伴高危细胞遗传学异常的复发难治性多发性骨髓瘤的免疫治疗进展

Immunotherapy advances in relapsed or refractory multiple myeloma with high-risk cytogenetic abnormalities

摘要

多发性骨髓瘤（multiple myeloma，MM）是一种临床表现和生物学行为具有高度异质性的血液系统恶性肿瘤，患者的预后与是否存在高危细胞遗传学异常（high risk cytogenetic abnormality，HRCA）密切相关。近年来，蛋白酶体抑制剂和免疫调节药物在MM中的广泛应用显著改善了患者的生存，但伴HRCA的高危患者仍面临着药物难治、早期疾病进展和不良预后的挑战，其治疗策略的探索与优化始终是临床难题。在复发难治的疾病状态下，后续治疗的选择对高危患者来说至关重要。随着MM治疗进入免疫治疗时代，新药的不断涌现为患者带来了治疗希望。文章聚焦于伴HRCA的复发难治性MM患者，综述了单克隆抗体、抗体药物偶联物、双特异性抗体以及嵌合抗原受体T细胞疗法在该类患者中的治疗效果，旨在探讨最优治疗策略并为临床决策提供指导。

Abstract

Multiple myeloma（MM）is a hematologic malignancy characterized by high heterogeneity in both its clinical presentation and biological behavior. The prognosis for patients with MM is closely associated with the presence or absence of high-risk cytogenetic abnormality（HRCA）. In recent years，although the widespread application of proteasome inhibitors and immunomodulatory drugs in MM has significantly improved survival，high-risk patients with HRCA continue to face challenges such as drug resistance，early disease progression，and poor prognosis. The exploration and optimization of treatment strategies for these patients remain a clinical challenge. In the relapsed or refractory disease state，the choice of subsequent treatment is crucial for high-risk patients. With the advent of the immunotherapy era in MM treatment，the continuous emergence of new drugs has brought hope to patients. This article focuses on patients with relapsed or refractory MM accompanied by HRCA，reviewing the efficacy of monoclonal antibodies，antibody-drug conjugates，bispecific antibodies，and chimeric antigen receptor T cells in these patients，aiming to explore optimal treatment strategies and provide guidance for clinical decision-making.

关键词

复发难治性多发性骨髓瘤 / 高危细胞遗传学异常 / 免疫治疗

Key words

relapsed or refractory multiple myeloma / high-risk cytogenetic abnormality / immunotherapy

参考文献

[1] CULLIS J. Haematology：multiple myeloma[J]. Clin Med, 2019, 19(2):188

[2] MANASANCH E E, ORLOWSKI R Z. Proteasome inhibitors in cancer therapy[J]. Nat Rev Clin Oncol, 2017, 14(7):417-433

[3] HOLSTEIN S A, MCCARTHY P L. Immunomodulatory drugs in multiple myeloma：mechanisms of action and clinical experience[J]. Drugs, 2017, 77(5):505-520

[4] MOHAN L B, VAN RHEE F, AL HADIDI S. Current state of evidence on definitions and management of high—risk multiple myeloma[J]. Curr Oncol Rep, 2025, 27(3):258-277

[5] REES M J, KUMAR S. High—risk multiple myeloma：redefining genetic，clinical，and functional high—risk disease in the era of molecular medicine and immunotherapy[J]. Am J Hematol, 2024, 99(8):1560-1575

[6] PALUMBO A, AVET—LOISEAU H, OLIVA S, et al. Revised international staging system for multiple myeloma：a report from international myeloma working group[J]. J Clin Oncol, 2015, 33(26):2863-2869

[7] D’AGOSTINO M, CAIRNS D A, LAHUERTA J J, et al. Second revision of the international staging system（R2—ISS）for overall survival in multiple myeloma：a European myeloma network（EMN）report within the HARMONY project[J]. J Clin Oncol, 2022, 40(29):3406-3418

