Real-world outcomes in older adults with triple-class exposed multiple myeloma

Abstract Introduction: Triple-class exposed (TCEx) multiple myeloma (MM) patients—those previously treated with an immunomodulatory agent (IMiD), proteasome inhibitor (PI), and anti-CD38 monoclonal antibody—represent a heavily pretreated population with limited remaining therapeutic options. Older adults (≥70 years) comprise nearly half of this group, yet data on their real-world treatment patterns and outcomes remain sparse. Methods: We conducted a retrospective cohort study using the Flatiron Health electronic health record-derived de-identified database. Adult patients diagnosed with MM who became TCEx between November 16, 2015, and December 31, 2024, were included. The index date was defined as the start of the first subsequent line of therapy following TCEx. Patients were stratified by age (<70 vs ≥70 years) at the TCEx date. Outcomes included overall survival (OS), progression-free survival (PFS), and time to next treatment (TTNT), which were estimated using Kaplan-Meier methods. Results: Among 6,301 TCEx MM patients, 3,099 (49.2%) were aged ≥70 years. Approximately 51% (n=3,193) of TCEx patients received a subsequent treatment, of which 1,426/3,193 (44.7%) were aged ≥70 years. The median age was 61 years in the younger cohort and 76 years in the older cohort. Males comprised 56% and 53% of the younger and older cohorts, respectively. Compared to younger patients, the older cohort who received a subsequent treatment had a higher comorbidity burden (mean Charlson Comorbidity Index: 2.61 vs 2.40) and lower rates of prior stem cell transplant (30.7% vs 72.3%). The median number of prior lines of therapy was 3.0 for patients aged ≥70 (vs 2.0 in patients aged <70) who received a subsequent treatment post-TCEx. Patients in both cohorts had similar levels of refractoriness status (double- and triple-class refractoriness); 11.8% of patients aged <70 were penta-refractory vs 9.5% for patients aged ≥70. Despite similar exposure to the three key drug classes, older patients were more likely to receive anti-CD38 monotherapy or doublets and less likely to receive a quadruplet as index treatment post-TCEx compared to younger patients. Older patients had shorter median follow-up compared to younger patients (12.7 vs 15.3 months). Median OS among patients with age <70 and age ≥70 was 46.0 vs 27.3 months and median PFS was 7.0 vs 6.5 months. Among patients aged ≥70, survival outcomes declined with increasing prior lines of therapy; median OS was 59.4 months for those initiating index therapy before third line (<3L), 26.5 months for those in 3rd or 4th line (3/4L), and 20.6 months for those in fifth line or beyond (≥5L). Corresponding median PFS for patients aged ≥70 was 9.7, 6.5, and 5.8 months, respectively. Conclusions: Older adults with TCEx MM experienced worse survival outcomes and received fewer triplet-based treatment regimens compared to younger patients. Outcomes further deteriorated with increasing prior lines of therapy. These findings highlight the urgent need to re-evaluate age-adjusted treatment strategies and offer novel therapeutic approaches to improve outcomes in the growing and vulnerable population of older adults.