Efficacy and Safety of CD38 Monoclonal Antibodies in Multiple Myeloma: a Meta-analysis

doi:10.12114/j.issn.1007-9572.2022.0090

Abstract

Abstract:

Background

Multiple myeloma is a malignant disease in which plasma cells abnormally proliferate in the bone marrow. Most patients may experience relapse/refractory and drug resistance with an unsatisfactory prognosis. CD38 monoclonal antibodies have been reported to achieve durable remission in patients with relapsed and refractory multiple myeloma (RRMM) . Although phase Ⅱand Ⅲclinical trials of CD38 monoclonal antibodies for MM have been initiated, a meta-analysis of these trials is lacking.

Objective

To systematically assess the efficacy and safety of CD38 monoclonal antibodies in RRMM, providing a theoretical basis for clinical treatment of this disease.

Methods

Databases including SinoMed, CQVIP, CNKI, Wanfang Data, Web of Science, PubMed, EMBase, and Cochrane Library were searched for randomized controlled trials (RCTs) of CD38 monoclonal antibodies treating RRMM published from inception to November 2021. The experimental group: the CD38 monoclonal antibody and the compatible drug were applied; the control group: only the compatible drug or CD38 monoclonal antibody (no other drug compatibility) was used. Treatment efficacy was assessed using overall response rate (ORR) , progression-free survival (PFS) , ≥very good partial response (≥VGPR) , partial response (PR) , ≥complete remission (≥CR) , and minimal residual disease (MRD) . Treatment safety was assessed using non-hematological adverse events, ≥grade 3 non-hematological adverse events, and hematological adverse events. The Cochrane Collaboration's tool for assessing risk of bias was used for quality assessment. A Meta-analysis was performed using Review Manager 5.3 and Stata 15.0.

Results

Eight RCTs were finally included, with a total of 2 821 patients (including 1 529 in the experimental group and 1 292 in the control group) . Meta-analysis showed that: in terms of efficacy, the experimental group had higher ORR, longer mean PFS, higher prevalence of≥VGPR, MRD and ≥CR than the control group〔RR=1.28, 95%CI (1.15, 1.43) , P<0.000 01; HR=0.49, 95%CI (0.39, 0.62) , P<0.000 01; RR=1.86, 95%CI (1.53, 2.27) , P<0.000 01; RR=5.28, 95%CI (2.80, 9.96) , P<0.001; RR=2.57, 95%CI (1.89, 3.50) , P<0.001〕. The experimental group also had lower prevalence of PR〔RR=0.67, 95%CI (0.53, 0.86) , P=0.002〕. In terms of safety, among the non-hematological adverse events occurred, the incidences of upper respiratory tract infection, pneumonia, bronchitis, diarrhea, and back pain in the experimental group were higher than those in the control group〔RR=1.55, 95%CI (1.36, 1.77) , P<0.001; RR=1.34, 95%CI (1.13, 1.59) , P<0.001; RR=1.64, 95%CI (1.07, 2.51) , P=0.02; RR=1.49, 95%CI (1.33, 1.68) , P<0.001; RR=1.29, 95%CI (1.07, 1.57) , P=0.009〕. Among the non-hematological adverse events of ≥grade 3, the incidences of upper respiratory tract infection, pneumonia, diarrhea, and fatigue in the experimental group were higher〔RR=1.99, 95%CI (1.15, 3.43) , P=0.01; RR=1.30, 95%CI (1.05, 1.62) , P=0.02; RR=2.44, 95%CI (1.58, 3.76) , P<0.001; RR=1.75, 95%CI (1.19, 2.56) , P=0.004〕. Among the hematological adverse events, the incidence of thrombocytopenia in the experimental group was also higher〔RR=1.10, 95%CI (1.01, 1.20) , P=0.02〕.

Conclusion

CD38 monoclonal antibodies may achieve good overall efficacy in RRMM, in particular, the PFS was significantly prolonged, although risks of treatment-emergent pulmonary infection, diarrhea, and thrombocytopenia may increase, the risks are controllable. To sum up, it is feasible to apply CD38 monoclonal antibodies for RRMM patient population, but be prepared to deal with high-risk complications.

