Introduction Recently, subcutaneous (SC) daratumumab monotherapy (compared to active monitoring) has been found to significantly lower the risk of progression from high-risk smoldering multiple myeloma (SMM) to active multiple myeloma (MM) or death and prolong overall survival (the AQUILA Trial). With a median follow-up of 65.2 months, progression to active MM or death occurred in 34.5% in the daratumumab group vs 50.5% in the active-monitoring group (hazard ratio=0.49; P<0.001). Importantly, only 8.8% of the patients receiving daratumumab monotherapy achieved a complete response or better suggesting that continued treatment may be needed to sustain long-term efficacy. We were motivated to develop a novel combination therapy using SC daratumumab plus the bispecific monoclonal antibody (BCMAxCD3) teclistamab (Dara/Tec) with the goal of achieving high rates of sustained minimal residual disease (MRD) negativity after a pre-defined, 24-month, duration of therapy.

Methods This is a single-center, phase II study of teclistamab plus daratumumab for patients with high-risk SMM. Eligible patients have high-risk SMM (by published IMWG, RLM PETHEMA, and/or Mayo criteria), with adequate organ function and clinical criteria, ECOG PS 0-2, and measurable disease. Newly diagnosed MM per IMWG criteria and/or prior treatment for SMM was not allowed. The primary endpoint is the rate of MRD-negativity (10-5) after 12 cycles of combination therapy. Key secondary endpoints include safety and tolerability (CTCAE v5), overall response rate, duration of response, progression-free; event-free; and overall survival (PFS, EFS, OS), 10-6MRD-negativity, and annual rate of MRD-negativity including sustained MRD negativity at 2, 3, 5 and 7 years (i.e. up to 5 years after stopping therapy as a surrogate for functional cure). The NCI-PROMIS patient-reported outcome instrument was used to capture important quality of life and function metrics. After 3 standard step-up-doses (SUD) of teclistamab (per FDA US label), patients receive up to twenty-four 28-day cycles of Dara/Tec. In C1, patients receive Dara 1800 mg SC on D1, 8, 15 and 22 and Tec 0.06 mg/kg on D2, 0.3 mg/kg on D4 and 1.5 mg/kg on D8 and D15. For C2-24 patients receive Dara 1800 mg SC and tec 3 mg/kg on day 1. One hour prior to the first step up dose of Tec, patients receive a single dose of tocilizumab 8 mg/kg to prevent cytokine release syndrome (CRS). This is the first pre-planned analysis of the two-stage Simon study design which stipulates achieving 10-5MRD-negativity in at least 2 of the first 15 patients is required for the study to continue to full accrual (n=50).

Results As of July 21, 2025, 15 patients have enrolled in the study. Median age is 57 (34-82) years; 62% are male, 8% are Asian, and 62% are Hispanic/Latino. At a median follow-up of 12 (range 1-20) months, the overall response rate is 100%. Of the 13 evaluable patients, 11 have achieved stringent complete response (sCR) and had an MRD assessment, and all these individuals attained 10-5MRD-negativity (85%; 95% CI 54%-98%); furthermore, MRD testing by clonoSEQ NGS confirms that all 11 patients attained 10-6MRD-negativity. The median time to MRD negativity was 7 (range 5-13) months. Among the remaining 2 patients, 1 has obtained sCR and is pending MRD assessment at the time of data cutoff (completed 3 cycles of treatment); 1 patient has a positive immunofixation IgG band (completed 4 cycles of treatment). Of the 13 enrolled patients, 12 required IVIG due to IgG levels <400 mg/L. Standard prophylaxis with antivirals and antibiotics were given to all patients per the study protocol. None of the patients had CRS or ICANS. There were 5 drug-related ≥ grade 3 adverse events (AEs) (3 neutropenia, 1 anemia, and 1 pneumonia). There were no serious AEs. To date, no patients have progressed to active MM nor have any died from any cause.

Discussion Here, we used a novel combination therapy with Dara/Tec with the goal of achieving high rates of sustained MRD negativity after a pre-defined duration of therapy (24 months). We were able to deliver very high rates of 10-6MRD-negativity in the setting of high-risk SMM (>80-90% of patients). No unexpected safety concerns were identified. At the meeting, we will present updated data on clinical efficacy including preliminary data on durability of MRD negative responses, i.e. sustained MRD negativity (clinicaltrials.gov NCT06100237).

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2025
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