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Multiple myeloma (MM) is a common malignant hematological tumor, particularly prevalent among the elderly population. Due to the presence of more comorbidities and a higher risk of infection in elderly patients, their tolerance to treatment is relatively poor. Therefore, treatment strategies for this special group require special attention.

In the field of MM treatment, we are experiencing a transformative period, especially in the elderly and frail patient population. Currently, for transplant-ineligible newly diagnosed multiple myeloma (TIE-NDMM) patients, the DRd regimen combining daratumumab, lenalidomide, and dexamethasone has become the standard treatment in the United States and Europe. This year at the European Hematology Association (EHA) Congress, the final analysis results of the multicenter, randomized, open-label phase III MAIA study[1] were announced, exploring the efficacy and safety of the DRd triplet regimen in TIE-NDMM patients.

The study data showed that after a median follow-up of 89.3 months, the death risk of patients in the DRd group was reduced by 33%, and the median overall survival (mOS) exceeded 7.5 years. This is the longest OS data reported in TIE-NDMM clinical studies to date, marking a milestone achievement. Notably, the frail subgroup results of the study indicated that compared to the Rd two-drug regimen, the DRd triplet regimen brought significant progression-free survival (PFS) benefits to elderly frail NDMM patients (not reached vs. 30.4 months, HR 0.62, P=0.003), and both the ≥ complete response rate (43.6% vs. 30.8%) and minimal residual disease (MRD) negativity rate (23.8% vs. 10.1%) were further improved. The MAIA study results confirmed the superior efficacy of the DRd regimen in TIE-NDMM patients, providing strong evidence-based medical evidence for the DRd regimen to become one of the standard treatment options for TIE-NDMM. Based on the MAIA study results, the 2024 NCCN guidelines, the 2024 Mayo Clinic guidelines, the Chinese Guidelines for the Diagnosis and Treatment of Multiple Myeloma (2022 revised edition), and other authoritative guidelines all recommend it as the preferred option for TIE-NDMM patients.

As research on the treatment of elderly frail MM patients deepens, we are transitioning from traditional uniform treatment plans to more personalized treatment strategies. This shift means that we need to develop treatment plans based on the degree of frailty and age of the patients. To accurately implement this stratified treatment model, we need to establish a clinically feasible and standardized frailty assessment system, which is an issue that needs to be addressed urgently.

Currently, several clinical trials are exploring the application of dexamethasone-free regimens in elderly frail MM patients to reduce toxicity, control the risk of infection, thereby extending survival and improving prognosis. For example:

• IFM 2017-03 trial: This trial explored the efficacy of the dexamethasone-free DR regimen (daratumumab combined with lenalidomide) in treating elderly frail NDMM patients. The interim analysis results showed that compared with the Rd regimen (lenalidomide combined with dexamethasone), the DR regimen brought a higher overall response rate (ORR) (96% vs. 85%), very good partial response rate and above (≥VGPR) (64% vs. 43%), and MRD negativity rate (10-5; 10% vs. 3%). No significant difference in infection incidence (13% vs. 18%; P=0.29) was observed, and there was no significant difference in treatment discontinuation rates due to adverse events (AE) between the two groups (14% vs. 16%; P=0.65), proving that the DR two-drug regimen not only ensures efficacy but also reduces the risk of infection. The interim analysis of the IFM 2017-03 trial has been completed, and we look forward to the upcoming final report for more treatment details.

At the same time, studies on the efficacy of the new generation of immunotherapies in elderly frail NDMM patients are also being carried out, such as:

• BENEFIT/IFM2020-05 trial: This is an open-label, multicenter, parallel-controlled phase III clinical trial aimed at comparing the efficacy and safety of the Isa-VRd (isatuximab + lenalidomide + dexamethasone + bortezomib) quadruplet regimen with the IsaRd (isatuximab + lenalidomide + dexamethasone) triplet regimen in TIE-NDMM patients. Preliminary analysis results showed that the Isa-VRd regimen showed a significant advantage in improving the MRD negativity rate of patients, which may make the isatuximab-based quadruplet regimen a new standard treatment option for NDMM patients aged 65 to 79 who are not suitable for transplantation.

• MajesTEC-7 (NCT05552222) trial: At this year's American Society of Clinical Oncology (ASCO) annual meeting, data from this phase III trial were announced, exploring the efficacy of the first bispecific antibody targeting CD3 and B-cell maturation antigen (BCMA) - teclistamab, combined with daratumumab and lenalidomide in 26 NDMM patients who are not eligible or do not intend to undergo autologous stem cell transplantation as initial treatment. The first safety cohort results of this trial showed that the overall response rate and progression-free survival rate of this triplet regimen in NDMM patients were 92.3% and 96.2%, respectively, showing early efficacy results and controllable safety. Although 30.8% of patients had grade 3 or 4 infections, most of these infection events occurred in the first three cycles, emphasizing the need for early infection prevention measures.

• MagnetisMM-3 (NCT04649359) trial: This is an open-label, multicenter, non-randomized, phase II trial evaluating the efficacy and safety of the second CD3/BCMA bispecific antibody - elranatamab, in treating relapsed/refractory multiple myeloma (R/R MM) patients. The trial results showed that for patients who used elranatamab as BCMA-targeted therapy for the first time, the objective response rate was 58%, with 82% of patients maintaining a response for at least 9 months; at a median follow-up time of 10.4 months, the objective response rate for this patient subgroup was 61%, confirming that elranatamab provided a higher response rate and longer duration of response for MM patients.
• CARTITUDE-4 (NCT04181827) trial: This global randomized open-label phase III study evaluated the efficacy and safety of the BCMA-targeted chimeric antigen receptor T-cell (CAR-T) therapy - ciltacabtagene autoleucel (cilta-cel) compared with pomalidomide, bortezomib, and dexamethasone (PVd) or daratumumab, pomalidomide, and dexamethasone (DPd) in relapsed and lenalidomide-resistant MM patients. The study achieved a statistically and clinically significant improvement in overall survival (OS). It is worth noting that in the experimental group, the treatment duration of cilta-cel was preset, which is different from the continuous treatment mode usually adopted for elderly patients. This fixed-duration treatment strategy provides a new treatment option for elderly patients, potentially allowing for the cessation of treatment and thus improving their quality of life.

In summary, the treatment of multiple myeloma is moving towards a more personalized and precise direction. With the continuous emergence of new treatment regimens and in-depth clinical trials, we hope to provide more and more effective treatment options for elderly frail patients, while improving their quality of life and prognosis. Future research will continue to explore how to better provide personalized treatment for elderly frail patients to achieve the best treatment effects and quality of life.