[8] AVET—LOISEAU H, DAVIES F E, SAMUR M K, et al. International myeloma society/international myeloma working group consensus recommendations on the definition of high—risk multiple myeloma[J]. J Clin Oncol, 2025, 43(24):2739-2751

[9] MIKHAEL J R, DINGLI D, ROY V, et al. Management of newly diagnosed symptomatic multiple myeloma：updated Mayo stratification of myeloma and risk—adapted therapy（mSMART）consensus guidelines 2013[J]. Mayo Clin Proc, 2013, 88(4):360-376

[10] ABDALLAH N H, BINDER M, RAJKUMAR S V, et al. A simple additive staging system for newly diagnosed multiple myeloma[J]. Blood Cancer J, 2022, 12(1):21

[11] MAO X H, YAN W Q, MERY D, et al. Development and validation of an individualized and weighted myeloma prognostic score system（MPSS）in patients with newly diagnosed multiple myeloma[J]. Am J Hematol, 2024, 99(4):523-533

[12] DAUDIGNON A, CUCCUINI W, BRACQUEMART C, et al. Cytogenetics in the management of multiple myeloma：the guidelines from the Groupe Francophone de Cytogénétique Hématologique（GFCH）[J]. Curr Res Transl Med, 2023, 71(4):103427

[13] 中国医师协会血液科医师分会, 中华医学会血液学分会. 中国多发性骨髓瘤诊治指南（2024年修订）[J]. 中华内科杂志, 2024, 63(12):1186-1195

[14] Chinese Society of Hematology, Chinese Medical Association, Hematology Physician Branch of Chinese Medical Doctor Association. Guidelines for diagnosis and management of multiple myeloma in China（2024）[J]. Chinese Journal of Hematology, 2024, 63(12):1186-1195

[15] KAISER M F, SONNEVELD P, CAIRNS D A, et al. Co—occurrence of cytogenetic abnormalities and high—risk disease in newly diagnosed and relapsed/refractory multiple myeloma[J]. J Clin Oncol, 2025, 43(24):2679-2691

[16] RAJKUMAR S V. Multiple myeloma：2024 update on diagnosis，risk—stratification，and management[J]. Am J Hematol, 2024, 99(9):1802-1824

[17] NOOKA A K, KAUFMAN J L, HOFMEISTER C C, et al. Daratumumab in multiple myeloma[J]. Cancer, 2019, 125(14):2364-2382

[18] USMANI S Z, NAHI H, PLESNER T, et al. Daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma：final results from the phase 2 GEN501 and SIRIUS trials[J]. Lancet Haematol, 2020, 7(6):e447-e455

[19] WEISEL K, SPENCER A, LENTZSCH S, et al. Daratumumab，bortezomib，and dexamethasone in relapsed or refractory multiple myeloma：subgroup analysis of CASTOR based on cytogenetic risk[J]. J Hematol Oncol, 2020, 13(1):115

[20] SONNEVELD P, CHANAN—KHAN A, WEISEL K, et al. Overall survival with daratumumab，bortezomib，and dexamethasone in previously treated multiple myeloma（CASTOR）：a randomized，open—label，phase Ⅲ trial[J]. J Clin Oncol, 2023, 41(8):1600-1609

[21] LANDGREN O, WEISEL K, ROSINOL L, et al. Subgroup analysis based on cytogenetic risk in patients with relapsed or refractory multiple myeloma in the CANDOR study[J]. Br J Haematol, 2022, 198(6):988-993

[22] USMANI S Z, QUACH H, MATEOS M V, et al. Final analysis of carfilzomib，dexamethasone，and daratumumab vs carfilzomib and dexamethasone in the CANDOR study[J]. Blood Adv, 2023, 7(14):3739-3748

[23] DIMOPOULOS M A, ORIOL A, NAHI H, et al. Daratumumab，lenalidomide，and dexamethasone for multiple myeloma[J]. N Engl J Med, 2016, 375(14):1319-1331

