Immuno-PRISM: A Randomized Phase II Platform Study of Bispecific Antibodies in High-Risk Smoldering Myeloma

Background: B-cell Maturation antigen-directed immunotherapies have demonstrated significant efficacy in relapsed and refractory multiple myeloma (RRMM), with recent approval of the bispecific antibody teclistamab (TEC) . However, the use of immunotherapy in high-risk smoldering myeloma (HR-SMM) has not been examined to date. We hypothesized that bispecific antibody therapy would have greater benefit in HR-SMM due to this population having a more intact immune system, lower disease burden and may therefore have a higher efficacy and less toxicity compared to RRMM. Based on previous studies of lenalidomide and dexamethasone demonstrating benefit in HR-SMM, the Immuno-PRISM trial is studying various bispecific antibodies against a control arm of lenalidomide and dexamethasone. Herein, we report our first results of TEC in HR-SMM.

Methods: This is a multiple arm, randomized, phase II, platform study evaluating TEC vs lenalidomide and dexamethasone in HR-SMM. Eligibility criteria included HR-SMM per Mayo 2018 “20-2-20” model, total IMWG risk score of 9 or greater, and other previously established high-risk criteria including PETHEMA criteria, evolving-type SMM, and high-risk FISH abnormalities.

This study has an initial, safety run-in cohort of 6 patients treated with TEC. All patients receive 2 step-up doses of subcutaneous TEC. In the safety run-in, patients receive a dose lower than the recommended phase 2 dose (RP2D) of TEC. If no dose limiting toxicities (DLTs) are observed, the next cohort receives the RP2D of TEC. Once safety run-in is complete, the randomized trial begins with 2:1 randomization to TEC (30 patients) vs control arm of lenalidomide and dexamethasone (15 patients). Treatment duration is for 24 cycles. All eligible patients undergo stem cell collection after 4 cycles of therapy.

The primary objective is complete response rate. Secondary objectives include PFS, ORR, MRD negativity rates, safety, pharmacokinetics of TEC, and safety. Exploratory objectives include mass spectrometry quantification of M protein, molecular evolution of tumor cells, and immune biomarkers of response.

Results: At the time of data cut off, 19 patients have been enrolled to study with median follow up of 6 months. The median age is 59 years old (range 35-73) with 9 females (47%) and 10 males ( 53%). Sixty-four percent of patients that had evaluable FISH results had high-risk abnormalities as follows: 1q gain (7 pts), t(4;14) 1 patient.

No DLTs were observed in the safety run-in cohort and patients are now enrolling into the randomized portion of trial. In the TEC-cohort (12 patients), grade 3 or greater hematologic toxicities were neutropenia (4 patients, resolved) and thrombocytopenia (1 patient, resolved). Grade 3 or greater non-hematologic toxicities were ALT increased in 3 patients (grade 3, resolved) and pancreatitis in 1 patient (grade 3, resolved). Infections occurred in 9 patients but only 1 patient had grade 3 infection (sinusitis). Remainder of the infections were low grade and were mostly upper respiratory infections (6 patients). One patient had grade 2 uveitis. CRS occurred in 75% of patients (all grade 1 except 2 patients with grade 2 CRS requiring tocilizumab, all resolved). No patients experienced ICANS with no delayed neurotoxicity observed. All patients treated with TEC are receiving IVIG with mean IgG level at start of IVIG treatment of 418 mg/dL, with 64% of patients achieving normalization of IgG values within two IVIG doses.

In the TEC- treated cohorts (12 patients), the ORR is 100% with 42% achieving a CR, 25% VGPR, 33% PR. Four patients with high risk FISH receiving TEC have achieved a CR within 5 cycles. In control arm of lenalidomide and dexamethasone (3 patients), the ORR is 66% without any complete responses to date. Of the 8 evaluable patients treated with TEC, the MRD negative rate at 10^-6 is 100%, including 2 patients with VGPR-MRD negative disease. Average time to MRD negativity observed among evaluable patients was 4.25 cycles. No patients have progressed on treatment. Stem cell collection was successful in all eligible patients with an average stem cell yield of 9.06 x 10⁶CD34+ cells/kg.

Conclusions: TEC in HR-SMM demonstrates significant activity with 100% ORR with MRD-negative disease in 100% of evaluable patients to date, and overall significantly improved safety profile compared to RRMM.