Key words: Multiple myeloma, Hematologic neoplasms, Antineoplastic agents, immunological, Treatment outcome, Safety, Drug-related side effects and adverse reactions, Meta analysis

摘要：

背景

多发性骨髓瘤（MM）是浆细胞的一种恶性增殖性疾病。绝大多数的患者可能会面临复发/难治及耐药的问题，预后不容乐观。CD38单克隆抗体可以使复发/难治性MM（RRMM）的患者维持缓解状态，目前已有关于CD38单克隆抗体Ⅱ、Ⅲ期临床试验，但尚缺乏针对这些临床试验的荟萃分析。

目的

系统评价CD38单克隆抗体治疗RRMM的疗效和安全性，为临床治疗RRMM患者提供更多的理论依据。

方法

计算机检索中国生物医学文献服务系统（SinoMed）、维普网（CQVIP）、中国知网（CNKI）、万方数据知识服务平台、Web of Science、PubMed、EMBase、Cochrane Library等国内外数据库，筛选自建库至2021年11月已发表的CD38单克隆抗体治疗RRMM的随机对照试验（RCT），试验组应用CD38单克隆抗体且进行药物配伍，对照组应用配伍药物或仅应用CD38单克隆抗体。以疗效指标〔总反应率（ORR）、无进展生存期（PFS）、≥非常好的部分缓解率（≥VGPR）、部分缓解率（PR）、≥完全缓解率（≥CR）、微小残留（MRD）阴性率〕以及安全性指标（非血液系统不良事件、非血液系统≥3级不良事件和血液系统不良事件）作为结局指标，采用Cochrane协作网对纳入文献进行质量评价，应用Review Manager 5.3和Stata 15.0软件进行Meta分析。

结果

本研究最终纳入8项RCT，共2 821例患者（其中试验组1 529例、对照组1 292例）。Meta分析结果：在疗效方面，试验组ORR、PFS、≥VGPR、MRD阴性率、≥CR均高于对照组〔RR=1.28，95%CI（1.15，1.43），P<0.000 01；HR=0.49，95%CI（0.39，0.62），P<0.000 01；RR=1.86，95%CI（1.53，2.27），P<0.000 01；RR=5.28，95%CI（2.80，9.96），P<0.001；RR=2.57，95%CI（1.89，3.50），P<0.001〕；试验组PR低于对照组〔RR=0.67，95%CI（0.53，0.86），P=0.002〕。在安全性方面，非血液系统不良事件中，试验组的上呼吸道感染、肺炎、支气管炎、腹泻、背痛发生率均高于对照组〔RR=1.55，95%CI（1.36，1.77），P<0.001；RR=1.34，95%CI（1.13，1.59），P<0.001；RR=1.64，95%CI（1.07，2.51），P=0.02；RR=1.49，95%CI（1.33，1.68），P<0.001；RR=1.29，95%CI（1.07，1.57），P=0.009〕；非血液系统≥3级不良事件发生率，试验组的上呼吸道感染、肺炎、腹泻、疲劳发生率高于对照组〔RR=1.99，95%CI（1.15，3.43），P=0.01；RR=1.30，95%CI（1.05，1.62），P=0.02；RR=2.44，95%CI（1.58，3.76），P<0.001；RR=1.75，95%CI（1.19，2.56），P=0.004〕；血液系统不良事件中，试验组的血小板减少发生率高于对照组〔RR=1.10，95%CI（1.01，1.20），P=0.02〕。

结论

CD38单克隆抗体在治疗RRMM方面具有良好的疗效，明显提高了患者的PFS，虽然在治疗过程中更易引起肺部感染、腹泻及血小板减少，但这些不良反应的风险是可控的。在RRMM患者人群中有依据的添加CD38单克隆抗体进行治疗是可行的，但要做好处理高风险并发症的准备。

