Selinexor plus low-dose dexamethasone in Chinese patients with relapsed/refractory multiple myeloma previously treated with an immunomodulatory agent and a proteasome inhibitor (MARCH): a phase II, single-arm study.

Abstract

BACKGROUND:

Selinexor 80 mg combined with low-dose dexamethasone (Sd) demonstrated significant clinical benefit in patients with relapsed/refractory multiple myeloma (RRMM) who had disease refractory to a proteasome inhibitor (PI), an immunomodulator (IMiD), and an anti-CD38 monoclonal antibody based on a global phase II STORM study. The present study, MARCH, addresses China regulatory needs to further validate the data from STORM in Chinese patients with RRMM.

METHODS:

The MARCH study was conducted at 17 sites in China, where eligible Chinese RRMM patients who had disease refractory to PI and IMiD were enrolled. Selinexor 80 mg combined with dexamethasone 20 mg was administered orally on day 1 and day 3 of each week in 4-week cycles. The primary endpoint was the overall response rate (ORR) per an independent review committee, with the null hypothesis of ≤15%. Patients who received at least 1 dose of study treatment were included in the safety population. The pharmacokinetic (PK) profile was characterized by parameter and ethnicity sensitivity analyses.

RESULTS:

A total of 82 patients with RRMM were enrolled in the study, with a median age of 60 years. Of the 82 patients, 55 patients (67.1%) had high-risk cytogenetic abnormalities, defined as one or more of del 17p13, t(4;14), t(14;16), or 1q amplification identified by fluorescence in situ hybridization (FISH); 18 patients (22.0%) had abnormal renal function. Enrolled patients were heavily pre-treated with a median prior regimen number of 5. All 82 patients (100%) were refractory to both PI and IMiD, including 20 patients (24.4%) categorized as triple-class refractory population (refractory to PI, IMiD, and daratumumab). Ten patients (12.2%) had undergone CAR-T therapy. ORR was 29.3% (95% CI 19.7, 40.4) with a median DOR of 4.7 months. The median PFS and OS were 3.7 and 13.2 months, respectively. ORR was 25.0% (95% CI 8.7, 49.1) in the triple-class refractory population. Efficacy was consistent across various subgroups. The most frequent grade 3/4 adverse events (AEs) included anemia (57.3%), thrombocytopenia (51.2%), lymphopenia (42.7%), neutropenia (40.2%), hyponatremia (29.3%), and lung infection (26.8%). Serious AEs were reported in 54.9% of patients. No significant drug accumulation was shown following multiple administrations. No human PK ethnicity difference was identified between Chinese and western patients.

CONCLUSIONS:

With an encouraging ORR, the MARCH study has demonstrated that selinexor combined with low-dose dexamethasone (Sd) delivers meaningful clinical benefit to Chinese patients with RRMM, including triple-class refractory patients. AEs were expected and manageable with supportive care and dose modification.

TRIAL REGISTRATION:

ClinicalTrials.gov, NCT03944057 (May 09, 2019); Chinadrugtrials.org.cn , CTR20190858 (June 05, 2019).

• Authors: Lugui Qiu, Zhongjun Xia, Chengcheng Fu, Wenming Chen, Chunkang Chang, Baijun Fang, Gang An, Yongqiang Wei, Zhen Cai, Sujun Gao, Jianyu Weng, Lijuan Chen, Hongmei Jing, Fei Li, Zhuogang Liu, Xiequn Chen, Jing Liu, Aihua Wang, Yang Yu, Wenxi Xiang, Kevin Lynch, Zhinuan Yu, Weijun Fu
• Journal: BMC medicine (BMC Med) Vol. 20 Issue 1 Pg. 108 (04 05 2022) ISSN: 1741-7015 [Electronic] England
• PMID: 35379237 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Hydrazines
• Immunologic Factors
• Proteasome Inhibitors
• Triazoles
• selinexor
• Dexamethasone

Topics

• Antineoplastic Combined Chemotherapy Protocols (adverse effects)
• Dexamethasone (therapeutic use)
• Humans
• Hydrazines
• Immunologic Factors (therapeutic use)
• In Situ Hybridization, Fluorescence
• Multiple Myeloma (chemically induced, drug therapy)
• Proteasome Inhibitors (therapeutic use)
• Triazoles