038/s41591-021-01232-w
Costa LJ, Chhabra S, Medvedova E, Dholaria BR, Schmidt TM, Godby KN, et al. Minimal residual disease response-adapted therapy in newly diagnosed multiple myeloma (MASTER): final report of the multicentre, single-arm, phase 2 trial. Lancet Haematol. 2023;10:e890–e901.
pubmed: 37776872
doi: 10.1016/S2352-3026(23)00236-3
Viola D, Dona A, Caserta E, Troadec E, Besi F, McDonald T, et al. Daratumumab induces mechanisms of immune activation through CD38+ NK cell targeting. Leukemia. 2021;35:189–200.
pubmed: 32296125
doi: 10.1038/s41375-020-0810-4
Cossarizza A, Chang HD, Radbruch A, Akdis M, Andra I, Annunziato F, et al. Guidelines for the use of flow cytometry and cell sorting in immunological studies. Eur J Immunol. 2017;47:1584–797.
pubmed: 29023707
pmcid: 9165548
doi: 10.1002/eji.201646632
Flores-Montero J, Sanoja-Flores L, Paiva B, Puig N, Garcia-Sanchez O, Bottcher S, et al. Next generation flow for highly sensitive and standardized detection of minimal residual disease in multiple myeloma. Leukemia. 2017;31:2094–103.
pubmed: 28104919
pmcid: 5629369
doi: 10.1038/leu.2017.29
Maura F, Rajanna AR, Ziccheddu B, Poos AM, Derkach A, Maclachlan K, et al. Genomic classification and individualized prognosis in multiple myeloma. J Clin Oncol. 2024;42:JCO2301277.
doi: 10.1200/JCO.23.01277
Maura F, Bolli N, Angelopoulos N, Dawson KJ, Leongamornlert D, Martincorena I, et al. Genomic landscape and chronological reconstruction of driver events in multiple myeloma. Nat Commun. 2019;10:3835.
pubmed: 31444325
pmcid: 6707220
doi: 10.1038/s41467-019-11680-1
Walker BA, Mavrommatis K, Wardell CP, Ashby TC, Bauer M, Davies FE, et al. Identification of novel mutational drivers reveals oncogene dependencies in multiple myeloma. Blood. 2018;132:587–97.
pubmed: 29884741
pmcid: 6097138
doi: 10.1182/blood-2018-03-840132
Portuguese AJ, Fang M, Tuazon SA, Pont M, Qu X, Shasha C, et al. Acquired CD38 gene deletion as a mechanism of tumor antigen escape in multiple myeloma. Blood Adv. 2023;7:7235–8.
pubmed: 37844282
pmcid: 10698540
doi: 10.1182/bloodadvances.2023011295
Alexandrov LB, Kim J, Haradhvala NJ, Huang MN, Ng AWT, Wu Y, et al. The repertoire of mutational signatures in human cancer. Nature. 2020;578:94–101.
pubmed: 32025018
pmcid: 7054213
doi: 10.1038/s41586-020-1943-3
Maura F, Degasperi A, Nadeu F, Leongamornlert D, Davies H, Moore L, et al. A practical guide for mutational signature analysis in hematological malignancies. Nat Commun. 2019;10:2969.
pubmed: 31278357
pmcid: 6611883
doi: 10.1038/s41467-019-11037-8
Maura F, Petljak M, Lionetti M, Cifola I, Liang W, Pinatel E, et al. Biological and prognostic impact of APOBEC-induced mutations in the spectrum of plasma cell dyscrasias and multiple myeloma cell lines. Leukemia. 2017;32:1043–7.
Rustad EH, Yellapantula V, Leongamornlert D, Bolli N, Ledergor G, Nadeu F, et al. Timing the initiation of multiple myeloma. Nat Commun. 2020;11:1917.
pubmed: 32317634
pmcid: 7174344
doi: 10.1038/s41467-020-15740-9
Walker BA, Wardell CP, Murison A, Boyle EM, Begum DB, Dahir NM, et al. APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma. Nat Commun. 2015;6:6997.
pubmed: 25904160
doi: 10.1038/ncomms7997
Rustad EH, Nadeu F, Angelopoulos N, Ziccheddu B, Bolli N, Puente XS, et al. mmsig: a fitting approach to accurately identify somatic mutational signatures in hematological malignancies. Commun Biol. 2021;4:424.
pubmed: 33782531
pmcid: 8007623
doi: 10.1038/s42003-021-01938-0
Maura F, Weinhold N, Diamond B, Kazandjian D, Rasche L, Morgan G, et al. The mutagenic impact of melphalan in multiple myeloma. Leukemia. 2021;35:1–6.
doi: 10.1038/s41375-021-01293-3
Samur MK, Aktas Samur A, Fulciniti M, Szalat R, Han T, Shammas M, et al. Genome-wide somatic alterations in multiple myeloma reveal a superior outcome group. J Clin Oncol. 2020;38:3107–18.
