Frailty-Based Outcomes with Bispecific Antibodies in Older Patients with Multiple Myeloma

Background: Multiple Myeloma (MM) is predominantly a disease of older adults. However, older patients vary widely in physiological status and treatment tolerance. The simplified frailty index (Facon 2020) incorporates age, ECOG performance status, and comorbidities (Charleston Comorbidity Index [CCI]) to classify patients as frail or non-frail. While frailty is associated with increased toxicity with conventional systemic therapies, its impact on outcomes of older patients treated with bispecific antibodies (BsAbs) has not been established. Thus, we conducted a retrospective study to evaluate the efficacy and toxicity of BsAbs in older patients based on frailty.

Methods: This is a single institution study. We included patients with MM ≥65 years who initiated treatment with a BsAb at Mayo Clinic in Rochester, MN from August, 2018 to January, 2024. Patients who received a BsAb on trial or as standard of care were included. For patients who received 2 different BsAbs at different timepoints, we included the first treatment only. We grouped patients into frail and non-frail based on the simplified frailty index (score ≥2 = frail). We evaluated the overall response (ORR) and ≥very good partial response (VGPR) rates, progression-free (PFS) and overall (OS) survival, early mortality (within 90 days) including early non-relapse mortality (NRM), and toxicities including cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS) and healthcare utilization. P values were insignificant (>0.05) unless otherwise stated. PFS and OS were calculated from the day of BsAb start.

Results: A total of 99 patients age 65-89 years were included. The products used were teclistamab (N=43), talquetamab (N=2), and investigational agents (N=54); 67% were ≥70 and 29% were ≥75 years; 39% were female, 95% were non-Hispanic White and 4% were Black/African American. Seventy patients (71%) were considered frail and 29 (29%) were non-frail. At the time of BsAb start, a higher proportion of frail patients had platelets <75 x 10^9/L (30% vs 8%, P=0.04). Otherwise, there was no significant difference between frail and non-frail patients in age (median: 72 vs 70), hemoglobin <8 g/dL (19% vs 12%), absolute neutrophil count <1 x 10^9/L (6% vs 8%), presence of high-risk FISH (70% vs 60%), ISS stage 3 (32% vs 41%), high LDH (58% vs 61%), presence of extramedullary disease (39% vs 25%), serum creatinine ≥2 mg/dL (15% vs 8%), bone marrow plasma cell% (20% in both), triple- (83% vs 90%) and penta-class refractoriness (63% vs 48%), number of prior lines of therapy (median: 6 in both), prior exposure to BCMA-directed therapy (24% vs 21%, P=0.80) and prior autologous stem cell transplant (73% vs 86%). Step-up dosing was used in 81% vs 48% of patients (P=0.001), and treatment was initiated in the outpatient setting in 46% vs 28% (P=0.12) in frail and non-frail patients, respectively.

The median follow-up was 1.9 (95%CI: 1.0-2.3) years. There was no significant difference between frail and non-frail patients in ORR (52% vs 62%), ≥VGPR (46% vs 48%), 1-year PFS (36% vs 48%, P=0.26), or 1-year OS (57% vs 61%, P=0.30), respectively. Age and CCI alone were not associated with PFS or OS, but ECOG >1 was associated with decreased PFS (hazard ratio: 3.1, P=0.001) and OS (hazard ratio: 3.1, P<0.001). There was no significant difference between frail vs non-frail patients in grade 3/4 thrombocytopenia (39% vs 17%, P=0.06), grade 3/4 neutropenia (27% vs 35%), total days of hospitalization (median: 8 vs 5, P=0.35), number of unplanned admissions in 6 months (median: 1 in both), or total hospital days for unplanned admissions (1 vs 2 days). There was no significant difference between frail and non-frail patients in early mortality (23% vs 10%, P=0.17), including early NRM (4% in both), CRS (59% vs 66%), grade 3-4 CRS (3% vs 7%), or CRS recurrence (21% vs 10%). ICANS occurred in 5 (9%) frail patients and 1 non-frail patient (grade 2); among frail patients, grades were: 1 in 3 patients, 3 in 1 patient, and 4 in 1 patient. Similarly, there was no significant difference in CRS/ICANS between the 2 groups when patients with and without step-up dosing were analyzed separately.

Conclusion: Frailty, defined using the simplified frailty index, was not significantly associated with inferior efficacy or increased toxicity with BsAb therapy among older patients with MM. Poor performance status predicted inferior PFS and OS, while age and comorbidity scores did not.