(PA-426) Geriatric Assessment in Hematology-Guided Selection for Quadruplet Therapy in Transplant-Ineligible Myeloma. A post hoc analysis from GEM2017FIT trial

The Geriatric Assessment in Hematology (GAH) scale, using a 42-point cutoff, predicts toxicity and helps guide frailty-adapted therapy in hematologic malignancies. Its role had not been evaluated in the context of novel agents for multiple myeloma (MM). The GEM2017FIT trial included transplant-ineligible MM patients with GAH score ≤42, treated with 18 induction cycles of VMP/Rd (control) or DKRd and KRd (experimental). The trial met its primary endpoint, showing significantly higher minimal residual disease (MRD) negativity rates with DKRd and KRd compared to VMP/Rd. Also, a GAH score < 20 could represent a clinically relevant threshold to identify patients with better tolerability to quadruplet combinations (Mateos, Lancet Haematol 2025).

Methods:

Patients in the GEM2017FIT trial were classified as ultra-fit (GAH < 20) or fit (GAH >20). A post hoc analysis was conducted to assess toxicity and efficacy.

Results:

Of 461 patients, 240 were ultra-fit (52.1%) and 221 fit (47.9%), evenly distributed across arms (VMP/Rd: 85 ultra-fit and 69 fit; DKRd: 78 ultra-fit and 75 fit; KRd: 77 ultra-fit and 77 fit). Baseline characteristics were comparable among groups.

Overall, 11.9% of patients experienced toxicity leading to discontinuation or toxicity-related death, with no differences by fitness group. Notably, in the DKRd arm, ultra-fit had lower rates of severe toxicity/toxicity-related death than fit patients (7.7% vs. 18.7%, P=0.037). No differences were seen in other arms.

In the intention to treat population, MRD negativity was similar in ultra-fit and fit patients (47.9% vs. 46.6%, P=0.331). Among ultra-fit patients, DKRd attained superior MRD negativity (69.2%) than VMP/Rd (28.2%) (P< 0.001) and KRd (44.6%) (P=0.007). In fit patients, DKRd showed improved MRD negativity (53.3%) over VMP/Rd (24.6%) (P< 0.001) but comparable to KRd (55.4%) (P=0.426). In the DKRd arm, ultra-fit patients achieved higher MRD negativity than fit patients (P=0.043). These differences were not shown with VMP/Rd (P=0.615) or KRd (P=0.146)

Progression-free survival (PFS) was similar between ultra-fit and fit patients (not reached (NR) vs. 53.9 months, P=0.195). In ultra-fit patients, DKRd resulted in prolonged PFS (NR) compared to VMP/Rd (NR, P=0.051) or KRd (NR, P=0.045), whereas no differences were shown in fit patients. In the DKRd arm, ultra-fit patients had significantly longer PFS than fit patients (NR in both, P=0.038). A similar benefit was seen with VMP/Rd (NR vs. 41.0 months, P=0.046), but not with KRd (NR vs. 53.9 months, P=0.077).

Conclusions:

The GAH scale effectively identified patients eligible for triplet and quadruplets combinations. A GAH score < 20 further defined a subset of patient suitable for quadruplets, which led to higher MRD negativity and longer PFS with acceptable toxicity. These results suggest that addressing modifiable GAH dimensions may enhance patient fitness, broaden access to intensive therapies and improve clinical outcomes.