This PMS subgroup analysis demonstrated the real-world safety and effectiveness of Isa-Pd in frail Japanese individuals with RRMM, consistent with results from the overall population of Japanese participants in the PMS [9].

While the incidence of infusion-related reactions was underestimated in this study, infectious diseases and infusion-related reactions were more common in frail participants than in those who were grouped as fit/intermediate. Bone-marrow suppression was also more common in frail participants than in fit/intermediate participants; when neutropenia AEs were harmonized according to the PTs for neutropenia, the impact of neutropenia was highest in the frail group. It is possible that the lower incidence of neutropenia across all the subgroups (when compared with the 96% incidence in the ICARIA trial of ISA-Pd [6]) could have been accounted for by the high proportion of patients who had missing frailty scores. Rates of anemia, decreased platelet count, and decreased white blood cell counts were similar in frail and fit/intermediate participants.

The effectiveness of Isa-Pd was comparable between frail and fit/intermediate individuals with RRMM, with no significant differences in ORR and ≥ VGPR between subgroups. Since numerically higher ORRs are indicative of a higher likelihood that the sample is representative of the target population, the low ORR in the frail group should be interpreted with caution. Discontinuations due to disease progression were also similar between groups.

The simplified frailty score used in the current study was originally devised to make use of available real-world clinical information [4, 5]. The original IMWG-devised frailty score used the patient-completed Activities of Daily Living questionnaires to determine the functional status of individuals [3]; however, it was felt that this was not commonly administered to participants and was time consuming. Thus, the simplified frailty score was devised to use commonly available information (i.e., age, ECOG PS, and mCCI) [12]. This simplified frailty classification has recently been externally validated [12] and applied in several studies of individuals with MM [4, 11, 13, 14].

In the RRMM setting, and in line with current results, Isa-Pd had similar efficacy in frail and fitter individuals, when frailty was defined using the simplified frailty score [15]. While there was a trend towards poorer tolerability in frail participants, the overall tolerability profile was manageable in both fit/intermediate and frail participants. The United Kingdom-based retrospective analysis of 106 participants with RRMM treated with Isa-Pd in clinical practice included 72 (67.9%) frail individuals. Median progression-free survival was similar in frail and fit/intermediate participants (10.1 vs 13.7 months, respectively; p = 0.5259). Median duration of response (10.1 vs 10.2 months; p = 0.685) and median overall survival (15 months vs not reached; p = 0.3571) were also non-significantly different between these subgroups, indicating that Isa-Pd was similarly effective in frail individuals. While the incidence of any grade AEs, any grade hematological AEs, and grade ≥ 3 infections were not significantly different between subgroups, grade ≥ 3 hematologic AEs were more frequent in frail than in fit/intermediate participants (58.3% vs 38.2%, respectively; p = 0.053) [15].

Although triple regimen therapies are optimal for disease control, it has been suggested that doublet regimens should be the preferred option for frail individuals with RRMM, due to toxicity concerns [16]. However, the current results strongly advocate the benefit of the Isa-Pd triplet regimen in frail individuals in the later-line setting, with clinically meaningful clinical responses (ORR 38.5%; ≥ VGPR 18.0%) and manageable tolerability. While incidence rates of infectious diseases, infusion-related reactions, and bone-marrow suppression were numerically higher in frail participants than fit/intermediate participants, rates of anemia, decreased platelet count, and decreased white blood cell counts were similar in frail and fit/intermediate participants. In addition, rates of discontinuation due to AEs were similar in frail and fit/intermediate participants (10.0% vs 6.9%). Furthermore, clinical response, long-term treatment benefit, and safety in frail individuals treated with Isa-Pd have been previously shown to be consistent with the elderly and the overall general RRMM population, thereby demonstrating the feasibility of this triplet regimen in the frail population [5, 15, 17].

There are limitations to this subgroup analysis. Of note, we were unable to calculate a frailty score for a large proportion of the participants due to a lack of medical history (missing frailty scores), resulting in relatively small sample numbers in the frail and fit/intermediate subgroups. Also, this was not a prespecified subgroup analysis. We recommend that future analyses of the frail population should be specified and carried out in larger sample groups.

In conclusion, although this PMS subgroup analysis was limited by small sample sizes, Isa-Pd was shown to be valuable and well tolerated in frail individuals, making it a potentially useful treatment option for this RRMM population. Close monitoring and dose adjustments may be required in order to manage toxicities and to maintain individuals on the triple therapy Isa-Pd regimen.