Efficacy and Safety of Isatuximab, Pomalidomide and Dexamethasone in Relapsed AL Amyloidosis: Interim Results of the Isamyp Phase 2 Joint Study from the IFM and ALLG

Background: Systemic AL amyloidosis is a rare disease caused by the accumulation of monoclonal immunoglobulin free light chains (FLC) in various tissues and organs. Treatment relies on multiple myeloma drugs and targets the FLC-secreting plasma cell clone. Organ responses and survivals are related to the rapidity and the depth of hematological response assessed by FLC levels. In the AMYDARA (Roussel, 2021) phase II trial with daratumumab (anti-CD38 monoclonal antibody) monotherapy at relapse, 45% of patients (pts) achieved a very good partial response or better (≥VGPR), by Cycle 6, mostly during the 1st cycle. A delayed hematological response was rare, justifying the use of a second drug to improve the ≥VGPR rates. The ISAMYP study evaluates the efficacy and safety of the combination of isatuximab (anti-CD38 mAb), pomalidomide and dexamethasone (IsaPd), in AL pts with suboptimal response to previous therapy or at relapse.

Methods: ISAMYP is an open-label, international, multicenter, phase II study (11 centers in France and 4 in Australia). Treatment comprised, according to hematological and organ responses, up to twelve 28-day cycles of isatuximab (IV, 10 mg/kg), pomalidomide (PO, 4 mg/day) and dexamethasone (PO, 10/20mg weekly). Pts with cardiac Mayo stage IIIb or symptomatic myeloma were excluded. The primary endpoint was ≥VGPR rates after 6 cycles. Secondary endpoints comprised: overall hematological response rates (ORR), organ response rates at 1 year, time to responses, duration of responses, survival outcomes and safety. We report here the hematological response rates at time of primary endpoint and preliminary results of toxicities.

Results: Accrual is completed with 51 pts screened, 42 pts included and 41 treated (1 consent withdrawal). At data cut-off (July 20^th), 5 pts are still on therapy, 21 completed the treatment phase, 14 stopped earlier including 3 deaths. The median age at inclusion was 68 years [51;83], 63% of pts self-declared as male, we don’t have access to ethnicity. Thirty-six pts had cardiac involvement, 25 had renal involvement, and 26 had at least 2 organs involved; 23 pts are Mayo stage II, 2 pts stage IIIa; 11 had dFLC≥180 mg/L. Ten pts (24.5%) had a t(11;14), 5 had 1q gain and 1 pt had a t(4;14). Median number of previous lines of therapy was 2. All pts were bortezomib-exposed, 3 daratumumab-exposed and 12 lenalidomide-exposed. Five Australian pts had received an autologous stem cell transplant.

Hematological responses were rapid with 15/39 pts (38.5%) reaching ≥VGPR at day 8. After 1 cycle (n=40), the ORR was 85.0% (n=34) with 60.0% (n=24) ≥ VGPR and 20.0% (n=8) in complete response (CR). After 6 cycles (n=41), 80.0% of pts (n=33) were in ≥VGPR and 51.0% (n=21) in CR. The median time to first hematological response was 1 week, and to VGPR was 4 weeks. Of note, 8/16 pts that were in PR or less after 1 cycle reached CR after 4 cycles. There was no difference regarding hematological response rates according to cytogenetic abnormalities and all t(11;14) pts achieved ≥ VGPR after 6 cycles.

Considering safety, 59 serious adverse events (SAEs) are reported in 24 pts including 4 deaths (2 SARS-COV2 infections, 1 organ progression and 1 cardiogenic shock), 26 infectious, 8 cardiac, 5 GI tract, and 8 respiratory events. All pts experienced AEs, including 80,5% with grade III/IV. The most frequent AEs were hematological (15%) and occurred mostly during the 1st cycle. They all resolved with growth factors, or transient discontinuation, 35% of pts required pomalidomide dose adjustments (3 mg/day) for neutropenia or skin rash, on average during the 4th cycle, with no further recurrence. Other AEs were infectious (13.5%), GI tract disorders (12%), and general condition events (10%). One patient discontinued therapy after cycle 2 because of grade 3 infusion-related AE while in CR. There was no drug-related death. As expected with IMiDs, a transient rise on NT-proBNP levels was observed in all but 1 pt with a peak at day 8: median NT-proBNP levels from 498 ng/l (95%CI:262-978) to 1105 ng/l (95%CI:481-2140).

Conclusion: IsaPd is an effective treatment in patients with suboptimal response to previous therapy or at relapse, with rapid VGPRs. It can provide, both early responses that deepen over the course of therapy, and some delayed responses even in poor-responders after the 1st cycle of treatment. Pomalidomide dose adjustments are required in that setting, mainly related to grade ≥3 neutropenia and infections.