关键词: 多发性骨髓瘤, 血液肿瘤, 抗肿瘤药，免疫, 治疗结果, 安全性, 药物相关性副作用和不良反应, Meta分析

Ke LI,Zheng LI,Hui GENG, et al. Efficacy and Safety of CD38 Monoclonal Antibodies in Multiple Myeloma: a Meta-analysis[J]. Chinese General Practice, 2022, 25(21): 2661-2669. DOI: 10.12114/j.issn.1007-9572.2022.0090.
李科,李征,耿惠等. CD38单克隆抗体治疗多发性骨髓瘤疗效和安全性的Meta分析[J]. 中国全科医学, 2022, 25(21): 2661-2669. DOI: 10.12114/j.issn.1007-9572.2022.0090.

Figures/Tables 14

Figure 1 Strategy for searching randomized controlled trials of CD38 monoclonal antibodies treating relapsed and refractory multiple myeloma in Web of Science

步骤	检索词
#1	Multiple Myeloma OR Multiple Myelomas OR Myelomas，Multiple OR Myeloma，Multiple OR Myeloma，Plasma-Cell OR Myeloma，Plasma Cell OR Myelomas，Plasma-Cell OR Plasma-Cell Myeloma OR Plasma-Cell Myelomas OR Myelomatosis OR Myelomatoses OR Plasma Cell Myeloma，Plasma OR Cell Myelomas，Plasma OR Myelomas，Plasma Cell OR Plasma Cell Myelomas OR Kahler Disease OR Disease，Kahler OR Myeloma-Multiple OR Myeloma Multiple OR Myeloma-Multiples
#2	randomized controlled trial OR randomized OR placebo
#3	Daratumumab OR humax-CD38 OR Darzalex
#4	Isatuximab OR Sarclisa OR SAR650984 OR SAR
#5	（#1 AND #2） AND #3
#6	（#1 AND #2） AND #4

Figure 1 The flow diagram of screening randomized controlled trials of CD38 monoclonal antibodies treating relapsed and refractory multiple myeloma

Figure 2 Summary and distribution ofrisk of bias in the included randomized controlled trials

Table 2 Basic characteristics of the included randomized controlled trials

第一作者	发表年份（年）	既往治疗次数（次）	随访时间（月）	纳入例数	年龄（岁）		干预措施		ORR（%）
第一作者	发表年份（年）	既往治疗次数（次）	随访时间（月）	纳入例数	试验组	对照组	试验组	对照组	试验组	对照组
MARTIN^[8]	2020	1~3	20.7	302	64（33，90）		IKd∶179	Kd∶123	86.6	82.9
DIMOPOULOS^[9]	2021	≥3	—	164	66（42，85）	68（37，84）	Id∶55	I∶109	43.6	23.9
ATTAL^[10]	2019	≥2	11.6	307	68（60，74）	66（59，71）	IPd∶154	Pd∶153	33.1	28.1
DIMOPOULOS^[11]	2020	1~3	17	466	64（57，70）	65（59，71）	DKd∶312	Kd∶154	84.3	74.7
MATEOS^[12]	2020	≥1	40	498	64（30，88）	64（33，85）	DVd∶251	Vd∶247	84.6	63.2
BAHLIS^[13]	2020	≥1	44.3	569	65（34，89）	65（42，87）	DRd∶286	Rd∶283	92.9	76.4
DIMOPOULOS^[14]	2021	≥1	16.9	304	67（42，86）	68（35，90）	DPd∶151	Pd∶153	68.9	46.4
LU^[15]	2021	≥1	8.2	211	61（28，79）	61（43，82）	DVd∶141	Vd∶70	82.5	58.6

Figure 3 Forest plot of rates of overall response to treatment for relapsed and refractory multiple myeloma in the experimental group and control group

Figure 4 L'Abbe plotof rates of overall response to treatment for relapsed and refractory multiple myeloma in the experimental group and control group

Figure 5 Forest plot of the progression-free survival in the experimental group and control group

Figure 6 Forest plot assessing≥very good partial response to treatment for relapsed and refractory multiple myelomain the experimental group and control group

