Efficacy Analysis of Ixazomib-Based Regimens Based on Dynamic Frailty Assessment in Elderly and Frail Patients with Newly Diagnosed Multiple Myeloma
Authors: Xu Jianmei , Xue Hua , Zhao Songying , Wang Jing , Guo Huimei , Zhang Jiangbo , Liu Jia , Hua Luoming , Tian Mingjie , Zhao Mingfeng 
Published: December 2023

Background: Elderly frail MM patients often lack evidence-based basis due to many comorbidities and poor treatment tolerance, and are often excluded by new drug clinical trials. There are many unsolved problems in clinical practice.There is still variation in the prognosis of frail patients identified using current frailty assessment tools. A potential treatment approach to improve outcomes in this heterogeneous population could involve starting with a well-tolerated low-intensity regimen and adjusting treatment based on ongoing dynamic frailty assessments.Therefore, our center conducted a retrospective study to explore the efficacy and safety of real-world isazomib-based two-drug regimen in the treatment of newly diagnosed elderly frail MM patients by adjusting treatment intensity based on dynamic frailty assessment.

Methods: Patients with NDMM who received 2 or more courses of ixazomib-based regimens at the Department of Hematology, Affiliated Hospital of Hebei University from January 1, 2018 to April 1, 2023. All patients were assessed for frailty using the IMWG Geriatric Assessment (IMWG-GA) tool, and a total of 21 patients with frailty assessed as Frail were included, including 11 patients (52.4%) aged 75 years and older and 17 patients (81.0%) with ECOG score ≥ 2.A two-drug regimen of ixazomib combined with dexamethasone (ID) was initiated, and dynamic frailty assessment and efficacy evaluation were performed during the 3-4 courses of treatment. After the frailty status improved, the third drug was used in the following cases: 1) R-ISS high-risk group, and 2) R-ISS intermediate-low risk group with efficacy &lt; PR. The combination of the two drugs was continued in the following cases: 1) R-ISS intermediate-low risk group with improved frailty status with efficacy ≥ PR, and 2) no improvement in frailty status with efficacy ≥ SD. The effectiveness of treatment, discontinuation rate, early death and related adverse effects were assessed.

Results: A total of 21 patients were included in this study, of whom 12 patients increased the intensity of treatment after improvement of frail status , the third drug was added with Cyclophosphamide (8 patients) or Lenalidomide (3 patients) or Daratumumab (1 patient) in courses 3-4. 9 patients continued to be treated with ID regimen. The median duration of treatment was 10 (2-19).The ORR was 85.7% (18/21), and the efficacy above MR was 95.2% (20/21). Two patients died, both over 80 years of age, with many underlying complications, including one patient who abandoned treatment and died (17 months), one patient who died (24 months) due to gastrointestinal bleeding, without early death. Four patients experienced disease progression after self-interruption of treatment, 15 patients were still using ixazomib-based therapy, and none discontinued due to adverse reactions. After a follow-up time of 9.0 (2.6-37.0) months, the PFS and OS were not reached. All patients overall tolerated well, mainly grade 1-2 adverse reactions (CTCAE 5.0).

Conclusion: This study is a single-center retrospective study that included 21 frail patients with newly diagnosed multiple myeloma and achieved good efficacy with a low discontinuation rate, no serious adverse effects, and no early deaths. This study confirmed that the frail state of the patient was dynamically altered over time and treatment during the remedy period. For elderly frail patients, the two-drug regimen for ID was initiated, the treatment regimen was dynamically adjusted based on frailty assessment, cytogenetic-based stratification (R-ISS) was introduced after frailty assessment was improved, the treatment intensity was increased in patients, and the third drug was added to make up for the lack of treatment; for intermediate-low risk patients with better efficacy, continuous two-drug treatment was performed to avoid adverse reactions caused by excessive treatment, early drug withdrawal and early death. For the heterogeneous population of frail MM in the elderly, the treatment was dynamically adjusted according to frailty assessment and an individualized treatment plan was developed, which achieved the combination of efficacy and safety. However, the benefit of dynamically adjusting treatment regimens according to frailty stratification and the optimal regimen suitable for frailty MM in the elderly still need to be confirmed by evidence-based medical data.