pubmed: 32687451
pmcid: 7499613
doi: 10.1200/JCO.20.00461
Weinhold N, Ashby C, Rasche L, Chavan SS, Stein C, Stephens OW, et al. Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma. Blood. 2016;128:1735–44.
pubmed: 27516441
pmcid: 5043128
doi: 10.1182/blood-2016-06-723007
Landau HJ, Yellapantula V, Diamond BT, Rustad EH, Maclachlan KH, Gundem G, et al. Accelerated single cell seeding in relapsed multiple myeloma. Nat Commun. 2020;11:1–10.
doi: 10.1038/s41467-020-17459-z
Pich O, Muiños F, Lolkema MP, Steeghs N, Gonzalez-Perez A, Lopez-Bigas N. The mutational footprints of cancer therapies. Nat Genet. 2019;51:1732–40.
pubmed: 31740835
pmcid: 6887544
doi: 10.1038/s41588-019-0525-5
Maura F, Boyle EM, Coffey D, Maclachlan K, Gagler D, Diamond B, et al. Genomic and immune signatures predict clinical outcome in newly diagnosed multiple myeloma treated with immunotherapy regimens. Nat Cancer. 2023;4:1660–74.
pubmed: 37945755
doi: 10.1038/s43018-023-00657-1
Jain MD, Ziccheddu B, Coughlin CA, Faramand R, Griswold AJ, Reid KM, et al. Whole-genome sequencing reveals complex genomic features underlying anti-CD19 CAR T-cell treatment failures in lymphoma. Blood. 2022;140:491–503.
pubmed: 35476848
pmcid: 9353150
doi: 10.1182/blood.2021015008
Rustad EH, Yellapantula VD, Glodzik D, Maclachlan KH, Diamond B, Boyle EM, et al. Revealing the impact of structural variants in multiple myeloma. Blood Cancer Discov. 2020;1:258–73.
pubmed: 33392515
pmcid: 7774871
doi: 10.1158/2643-3230.BCD-20-0132
Hofman IJF, van Duin M, De Bruyne E, Fancello L, Mulligan G, Geerdens E, et al. RPL5 on 1p22.1 is recurrently deleted in multiple myeloma and its expression is linked to bortezomib response. Leukemia. 2017;31:1706–14.
pubmed: 27909306
doi: 10.1038/leu.2016.370
Coffey DG, Maura F, Gonzalez-Kozlova E, Diaz-Mejia JJ, Luo P, Zhang Y, et al. Immunophenotypic correlates of sustained MRD negativity in patients with multiple myeloma. Nat Commun. 2023;14:5335.
pubmed: 37660077
pmcid: 10475030
doi: 10.1038/s41467-023-40966-8
Zavidij O, Haradhvala NJ, Mouhieddine TH, Sklavenitis-Pistofidis R, Cai S, Reidy M, et al. Single-cell RNA sequencing reveals compromised immune microenvironment in precursor stages of multiple myeloma. Nat Cancer. 2020;1:493–506.
pubmed: 33409501
pmcid: 7785110
doi: 10.1038/s43018-020-0053-3
Casneuf T, Xu XS, Adams HC 3rd, Axel AE, Chiu C, Khan I, et al. Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma. Blood Adv. 2017;1:2105–14.
pubmed: 29296857
pmcid: 5728278
doi: 10.1182/bloodadvances.2017006866
Ziccheddu B, Biancon G, Bagnoli F, De Philippis C, Maura F, Rustad EH, et al. Integrative analysis of the genomic and transcriptomic landscape of double-refractory multiple myeloma. Blood Adv. 2020;4:830–44.
pubmed: 32126144
pmcid: 7065476
doi: 10.1182/bloodadvances.2019000779
Poli A, Michel T, Theresine M, Andres E, Hentges F, Zimmer J. CD56bright natural killer (NK) cells: an important NK cell subset. Immunology 2009;126:458–65.
pubmed: 19278419
pmcid: 2673358
doi: 10.1111/j.1365-2567.2008.03027.x
Dhodapkar KM, Cohen AD, Kaushal A, Garfall AL, Manalo RJ, Carr AR, et al. Changes in bone marrow tumor and immune cells correlate with durability of remissions following BCMA CAR T therapy in myeloma. Blood Cancer Discov. 2022;3:490–501.
pubmed: 36026513
pmcid: 9627239
doi: 10.1158/2643-3230.BCD-22-0018
Friedrich MJ, Neri P, Kehl N, Michel J, Steiger S, Kilian M, et al. The pre-existing T cell landscape determines the response to bispecific T cell engagers in multiple myeloma patients. Cancer Cell. 2023;41:711–25.e6.
pubmed: 36898378
doi: 10.1016/j.ccell.2023.02.008