Figure 7 Forest plot assessing lymphocytopenia caused by treatment for relapsed and refractory multiple myeloma in the experimental group and control group

Figure 8 Forest plot assessing anemia caused by treatment for relapsed and refractory multiple myeloma in the experimental group and control group

Figure 9 Forest plot assessing thrombocytopenia caused by treatment for relapsed and refractory multiple myeloma in the experimental group and control group

Figure 10 Forest plot assessing neutropenia caused by treatment for relapsed and refractory multiple myeloma in the experimental group and control group

Figure 11 Funnel plot assessing publication bias of the rate of overall response to treatment for relapsed and refractory multiple myeloma between the experimental group and control group

Table 4 Egger's test assessing potential publication bias

Std_Eff	截距	SE	t值	P>\|t\|	95%CI
slope	0.035	0.081	0.43	0.679	（-0.163，0.235）
bias	2.807	1.305	2.15	0.075	（-0.386，6.000）

References 27

[1]	GERECKE C, FUHRMANN S, STRIFLER S，et al. The diagnosis and treatment of multiple myeloma[J]. Dtsch Arztebl Int，2016，113（27/28）：470-476. DOI：10.3238/arztebl.2016.0470.
[2]	《中国多发性骨髓瘤诊治指南（2020年修订）》发布[J].中华医学信息导报，2020，35（11）：12.
[3]	VAN DE DONK N W C J, JANMAAT M L, MUTIS T，et al. Monoclonal antibodies targeting CD38 in hematological malignancies and beyond[J]. Immunol Rev，2016，270（1）：95-112. DOI：10.1111/imr.12389.
[4]	KREJCIK J, CASNEUF T, NIJHOF I S，et al. Daratumumab depletes CD⁺₃₈ immune regulatory cells，promotes T-cell expansion，and skews T-cell repertoire in multiple myeloma[J]. Blood，2016，128（3）：384-394. DOI：10.1182/blood-2015-12-687749.
[5]	LIN P, OWENS R, TRICOT G，et al. Flow cytometric immunophenotypic analysis of 306 cases of multiple myeloma[J]. Am J Clin Pathol，2004，121（4）：482-488. DOI：10.1309/74R4-TB90-BUWH-27JX.
[6]	王良哲，刘惠敏，侯健. 多发性骨髓瘤发病机制研究新进展[J]. 国际输血及血液学杂志，2007，30（4）：319-322. DOI：10.3760/cma.j.issn.1673-419X.2007.04.008.
[7]	屈云，何俐，刘鸣. Cochrane系统评价的基本方法[J]. 中国临床康复，2003，7（4）：532-533，536. DOI：10.3321/j.issn:1673-8225.2003.04.003.
[8]	MARTIN T, MIKHAEL J, HAJEK R，et al. Depth of response and response kinetics of isatuximab plus carfilzomib and dexamethasone in relapsed multiple myeloma：ikema interim analysis[J]. Blood，2020，136：7-8. DOI：10.1182/blood-2020-137681.
[9]	DIMOPOULOS M, BRINGHEN S, ANTTILA P，et al. Isatuximab as monotherapy and combined with dexamethasone in patients with relapsed/refractory multiple myeloma[J]. Blood，2021，137（9）：1154-1165. DOI：10.1182/blood.2020008209.
[10]	ATTAL M, RICHARDSON P G, RAJKUMAR S V，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[J]. Lancet，2019，394（10214）：2096-2107. DOI：10.1016/S0140-6736(19)32556-5.
[11]	DIMOPOULOS M, QUACH H, MATEOS M V，et al. Carfilzomib，dexamethasone，and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma （CANDOR）：results from a randomised，multicentre，open-label，phase 3 study[J]. Lancet，2020，396（10245）：186-197. DOI：10.1016/S0140-6736(20)30734-0.