[24] DIMOPOULOS M A, ORIOL A, NAHI H, et al. Overall survival with daratumumab，lenalidomide，and dexamethasone in previously treated multiple myeloma（POLLUX）：a randomized，open—label，phase Ⅲ trial[J]. J Clin Oncol, 2023, 41(8):1590-1599

[25] DIMOPOULOS M A, TERPOS E, BOCCADORO M, 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[J]. Lancet Oncol, 2021, 22(6):801-812

[26] DIMOPOULOS M A, TERPOS E, BOCCADORO M, et al. Subcutaneous daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma（APOLLO）：extended follow up of an open—label，randomised，multicentre，phase 3 trial[J]. Lancet Haematol, 2023, 10(10):e813-e824

[27] KAUFMAN J L, DIMOPOULOS M A, WHITE D, et al. Daratumumab，lenalidomide，and dexamethasone in relapsed/refractory myeloma：a cytogenetic subgroup analysis of POLLUX[J]. Blood Cancer J, 2020, 10(11):111

[28] HARRISON S J, PERROT A, ALEGRE A, et al. Subgroup analysis of ICARIA—MM study in relapsed/refractory multiple myeloma patients with high—risk cytogenetics[J]. Br J Haematol, 2021, 194(1):120-131

[29] RICHARDSON P G, PERROT A, SAN—MIGUEL J, 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）：follow—up analysis of a randomised，phase 3 study[J]. Lancet Oncol, 2022, 23(3):416-427

[30] MARTIN T, RICHARDSON P G, FACON T, et al. Primary outcomes by 1q21+ status for isatuximab—treated patients with relapsed/refractory multiple myeloma：subgroup analyses from ICARIA—MM and IKEMA[J]. Haematologica, 2022, 107(10):2485-2491

[31] MOREAU P, DIMOPOULOS M A, MIKHAEL J, et al. Isatuximab，carfilzomib，and dexamethasone in relapsed multiple myeloma（IKEMA）：a multicentre，open—label，randomised phase 3 trial[J]. Lancet, 2021, 397(10292):2361-2371

[32] SPICKA I, MOREAU P, MARTIN T G, et al. Isatuximab plus carfilzomib and dexamethasone in relapsed multiple myeloma patients with high—risk cytogenetics：IKEMA subgroup analysis[J]. Eur J Haematol, 2022, 109(5):504-512

[33] YONG K, MARTIN T, DIMOPOULOS M A, et al. Isatuximab plus carfilzomib—dexamethasone versus carfilzomib—dexamethasone in patients with relapsed multiple myeloma（IKEMA）：overall survival analysis of a phase 3，randomised，controlled trial[J]. Lancet Haematol, 2024, 11(10):e741-e750

[34] LONIAL S, DIMOPOULOS M, PALUMBO A, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma[J]. N Engl J Med, 2015, 373(7):621-631

[35] DIMOPOULOS M A, LONIAL S, WHITE D, et al. Elotuzumab，lenalidomide，and dexamethasone in RRMM：final overall survival results from the phase 3 randomized ELOQUENT—2 study[J]. Blood Cancer J, 2020, 10(9):91

[36] DIMOPOULOS M A, DYTFELD D, GROSICKI S, et al. Elotuzumab plus pomalidomide and dexamethasone for multiple myeloma[J]. N Engl J Med, 2018, 379(19):1811-1822

[37] DIMOPOULOS M A, DYTFELD D, GROSICKI S, et al. Elotuzumab plus pomalidomide and dexamethasone for relapsed/refractory multiple myeloma：final overall survival analysis from the randomized phase Ⅱ ELOQUENT—3 trial[J]. J Clin Oncol, 2023, 41(3):568-578

[38] LONIAL S, LEE H C, BADROS A, et al. Longer term outcomes with single—agent belantamab mafodotin in patients with relapsed or refractory multiple myeloma：13—month follow—up from the pivotal DREAMM—2 study[J]. Cancer, 2021, 127(22):4198-4212

