法国图卢兹大学癌症研究所Michel Attal联合美国波士顿哈佛医学院Paul G Richardson研究团队发现，Isatuximab+泊马度胺+地塞米松可有效治疗复发和难治性多发性骨髓瘤（ICARIA-MM）患者。相关论文于2019年11月14日在线发表在《柳叶刀》杂志上。

Isatuximab是一种结合人CD38受体特异性表位的单克隆抗体，经由多种作用机制而具有抗肿瘤活性。在此前的临床1b期研究中，Isatuximab+泊马度胺+小剂量地塞米松治疗复发和难治性多发性骨髓瘤患者的总缓解率为65%。

2017年1月10日至2018年2月2日，研究组在欧洲、北美和亚太地区24个国家的102家医院进行了一项随机、多中心、开放标签的临床3期研究，招募了307名复发和难治性多发性骨髓瘤的成年患者，他们之前至少接受过两种疗法，包括来那度胺和蛋白酶抑制剂，排除抗CD38单抗治疗无效的患者。研究组将这些患者按1：1随机分配，154名接受Isatuximab +泊马度胺+地塞米松治疗，153名接受泊马度胺+地塞米松治疗。

在中位随访11.6个月后，Isatuximab-泊马度胺-地塞米松组的中位无进展生存期为11.5个月，泊马度胺-地塞米松组为6.5个月。最常见的治疗相关不良事件主要包括输液反应、上呼吸道感染和腹泻，Isatuximab-泊马度胺-地塞米松组的发生率分别为38%、28%和26%，泊马度胺-地塞米松组则分别为0、17%和20%。Isatuximab-泊马度胺-地塞米松组发生12例（8%）致死性严重不良事件，其中1例死亡；泊马度胺-地塞米松组中有14例（9%），其中2例死亡。

总之，Isatuximab+泊马度胺+地塞米松可显著延长复发和难治性多发性骨髓瘤患者的无进展生存期，Isatuximab为来那度胺和蛋白酶抑制剂应答不足的患者提供了一种新选择。

附：英文原文

Title: 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

Author: Michel Attal, Paul G Richardson, S Vincent Rajkumar, Jesus San-Miguel, Meral Beksac, Ivan Spicka, Xavier Leleu, Fredrik Schjesvold, Philippe Moreau, Meletios A Dimopoulos, Jeffrey Shang-Yi Huang, Jiri Minarik, Michele Cavo, H Miles Prince, Sandrine Macé, Kathryn P Corzo, Frank Campana, Solenn Le-Guennec, Franck Dubin, Kenneth C Anderson, Michel Attal, Paul G. Richardson, Vincent Rajkumar, Jesus San-Miguel, Meral Beksac, Ivan Spicka, Xavier Leleu, Fredrik Schjesvold, Philippe Moreau, Meletios A. Dimopoulos, Jeffrey Shang-Yi Huang, Jiri Minarik, Michele Cavo, H. Miles Prince, Sandrine Macé, Kathryn P. Corzo, Frank Campana, Solenn Le-Guennec, Franck Dubin, Kenneth C. Anderson, Simon Harrison, Wojt Janowski, Ian Kerridge, Andrew Spencer, Michel Delforge, Karel Fostier, Philip Vlummens, Ka Lung Wu, Richard Leblanc, Michel Pavic, Michael Sebag, Roman Hajek, Vladimir Maisnar, Ludek Pour, Henrik Gregersen, Lotfi Benbouker, Denis Caillot, Martine Escoffre-Barbe, Thierry Facon, Laurent Frenzel, Cyrille Hulin, Lionel Karlin, Brigitte Kolb, Brigitte Pegourie, Aurore Perrot, Mourad Tiab, Laure Vincent, Dietger Niederwieser, Achilles Anagnostopoulos, Sosana Delimpasi, Marie-Christine Kyrtsonis, Anargyros Symeonidis, Arpad Illes, Gabor Mikala, Zsolt Nagy, Sara Bringen, Paolo Corradini, Ciceri Fabio, Roberto Lemoli, Anna Liberati, Chiara Nozzoli, Renato Zambello, Shinsuke Iida, Takashi Ikeda, Satoshi Iyama, Morio Matsumoto, Chihiro Shimazaki, Kazutaka Sunami, Kenshi Suzuki, Michihiro Uchiyama, Youngil Koh, Kihyun Kim, Jae Hoon Lee, Chang-Ki Min, Hillary Blacklock, Hugh Goodman, Annette Neylon, David Simpson, Sebastian Grosicki, Artur Jurczyszyn, Adam Walter-Croneck, Krzysztof Warzocha, Luis Araujo, Claudia Moreira, Vadim Doronin, Larisa Mendeleeva, Vladimir Vorobyev, Andrej Vranovsky, Adrian Alegre, Mercedes Gironella, Marta Sonia Gonzalez Perez, Carmen Montes, Enrique Ocio, Paula Rodriguez, Mats Hardling, Birgitta Lauri, Ming-Chung Wang, Su-Peng Yeh, Mutlu Arat, Fatih Demirkan, Zafer Gulbas, Sevgi Kalayoglu Besisik, Ihsan Karadogan, Tulin Tuglular, Ali Unal, Filiz Vural, Jonathan Sive