[12]	MATEOS M V, SONNEVELD P, HUNGRIA V，et al. Daratumumab，bortezomib，and dexamethasone versus bortezomib and dexamethasone in patients with previously treated multiple myeloma：three-year follow-up of CASTOR[J]. Clin Lymphoma Myeloma Leuk，2020，20（8）：509-518. DOI：10.1016/j.clml.2019.09.623.
[13]	BAHLIS N J, DIMOPOULOS M A, WHITE D J，et al. Daratumumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma：extended follow-up of POLLUX，a randomized，open-label，phase 3 study[J]. Leukemia，2020，34（7）：1875-1884. DOI：10.1038/s41375-020-0711-6.
[14]	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. DOI：10.1016/S1470-2045(21)00128-5.
[15]	LU J, FU W J, LI W，et al. Daratumumab，bortezomib，and dexamethasone versus bortezomib and dexamethasone in Chinese patients with relapsed or refractory multiple myeloma：phase 3 LEPUS（MMY3009） study[J]. Clin Lymphoma Myeloma Leuk，2021，21（9）：e699-709. DOI：10.1016/j.clml.2021.04.012.
[16]	BRIGLE K, ROGERS B. Pathobiology and diagnosis of multiple myeloma[J]. Semin Oncol Nurs，2017，33（3）：225-236. DOI：10.1016/j.soncn.2017.05.012.
[17]	KUMAR S K, DISPENZIERI A, LACY M Q，et al. Continued improvement in survival in multiple myeloma：changes in early mortality and outcomes in older patients[J]. Leukemia，2014，28 （5）：1122-1128. DOI：10.1038/leu.2013.313.
[18]	SONNEVELD P, BROIJL A. Treatment of relapsed and refractory multiple myeloma[J]. Haematologica，2016，101（4）：396-406. DOI：10.3324/haematol.2015.129189.
[19]	VAN DE DONK N W C J, RICHARDSON P G, MALAVASI F. CD38 antibodies in multiple myeloma：back to the future[J]. Blood，2018，131（1）：13-29. DOI：10.1182/blood-2017-06-740944.
[20]	NOOKA A K, KAUFMAN J L, HOFMEISTER C C，et al. Daratumumab in multiple myeloma[J]. Cancer，2019，125（14）：2364-2382. DOI：10.1002/cncr.32065.
[21]	MUSTO P, LA ROCCA F. Monoclonal antibodies in relapsed/refractory myeloma：updated evidence from clinical trials，real-life studies，and meta-analyses[J]. Expert Rev Hematol，2020，13（4）：331-349. DOI：10.1080/17474086.2020.1740084.
[22]	DHILLON S. Isatuximab：first approval[J]. Drugs，2020，80（9）：905-912. DOI：10.1007/s40265-020-01311-1.
[23]	ZHU C, SONG Z L, WANG A L，et al. Isatuximab acts through fc-dependent，independent，and direct pathways to kill multiple myeloma cells[J]. Front Immunol，2020，11：1771. DOI：10.3389/fimmu.2020.01771.
[24]	JIANG H, ACHARYA C, AN G，et al. SAR650984 directly induces multiple myeloma cell death via lysosomal-associated and apoptotic pathways，which is further enhanced by pomalidomide[J]. Leukemia，2016，30（2）：399-408. DOI：10.1038/leu.2015.240.
[25]	LONG J, LIU S, LI K，et al. High proportion of CD34+/CD38-cells is positively correlated with poor prognosis in newly diagnosed childhood acute lymphoblastic leukemia[J]. Leuk Lymphoma，2014，55（3）：611-617. DOI：10.3109/10428194.2013.807924.
[26]	FENG X Y, ZHANG L, ACHARYA C，et al. Targeting CD38 suppresses induction and function of T regulatory cells to mitigate immunosuppression in multiple myeloma[J]. Clin Cancer Res，2017，23（15）：4290-4300. DOI：10.1158/1078-0432.CCR-16-3192.
[27]	MORè S, PETRUCCI M T, CORVATTA L，et al. Monoclonal antibodies：leading actors in the relapsed/refractory multiple myeloma treatment[J]. Pharmaceuticals （Basel），2020，13（12）：E426. DOI：10.3390/ph13120426.