Optimizing Treatment for Elderly Patients with NDMM Based on Frailty Assessment: A Real-World Observational Study

Introduction Elderly patients with multiple myeloma (MM) represent a heterogeneous population, and the efficacy has not been further improved in the era of new drugs. The European Myeloma Network (EMN) recommends that frailty assessment be conducted for elderly patients with newly diagnosed multiple myeloma (NDMM) to avoid overtreatment and undertreatment. The International Myeloma Working Group Frailty Index (IMWG-FI) is considered the “gold standard” for evaluating frailty in elderly MM patients. It is of great importance to explore optimal treatment strategies for elderly NDMM. Methods Patients who were initially diagnosed with MM at Affiliated Hospital of Hebei University from January 1, 2019 to April 1, 2024 were enrolled in this study. Based on the IMWG-FI, the fit group received treatment with VRD regimen, consisting of bortezomib and lenalidomide, dexamethasone. The intermediate-fit group received treatment with VCD regimen, consisting of bortezomib and cyclophosphamide, dexamethasone. As the patient's condition improved or deteriorated, the drug dosage was adjusted in the VRD and VCD groups accordingly. The frail group was treated with either the VD or ID regimen initially, where the VD regimen consisted of bortezomib and dexamethasone; and the ID regimen consisted of ixazomib and dexamethasone. Within the cohort of frail patients, a dynamic assessment of frailty and efficacy evaluation were performed every 3 cycles. With the improvement their frailty status, patients in the R-ISS high risk group or those with an efficacy < PR received a third drug: cyclophosphamide. The primary endpoint of this study is the objective response rate (ORR), as well as monitoring discontinuation rates, early mortality, and adverse events. Results A total of 158 elderly NDMM patients underwent screening, among whom 114 met the eligibility criteria. The median age was 69.5 years (range 60-92). The R-ISS high risk group comprised 63 patients (55.3%), while there were double-hit cases in 14 individuals (12.3%) and triple-hit cases in 6 individuals (5.3%). All patients underwent IMWG-FI assessment, resulting in classification of 39 patients (34.2%) as fit, 27 patients (23.7%) as intermediate-fit, and 48 patients (42.1%) as frail. All patients completed more than 2 courses of treatment, with a best overall response rate (ORR) of 85.9%, including CR (27.3%), VGPR (28.2%), and PR (30.4%). The ORR was 92.3%, 88.9%, and 79.2% for fit, intermediate-fit, and frail patients, respectively. The 12-month PFS and OS were 84.6% and 100% for fit, 92.6% each for intermediate fit, and 89.6% and 79.2% for frail, respectively. The median follow-up time was 22 months (range 4-70). The median PFS and OS were 17 months (range 4-58) and 45 months（range 4-70). The best ORR of 20 patients with double-hit or triple-hit was 80% (16/20) with 12-month PFS and OS both being 100%. Among patients aged 75 or above, 26 were categorized as intermediate-fit and 4 as frail. The best ORR was 76.7% (23/30) with 12-month PFS and OS being 80%. During the follow-up period, a total of 22 patients discontinued treatment. Among them, 6/39 (15.4%) in the fit group, 4/27 (14.8%) in the intermediate-fit group, and 12/48 (25%) in the frail group discontinued treatment. By the end of the follow-up period, a total of 39 patients had died. Among them, 6 patients died within 6 months, all of whom were from the frail group, and the main cause of death was severe infection or heart failure. All 114 patients underwent safety evaluations during the induction phase, with good tolerability and mainly grade 1-2 adverse events (CTCAE 5.0). Sixteen patients (14.0%) and twenty patients (17.5%) experienced ≥3 grade cumulative non-hematological and hematological adverse events (AE). Conclusions This study affirms the necessity of further optimizing the treatment for elderly MM patients in accordance with the IMWG-FI frailty stratification guidelines to improve efficacy, reduce discontinuation and adverse events. Particularly for advanced age, frail, and R-ISS high-risk patients, by integrating dynamic frailty assessment along with cytogenetics at different stages can further enhance efficacy and lower early mortality; thus warranting prospective studies.