A Novel Conditioning Regimen Combining Selinexor with Melphalan Could Improve Survival of Patients with Multiple Myeloma
Authors: Ma Liangliang , Zhang Jingping , Chen Xiaoqing , Yang Shanglun , Fei Youmei , Hu QIan , Li Jian , Xu Caigang , Niu Ting , Jia Yongqian 
Published: December 2024

Background:

High-dose melphalan followed by autologous hematopoietic stem cell transplantation (ASCT) is regarded as the standard consolidation option for patients with multiple myeloma (MM). The previous attempted strategies aimed at refining the conditioning regimen for high-dose melphalan have encountered less superiority. Selinexor, a selective inhibitor of nuclear export protein (XPO-1), has demonstrated a synergistic anti-tumor effect with melphalan in preclinical studies. Thus, we present a cohort study to evaluating the efficacy and the safety of a new conditioning regimen that combines selinexor with high-dose melphalan.

Methods:

Referring to the RP2D dose recommended by Dr. Nishihori et al. (Blood (2019) 134 (Supplement_1): 3314.), our initial dose of selinexor was administered at 60 mg on days -4 and -1, and melphalan at 100 mg/m² on days -3 and -2. However, the first case experienced severe vomiting resulting in Mallory-Weiss syndrome. All the remaining cases received a modified regimen with selinexor 60 mg on days -11 and -4 and melphalan 100 mg/m² on days -3 and -2 (with melphalan reduced to 70 mg/m² on days -3 and -2 for patients with Serum Creatinine Clearance (CrCl) &lt; 60 mL/min).This study has obtained approval from the ethics committee of the hospital, and the informed consent was obtained from patients. The further study is ongoing according to the clinical trial (ChiCTR2400086849).

Results:

From January 2022 to May 2024, a total of 25 patients with MM who achieved a response of ≥ partial remission (PR) after induction therapy were enrolled from West China Hospital of Sichuan University and Meishan People's Hospital. The median age was 59 years(range:33-69),with a male-to-female ratio of 12:13. Two patients exhibited renal dysfunction with CrCl &lt; 60 mL/min;Monoclonal immunoglobulin type were:IgG subtype=11,IgA subtype=7,IgD subtype=2,light chain type=5.17 patients(68%) had Durie-Salmon stage III; 7 patients(28%) had International Staging System stage Ⅲ;5 patients(20%) had Revised International Staging System stageⅢ;44% of patients had high-risk cytogenetic abnormalities, with del 17p(n=1,4%),TP53 mutation(n=1,4%), t(4;14)(n=1,4%)and 1q21 amplification(n=10,40%).6 patients (24%) had concurrent extramedullary disease; 14 patients (56%) underwent proteasome based first-line therapy, while 11 patients (44%) received second-line therapy with daratumumab. The pre-transplantation disease states were: sCR=8, CR=4, VGPR=6, PR=7. After infused with a median of 2.66 (range: 1.65-5.54) × 10^6 CD34+ cells/kg , the median time to neutrophil engraftment was 10 days(range:9-12) , and the median time to platelet engraftment was 14 (range:10-17) days.Except for the first case exhibiting severe vomiting, no occurrences of grade 3-4 hepatic or renal function impairment, no reports of grade 4-5 adverse events, and no transplant-related deaths were observed.With a median follow-up time of 12 months(range:2-30),13 patients (52%) achieved deeper responses, including 4 patients converted from PR to ≥CR, 1 patient converted from PR to VGPR,6 patients converted from VGPR to≥CR,and 2 patients converted from CR to sCR.Among the 14 patients with positive residual disease before transplantation, 6 patients(43%) achieved negative status after transplantation.During the follow-up period,the 1-year PFS rate was 87%, the 1-year OS rate was 96%,one patient (4%) experienced a biochemical relapse,another two (8%) had a disease relapse with one patient died to disease progression at 12 months post transplantation.

Conclusion:

Our data indicate that the XPO-1 inhibitor, Selinexor, may have a good synergistic effect with melphalan as a conditioning regimen, demonstrating a deeper remission response and indicating a better trend of survival advantage, without obvious adverse reactions observed. This highlights the need for further clinical trials.

Disclosure:No relevant conflicts of interest to declare.