Interim analysis of efficacy and safety for ALLG MM25 (Viber-M): A phase I b/II study of venetoclax, iberdomide and dexamethasone for patients in first or second relapse of multiple myeloma with t(11;14)

Abstract

Abstract Background: Translocation t(11;14) is seen in 20% of multiple myeloma (MM) patients at diagnosis. Cumulative evidence suggests that it is associated with inferior survival, typically with clinical outcomes that fall between standard and high-risk disease. t(11;14) MM cells overexpress prosurvival BCL2-protein and are highly susceptible to BCL2-inhibition with venetoclax (Ven). Ven-based treatments have been found to be effective in relapsed/refractory (RR)MM. Given the high attrition rates in patient numbers at each relapse, prioritising effective treatments early in the disease course is vital. In the era of lenalidomide (Len)-based induction and maintenance, there is need for a Len-free regimen at relapse. Iberdomide (Iber) is a potent oral cereblon E3 ligase modulator (CELMoD). In vitro studies have demonstrated direct anti-myeloma and immunostimulatory activity including in Len-resistant cells, with promising clinical efficacy reported in combination with standard-of-care agents. We report here the investigator-initiated Phase Ib/II study of Ven, Iber and dexamethasone (Dex) for patients in first or second relapse of MM with t(11;14). Aims: The aim of this study is to assess the efficacy of Ven-Iber-Dex in this patient population; primary endpoint is achievement of ≥very good partial response (VGPR). We report the planned interim analysis of efficacy and safety following completion of three treatment cycles by 20 patients. Methods: Eligible patients have t(11;14) RRMM with 1-2 prior lines of therapy (LOT). Treatment is an all-oral regimen in a 28-day cycle: Ven D1-28; Iber D1-21; weekly Dex. In anticipation of overlapping haematological toxicities, there was intra-patient dose escalation over three cycles; provided there was no Grade (G) 3 neutropenia with fever, G4 neutropenia for >5 days, G4 thrombocytopenia or ≥G3 treatment-related non-haematological toxicities, doses were escalated (C1: Iber 1.3mg/Ven 200mg; C2: Iber 1.3mg/Ven 400mg; C3: Iber 1.6mg/Ven 400mg). During this study, there was notification regarding changes to the recommended phase 3 dose for Iber to 1.0mg; protocol was amended to dose escalation over two cycles (C1: Iber 1.0mg/Ven 200mg; C2: Iber 1.0mg/Ven 400mg). Treatment is until disease progression. This is a cooperative trial group study lead by the Australasian Leukaemia and Lymphoma Group (ALLG). Results: As of data cutoff, 44 of 50 patients have been enrolled. The planned interim analysis was conducted for the first 20 patients (median age 65 years; range 41-83) following completion of three treatment cycles. Of these, 12 (60%) underwent planned dose escalation over three cycles, and 8 (40%) over two cycles. The majority (75%) had one prior LOT. Fifteen patients (75%) were Len-exposed, of whom 13 (65%) were Len-refractory. Four patients (20%) were refractory to anti-CD38 mAb. Three patients (15%) were triple-class exposed. Three patients had concurrent del17p and three had 1q21gain. Treatment-emergent adverse effects (TEAE) during the first three cycles were predominantly G1/2 (74 of 94 events). G3/4 TEAEs were reported in 11 patients (55%), with neutropenia being the most common (45%); 12 patients (60%) required filgrastim support. G3/4 thrombocytopenia occurred in 10% of patients and G3/4 infections occurred in 4 patients (20%), none of which overlapped with G3/4 neutropenia. The most frequent non-haematological AE related to Ven or Iber was gastrointestinal (30%), all G1/2. No deaths were reported at end of C3. One patient discontinued therapy due to G3/4 rash. Only one-third of patients who were scheduled to dose escalate to Iber 1.6mg/Ven 400mg over the first 3 cycles achieved target dose. In contrast, all eight patients capped at Iber 1.0mg successfully achieved target dosing. The overall response rate (ORR) after completion of C3 was 80%, with ≥VGPR in 25% of patients. In Len and anti-CD38 refractory groups, ORRs were 85% (11/13) and 75% (3/4) respectively, with ≥VGPR rates of 23% and 25% respectively. The longest duration of treatment to date is 24 months and ongoing. Summary: The novel combination of Ven-Iber-Dex demonstrates encouraging early efficacy in t(11;14) MM patients at first or second relapse, including in Len-refractory patients. The safety profile appears manageable and consistent with known toxicities of the individual agents. Neutropenia was the most common overlapping haematologic AE while infection rates were within expected range for the relapsed/refractory MM setting.