ISAMAR: Multicenter phase II single arm trial of isatuximab (ISA) with/without lenalidomide (LEN) in pts with high risk smoldering multiple myeloma (HRSMM).
Authors: Manasanch Elisabet Esteve , Korde Neha , Lee Hans C. , Patel Krina K. , Becnel Melody , Berrios David , Thomas Sheeba K. , Iyer Swaminathan Padmanabhan , Mailankody Sham , Amini Behrang , Lin Pei , Berkova Zuzana , Weber Donna M. , Feng Lei , Neelapu Sattva Swarup , Jagannath Sundar , Hildebrandt Michelle Ann Theobald , Orlowski Robert Z. , Landgren Ola 
Published: June 2023

8046 Background: HRSMM patients (pts) have a median time to progression of < 2 years. ISA is a monoclonal antibody that binds to highly expressed CD38 on myeloma cells and is approved in RRMM. We designed a phase II study to test the efficacy of ISA +/- LEN in HRSMM (NCT02960555). Methods: The primary endpoint of the study was the overall response rate (ORR) after 6 months of ISA 20 mg/kg IV days 1, 8, 15, 22 cycle 1; days 1, 15 cycles 2-6; day 1 cycles 7-30 monotherapy (stage 1, n = 25) or with LEN 25 mg po daily on days 1-21 every 28 days, cycles 1-6 (stage 2, n = 36). Secondary endpoints are progression free survival (PFS), overall survival (OS) while exploratory endpoints included quality of life (QoL), flow and sequencing. Results: 61 HRSMM pts (+immunoparesis and ≥95%abnormal plasma cells in bone marrow) (stage 1 n = 25; stage 2 n = 36) were accrued 02/2017-10/2022. The study met its primary endpoint of ORR ≥ 70% after 6 cycles of therapy [Stage 2 ORR (89%) = VGPR 9 (25%), PR 23 (64%), MR 3(8%), PD 1(3%)]. Median time to response was 1 cycle. In stage 2, 17/36 (47%) patients had grade 3 treatment related adverse events (AEs): 1 pt related to ISA (myalgia, 3%) and 16 pts related to LEN (44%) [ANC decrease (36%), skin rash (8%), ALC decrease (11%), WBC decrease (8%), fatigue (6%)] and 1/36 pts a grade 4 (related to LEN) [ANC decrease 3%]. Most common grade 1-2 AEs: WBC decrease (53%), ANC decrease (56%), skin rash (28%), fatigue (39%), ALC decrease (42%), thrombocytopenia (28%), diarrhea (39%), constipation (28%). There were no grade 5 AEs. No patients discontinued treatment due to AEs. There were 3 deaths in stage 1 unrelated to therapy: 1 patient progressed to and died while on systemic AL amyloidosis therapy, one patient (with COPD) died of COVID19 while in sustained PR, one heavy smoker died of squamous cell cancer of the tongue. Pre- and post- treatment BM flow showed that ISA/LEN increased CD4+/CD8+ and effector memory cytotoxic T cells. QoL measures (n = 32; 15 in stage 1, 17 in stage 2 and 21 with both BL/after 6 months data) showed that ISA+/- LEN resulted in decreased cancer worry/anxiety and improved future perspective at 6 months compared to BL in both stages. QoL was favorable and conserved throughout treatment, suggesting minimal effects of treatment on patient assessment of well-being. For stage 1, median PFS was 49.3 months (95% CI:40.8~NA months); median OS not reached at a median f/u of 49 months (range 6.3-68 months). Stage 2 median PFS/OS is not reached. Conclusions: ISA/LEN results in high ORR without decrease in patient well-being. ISA monotherapy also results in prolonged PFS when compared to historical data. ISA/LEN therapy remodels the BM TME with increase in memory cytotoxic T cells. The results of this study give rationale for the ongoing phase 3 ITHACA evaluating ISA +/- LEN/DEX with the potential to change the standard of care in HRSMM (NCT04270409). RO and OL have equal contribution. Clinical trial information: NCT02960555 .