Dual-Risk Adjusted Therapy for Elderly Patients with Multiple Myeloma Based on Dynamic Frailty Assessment and R-ISS: A Prospective Clinical Trial
Authors: Xue Hua , Xu Jianmei , Li Jie , Suo Xiaohui , Liu Haisheng , Wang Juan , Wang Jing , Zhao Songying , Guo Huimei , Liu Yao 
Published: December 2024

Introduction
Elderly patients with multiple myeloma (MM) represent a heterogeneous population, and face a huge dilemma due to their more frailty and high-risk cytogenetics. Frailty is increasingly recognized as a prognostic factor in elderly MM, and dynamic frailty assessment is more predictive than baseline assessment. Incorporating R-ISS following improvements in frailty status, sequential therapy, better reflects the unique characteristics of elderly newly diagnosed multiple myeloma (NDMM). Meanwhile, the exclusively oral medication regimen for the elderly ensures sustained patient adherence, thereby reducing discontinuation and economic burdens associated with recurrent hospitalizations. Our institution conducted a prospective, multi-center IIT clinical trial based on retrospective studies (2023 ASH-6690) to assess the efficacy and safety of a dual-risk adjusted treatment for elderly patients with NDMM based on dynamic frailty assessment and R-ISS. This trail was registered at https://www.chictr.org.cn, as ChiCTR2300078876.
Methods
In this prospective trial treatment consisted of initial 28 day-induction cycles consisting of ixazomib (I) 4 mg (days 1, 8, 15) and dexamethasone (D) 40mg (days 1, 8, 15) for intermediate-fit patients, dexamethasone (D) 20mg (days 1, 8, 15) for frail patients. The dynamic frailty were evaluated using gait speed, grip strength and the International Myeloma Working Group Frailty Index (IMWG-FI) at the 3rd, 6th, and 12th treatment cycles. After the frailty status improved, the third drug (intermediate-fit: lenalidomide; frail: cyclophosphamide) was added in the following cases: 1) R-ISS high-risk group, and 2) R-ISS intermediate-low risk group with efficacy &lt; PR. The remaining patients continued the ID regimen. Patients achieving VGPR or higher at the 12th cycle proceeded to ixazomib or lenalidomide maintenance therapy.
Inclusion criteria were NDMM patients aged 60 years or older, either being intermediate-fit or frail according to the IMWG-FI. Main exclusion criteria were documented gastrointestinal disorders or unmanageable gastrointestinal symptoms that impeded the oral absorption of medications. We here report the results of the planned safety and effectiveness analysis of the first 17 included patients.
Results
As of July 1, 2024, a total of 31 patients underwent screening, with 17 meeting the inclusion criteria. There were 2 cases in the intermediate-fit group and 15 cases in the frail group based on IMWG-FI. Among them, there were 11 cases with a score equal to or greater than 3. The median age was recorded as 75 years (range:61-84). All patients underwent FISH testing, resulting in identification of high-risk cytogenetic abnormalities in 11 patients and extramedullary plasmacytoma in 2 cases.
In the 12 evaluable patients, the preliminary efficacy was satisfactory, with an ORR of 91.7% (11/12), of which 1 CR, 5 VGPR, 5 PR, 1 MR. One patient died due to unexpected occurrences during the fourth course, while no patients discontinued prematurely and there were no early relapse. Six patients exhibited improvement in their frailty status, while 5 patients were administered a third drug (IRD, n=1; ICD, n=4) due to high-risk R-ISS or failure to achieve PR efficacy. One patient attained VGPR efficacy without treatment adjustments. The remaining 6 patients continued ID as their frailty state did not ameliorate. The other 5 patients failed to reach the adjusted treatment milestone within three cycles.All patients demonstrated favorable overall tolerability, predominantly exhibiting grade 1-2 adverse events (CTCAE 5.0). Only one patient experienced grade 3 pulmonary infection and respiratory failure but successfully recovered.
This study examined the consistency between gait speed, grip strength and the IMWG-FI for exploring more suitable frailty assessment methods and the optimal timing for dynamic assessment. The findings will be detailed in subsequent sections.
Conclusion
The preliminary results indicate that the dual-risk adjusted therapy demonstrates reduced treatment-related toxicity, discontinuation, and early mortality. Furthermore, it indicates satisfactory initial response rates and confirms the benefits and the sustainable application of an all-oral drug regimen in elderly patients. This treatment may be able to alleviate the current treatment dilemma for frail elderly patients with MM.