[39] TALBOT A, BOBIN A, TABONE L, et al. Real—world study of the efficacy and safety of belantamab mafodotin（GSK2857916）in relapsed or refractory multiple myeloma based on data from the nominative ATU in France：the IFM 2020—04 study[J]. Haematologica, 2023, 108(10):2774-2782

[40] HUNGRIA V, ROBAK P, HUS M, et al. Belantamab mafodotin，bortezomib，and dexamethasone for multiple myeloma[J]. N Engl J Med, 2024, 391(5):393-407

[41] HUNGRIA V, ROBAK P, HUS M, et al. Belantamab mafodotin plus bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma（DREAMM—7）：updated overall survival analysis from a global，randomised，open—label，phase 3 trial[J]. Lancet Oncol, 2025, 26(8):1067-1080

[42] KELLY K R, AILAWADHI S, SIEGEL D S, et al. Indatuximab ravtansine plus dexamethasone with lenalidomide or pomalidomide in relapsed or refractory multiple myeloma：a multicentre，phase 1/2a study[J]. Lancet Haematol, 2021, 8(11):e794-e807

[43] MOREAU P, GARFALL A L, VAN DE DONK N W C J, et al. Teclistamab in relapsed or refractory multiple myeloma[J]. N Engl J Med, 2022, 387(6):495-505

[44] TOUZEAU C, KRISHNAN A Y, MOREAU P, et al. Efficacy and safety of teclistamab in patients with relapsed/refractory multiple myeloma after BCMA—targeting therapies[J]. Blood, 2024, 144(23):2375-2388

[45] COSTA L J, BAHLIS N J, PERROT A, et al. Teclistamab plus daratumumab in relapsed or refractory multiple myeloma[J]. N Engl J Med, 2026, 394(8):739-752

[46] BAHLIS N J, COSTELLO C L, RAJE N S, et al. Elranatamab in relapsed or refractory multiple myeloma：the MagnetisMM—1 phase 1 trial[J]. Nat Med, 2023, 29(10):2570-2576

[47] LESOKHIN A M, TOMASSON M H, ARNULF B, et al. Elranatamab in relapsed or refractory multiple myeloma：phase 2 MagnetisMM—3 trial results[J]. Nat Med, 2023, 29(9):2259-2267

[48] BUMMA N, RICHTER J, JAGANNATH S, et al. Linvoseltamab for treatment of relapsed/refractory multiple myeloma[J]. J Clin Oncol, 2024, 42(22):2702-2712

[49] CHARI A, TOUZEAU C, SCHINKE C, et al. Safety and activity of talquetamab in patients with relapsed or refractory multiple myeloma（MonumenTAL—1）：a multicentre，open—label，phase 1—2 study[J]. Lancet Haematol, 2025, 12(4):e269-e281

[50] AL HADIDI S, SZABO A, MOHAN L B, et al. Talquetamab in relapsed refractory multiple myeloma：multi—institutional real—world study[J]. Blood Cancer J, 2025, 15(1):196

[51] COHEN A D, HARRISON S J, KRISHNAN A, et al. Initial clinical activity and safety of BFCR4350A，a FcRH5/CD3 T—cell—engaging bispecific antibody，in relapsed/refractory multiple myeloma[J]. Blood, 2020, 136:42-43

[52] COHEN Y C, MAGEN H, GATT M, et al. Talquetamab plus teclistamab in relapsed or refractory multiple myeloma[J]. N Engl J Med, 2025, 392(2):138-149

[53] RAJE N S, SIEGEL D S, JAGANNATH S, et al. 68 idecabtagene vicleucel（ide—cel，bb2121）in relapsed and refractory multiple myeloma（RRMM）：analyses of high—risk subgroups in the KarMMa study[J]. Transplant Cell Ther, 2021, 27(3):S66-S67

[54] RODRIGUEZ—OTERO P, AILAWADHI S, ARNULF B, et al. Ide—cel or standard regimens in relapsed and refractory multiple myeloma[J]. N Engl J Med, 2023, 388(11):1002-1014

