P-153: Maintenance therapy with carfilzomib, pomalidomide and dexamethasone (KPd) in high-risk myeloma patients (pts): A Phase 2 study with a safety run-in

Introduction: High-risk pts derive survival benefit from combination maintenance (PI and IMiD) strategies. We have evaluated the safety and efficacy of the next generation PI (carfilzomib) and IMiD (pomalidomide) in combination with dexamethasone in high-risk myeloma (NCT03756896)

Methods: Newly diagnosed high-risk myeloma pts that have achieved ≥PR post-ASCT were included. High-risk myeloma was defined by the presence of t(4;14) in 31%, t(14;16) in 17.2%, del17p in 58.6% pts by FISH or CTG or presence of ≥20% circulating cells (pPCL) in 6.9%. Double-hit myeloma (as defined by presence of ≥2 high-risk cytogenetic abnormalities including gain of 1q) was seen in 58.6% of pts. Each cycle is 28 days. Carfilzomib 20/56 mg/m2 IV was given on days 1,8,15 and pomalidomide 2 mg PO on days 1 to 21 and dexamethasone 40 mg PO was administered on days of carfilzomib. Statistical analysis was conducted using SAS Version 9.4.

Results: After the safety run in the first 3 pts, 26 additional pts were enrolled. Median age was 60 years (range, 46−75); 58.6% male and 58.6% black. At diagnosis, 65.5% had RISS stage 3 disease. 54.5% of whites and 64.7% of blacks had double-hit disease. Median time from diagnosis and from transplant to study entry was 9.3 (range, 6.08-12.42) and 2.89 (range, 2-8.51) months, respectively. At study entry, ≥CR and ≥VGPR rates were 24.1% and 68.9%, respectively, which deepened to 89.7% and 100% while on study. The median time to best response was 1.84 months (range, 0-13.34). Of the 15 pts with available MRD data, MRD (10-5) and (10-6) were achieved in 86.7% and 66.7%, respectively. After a median follow-up of 30.5 months, 48 month PFS was 54% and 48 month OS was 67%. Interestingly, all pts that have progressed and/or died had double-hit disease expect 1 patient. There was no PFS or OS difference by RISS. At data cut-off as of May 1st 2023, 27.6% of pts were still receiving treatment; most common reason for permanent treatment discontinuation was progressive disease (34.5%). Among the 6 pt deaths, the most common cause of death was progressive disease (83.3%).
Most common hematological treatment-emergent adverse events (TEAEs) reported in the cohort included neutropenia [55.2% (Grade 3/4: 55.2%)], anemia [13.8% (Grade 3/4: 0%)] and thrombocytopenia [10.3% (Grade 3/4: 3.4%)]. Non-hematological TEAEs include hypophosphatemia [69% (Grade 3/4: 27.6%)], muscle cramps [38.8% (Grade 3/4: 3.4%)], hypomagnesemia [27.5% (Grade 3/4: 0%)], head ache [24.1% (Grade 3/4: 3.42%)], agitation [20.7% (Grade 3/4: 0%)] and acneiform rash [(20.7% (Grade 3/4: 0%)]. The TEAEs of interest included cardiac [13.8% (Grade 3/4: 3.4%)], cataracts [17.2% (Grade 3/4: 17.2%)] and CVA [3.4% (Grade 3/4: 3.4%)]

Conclusions: In pts with high-risk myeloma, KPd combination maintenance is safe, well-tolerated and efficacious. Presence of double-hit disease is a predictor for progression. These results support further exploration of combination maintenance strategies among high-risk pts.