In-Class Transition (iCT) of Proteasome Inhibitor-Based Therapy Prolongs Progression-Free Survival in High-Risk Myeloma Patients: A Real-World Chinese Cohort Study
Authors: Fu Rong , Yu Hong , Liu Aijun , Hou Rui , Zhu Zunmin , Zhuang Junling , Bao Li , Li Zhenling , Liu Lihong , Hua Luoming , Ma Yanping , Gao Da , Jin ARong , Suo Xiaohui , Yang Wei , Bai Yuansong , Zheng Deqiang , Chen Wenming 
Published: December 2024

Background: Patients with multiple myeloma who have high-risk factors have a poorer prognosis. The efficacy and tolerability of using In-class transition (iCT) from bortezomib to an all-oral ixazomib-based regimen for continuous treatment of newly diagnosed and relapsed/refractory multiple myeloma (MM) patients has been demonstrated in previous studies. The objective of this study is to analyze the utilization of iCT therapy among high-risk subgroups of newly diagnosed and first relapsed multiple myeloma (MM) patients in the multicenter real-world setting in China.

Methods: The efficacy and safety of PI after iCT were evaluated in Mayo high-risk(Mayo-HR) patients. mSART3.0 stratified the risk, using fluorescence in situ hybridization and cytogenetic testing. High-risk cytogenetics included t(4;14), t(14;16), and/or del17p abnormalities. Expanded high-risk cytogenetics included t(4;14), t(14;16), del17p abnormalities, and/or 1q21 amplification. This retrospective study analyzed real-world data from 16 hospitals in China between October 2017 and April 2023. A total of 199 patients received bortezomib-based induction therapy until achieving at least a partial response, followed by ixazomib-based oral therapy for two years or until disease progression or intolerable adverse reactions.

Results: Ninety-seven patients were classified as Mayo-HR. At a median follow-up of 21 months, the median PFS was 44.2 (95% CI, 23.8~NA) months. The overall response rate (ORR) after bortezomib induction was 100% and the ORR following treatment with an ixazomib-based regimen was 87.8%. iCT deepens the remission in the high-risk subgroups of patients, the CR or better rates after iCT increased by 8.1%. Additionally, the ORR after iCT in patients with high-risk cytogenetics, expanded high-risk cytogenetics, 1q21 abnormalities, and R-ISS stage III were 82.4%, 86.4%, 84.9%, and 85.3%, respectively. The ORR for single-hit and double/triple-hit subgroups after iCT were 91.1% and 76.2%, respectively.

iCT enhanced the response depth in patients with Amp 1q21 regardless of clone size. Using 5%, 20%, and 60% as the cut-off values of the number of positive cells, the CR or better rates after iCT increased by 12.2%, 6.7%, and 5.6%, respectively. After iCT, there was no significant difference in median PFS between patients with Amp 1q21 positive and Amp 1q21 negative (HR=1.81; 95% CI, 0.96-3.40; P=0.064). In patients with Amp 1q21, no significant difference in PFS was found between those with 1q21 alone and those with a combination of other CAs (HR=1.83; 95% CI, 0.81-4.11; P=0.14).

Patients were divided into the long course group (≥10 courses, n=20）, medium course group (5-9 courses, n=42）, and short course group (≤4 courses, n=49）based on the number of ixazomib treatment courses. After iCT, the ORR was 100%, 97.6%, and 79.6% respectively for the three groups. The ≥VGPR rates were 90%, 78.6%, and 55.1%, and the proportion of VGPR deepening to (s)CR was 20%, 14.3%, and 8.2%, respectively. Longer cycle ixazomib-based regimen after iCT significantly prolongs patient survival (p=0.006).

The safety profile of ixazomib in Mayo HR patients aligned with the overall study population and previous clinical research data. AEs of any grade were reported in 48% of patients. The most frequently encountered AEs were PN (28.6%), diarrhea (9.2%), nausea (3.1%), and skin rash (3.1%). 14% discontinued the ixazomib-based regimen due to AEs, with PN (n=6) and diarrhea (n=3), being the primary reasons for discontinuation. These 6 patients who discontinued ixazomib treatment due to peripheral neuropathy (PN) already had PN during the bortezomib induction period.

Conclusion: The real-world data from China showed that high-risk NDMM and FRMM patients responded well to continuous Ixazomib-based treatment, resulting in a higher remission rate. Continuous ixazomib-based treatment after iCT offers a potential therapeutic option.