Issue&Volume: November 14, 2019

Abstract: 

Background

Isatuximab is a monoclonal antibody that binds a specific epitope on the human CD38 receptor and has antitumour activity via multiple mechanisms of action. In a previous phase 1b study, around 65% of patients with relapsed and refractory multiple myeloma achieved an overall response with a combination of isatuximab with pomalidomide and low-dose dexamethasone. The aim of this study was to determine the progression-free survival benefit of isatuximab plus pomalidomide and dexamethasone compared with pomalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma.

Methods

We did a randomised, multicentre, open-label, phase 3 study at 102 hospitals in 24 countries in Europe, North America, and the Asia-Pacific regions. Eligible participants were adult patients with relapsed and refractory multiple myeloma who had received at least two previous lines of treatment, including lenalidomide and a proteasome inhibitor. Patients were excluded if they were refractory to previous treatment with an anti-CD38 monoclonal antibody. We randomly assigned patients (1:1) to either isatuximab 10 mg/kg plus pomalidomide 4 mg plus dexamethasone 40 mg (20 mg for patients aged ≥75 years), or pomalidomide 4 mg plus dexamethasone 40 mg. Randomisation was done using interactive response technology and stratified according to the number of previous lines of treatment (2–3 vs >3) and age (<75 years vs ≥75 years). Treatments were assigned based on a permuted blocked randomisation scheme with a block size of four. The isatuximab–pomalidomide–dexamethasone group received isatuximab intravenously on days 1, 8, 15, and 22 in the first 28-day cycle, then on days 1 and 15 in subsequent cycles. Both groups received oral pomalidomide on days 1 to 21 in each cycle, and oral or intravenous dexamethasone on days 1, 8, 15, and 22 of each cycle. Treatment continued until disease progression, unacceptable toxicity, or consent withdrawal. Dose reductions for adverse reactions were permitted for pomalidomide and dexamethasone, but not for isatuximab. The primary endpoint was progression-free survival, determined by an independent response committee and assessed in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of study drug. This study is registered at ClinicalTrials.gov, number NCT02990338.

Findings

Between Jan 10, 2017, and Feb 2, 2018, we randomly assigned 307 patients to treatment: 154 to isatuximab–pomalidomide–dexamethasone, and 153 to pomalidomide–dexamethasone. At a median follow-up of 11·6 months (IQR 10·1–13·9), median progression-free survival was 11·5 months (95% CI 8·9–13·9) in the isatuximab–pomalidomide–dexamethasone group versus 6·5 months (4·5–8·3) in the pomalidomide–dexamethasone group; hazard ratio 0·596, 95% CI 0·44–0·81; p=0·001 by stratified log-rank test. The most frequent treatment-emergent adverse events (any grade; isatuximab–pomalidomide–dexamethasone vs pomalidomide–dexamethasone) were infusion reactions (56 [38%] vs 0), upper respiratory tract infections (43 [28%] vs 26 [17%]), and diarrhoea (39 [26%] vs 29 [20%]). Adverse events with a fatal outcome were reported in 12 patients (8%) in the isatuximab–pomalidomide–dexamethasone group and 14 (9%) in the pomalidomide–dexamethasone group. Deaths due to treatment-related adverse events were reported for one patient (<1%) in the isatuximab–pomalidomide–dexamethasone group (sepsis) and two (1%) in the pomalidomide–dexamethasone group (pneumonia and urinary tract infection).

Interpretation

The addition of isatuximab to pomalidomide–dexamethasone significantly improves progression-free survival in patients with relapsed and refractory multiple myeloma. Isatuximab is an important new treatment option for the management of relapsed and refractory myeloma, particularly for patients who become refractory to lenalidomide and a proteasome inhibitor.

DOI: 10.1016/S0140-6736(19)32556-5

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)32556-5/fulltext