[55] ZHAO W H, WANG B Y, CHEN L J, et al. Four—year follow—up of LCAR—B38M in relapsed or refractory multiple myeloma：a phase 1，single—arm，open—label，multicenter study in China（LEGEND—2）[J]. J Hematol Oncol, 2022, 15(1):86

[56] EINSELE H, SAN—MIGUEL J, DHAKAL B, et al. Ciltacel in lenalidomide—refractory multiple myeloma（CARTITUDE—4）：an updated analysis including overall survival from an open—label，multicentre，randomised，phase 3 trial[J]. Lancet Oncol, 2026, 27(2):254-268

[57] YU Q X, WANG D, LI Z, et al. Long—term safety and efficacy of the fully human CAR—T therapy CT103A in relapsed/refractory multiple myeloma[J]. Mol Ther, 2025, 33(6):2768-2777

[58] MAILANKODY S, DEVLIN S M, LANDA J, et al. GPRC5D—targeted CAR T cells for myeloma[J]. N Engl J Med, 2022, 387(13):1196-1206

[59] ZHANG M M, WEI G Q, ZHOU L H, et al. GPRC5D CAR T cells（OriCAR—017）in patients with relapsed or refractory multiple myeloma（POLARIS）：a first—in—human，single—centre，single—arm，phase 1 trial[J]. Lancet Haematol, 2023, 10(2):e107-e116

[60] FERNÁNDEZ DE LARREA C, STAEHR M, LOPEZ A V, et al. Defining an optimal dual—targeted CAR T—cell therapy approach simultaneously targeting BCMA and GPRC5D to prevent BCMA escape—driven relapse in multiple myeloma[J]. Blood Cancer Discov, 2020, 1(2):146-154

[61] DU J, FU W J, JIANG H, et al. Updated results of a phase I，open—label study of BCMA/CD19 dual—targeting fast CAR—T GC012F for patients with relapsed/refractory multiple myeloma（RRMM）[J]. J Clin Oncol, 2023, 41(16_suppl):8005

[62] SHI M, WANG J J, HUANG H M, et al. Bispecific CAR—T cell therapy targeting BCMA and CD19 in relapsed/refractory multiple myeloma：a phase Ⅰ/Ⅱ trial[J]. Nat Commun, 2024, 15(1):3371

[63] MEI H, LI C G, JIANG H W, et al. A bispecific CAR—T cell therapy targeting BCMA and CD38 in relapsed or refractory multiple myeloma[J]. J Hematol Oncol, 2021, 14(1):161

[64] LI C G, XU J, LUO W J, et al. Bispecific CS1—BCMA CAR—T cells are clinically active in relapsed or refractory multiple myeloma[J]. Leukemia, 2024, 38(1):149-159

[65] OUYANG W Y, MI J Q. Challenges facing CAR T—cell immunotherapy in multiple myeloma[J]. Crit Rev Oncol Hematol, 2025, 213:104803

[66] MEERMEIER E W, WELSH S J, SHARIK M E, et al. Tumor burden limits bispecific antibody efficacy through T cell exhaustion averted by concurrent cytotoxic therapy[J]. Blood Cancer Discov, 2021, 2(4):354-369

[67] MCLELLAN A D, ALI HOSSEINI RAD S M. Chimeric antigen receptor T cell persistence and memory cell formation[J]. Immunol Cell Biol, 2019, 97(7):664-674

[68] FRIEDRICH M J, NERI P, KEHL N, et al. The pre—existing T cell landscape determines the response to bispecific T cell engagers in multiple myeloma patients[J]. Cancer Cell, 2023, 41(4):711-725.e6

[69] LORENZO—SANZ L, MUÑOZ P. Tumor—infiltrating immunosuppressive cells in cancer—cell plasticity，tumor progression and therapy response[J]. Cancer Microenviron, 2019, 12(2/3):119-132

基金资助

国家自然科学基金(82400247)

国家自然科学基金(82570256)