Teclistamab/Daratumumab Combo Elicits Encouraging Responses in Relapsed/Refractory Myeloma

The subcutaneous combination of the BCMA-targeting bispecific antibody teclistamab (JNJ-64007957) and daratumumab (Darzalex) produced promising preliminary efficacy and favorable tolerability in heavily pretreated patients with relapsed or refractory multiple myeloma, according to results from the phase 1b TRIMM-2 trial (NCT04108195).¹

The results, which were presented during the 2021 ASH Annual Meeting, showed that at a median follow-up of 5.1 months (range, 0.3-12.9), evaluable patients in the first cohort who received teclistamab at 3 mg/kg once every 2 weeks (n = 10) experienced an ORR of 70.0%, with 60.0% of patients achieving a very good partial response (VGPR) and 10.0% experiencing a partial response (PR). Moreover, 30% of patients had stable disease.

Evaluable patients in the second cohort who were administered teclistamab at 1.5 mg/kg once weekly (n = 19) achieved an ORR of 84.0%. Of those who responded, 31.6% achieved a complete response (CR), 36.8% experienced a VGPR, and 15.8% had a PR. Additionally, 5.3% of patients had stable disease, and 10.5% experienced disease progression. Evaluable patients in the third cohort who received teclistamab at 3 mg/kg weekly (n = 4) experienced an ORR of 100%; 75% achieved a CR and 25% had a VGPR.

“The preclinical data showed that daratumumab, an anti-CD38 monoclonal antibody, may lead to synergistic clinical efficacy when combined with teclistamab, a bispecific antibody targeting BCMA,” lead study author Paula Rodriguez-Otero, MD, Department of Hematology, Clínica Universidad de Navarra, Pamplona, Spain, said in an interview with OncLive®. “[We have data showing that] daratumumab monotherapy [lead] to T-cell expansion and enhanced T-cell cytotoxic potential, [and] preclinical studies showed that the addition of daratumumab may enhance the teclistamab-mediated lysis of myeloma cells.”

Prior data from the phase 1 MajesTEC-1 trial (NCT04557098) showed that teclistamab monotherapy, when given at the recommended phase 2 dose (RP2D), elicited an ORR of 65% and a VGPR or better rate of 56% in heavily pretreated patients with relapsed or refractory multiple myeloma at a median follow-up of 6.1 months (range, 1.2-15.2).²

TRIMM-2 enrolled patients who were at least 18 years of age and who had a diagnosis of multiple myeloma based on the International Myeloma Working Group criteria. Eligible patients were required to have received at least 3 prior lines of therapy, including a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), or to have been double refractory to a PI and IMiD. Notably, patients who received anti-CD38 therapy within 90 days were excluded from the study. Patients who were outside of the 90-day window or refractory to anti-CD38 therapy were eligible.

Across the 3 cohorts, a total of 37 patients received subcutaneous teclistamab at a weekly dose of 1.5 mg/kg weekly, a weekly dose of 3 mg/kg weekly, or at 3 mg/kg given every other week. Nine patients had a schedule change from teclistamab 1.5 mg/kg weekly to 3 mg/kg every other week for cycles 4 through 9. Notably, there was no steroid requirement for teclistamab after the first cycle. All patients were also administered subcutaneous daratumumab at a weekly dose of 1800 mg for the first 2 cycles, every other week for cycles 3 through 6, and monthly beyond cycle 7.

Responses were assessed per International Myeloma Working Group 2016 criteria. Additionally, adverse effects (AEs) were evaluated per Common Terminology Criteria for Adverse Events v5.0, except for cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS), which were assessed using American Society for Transplantation and Cellular Therapy criteria.

The primary end points of the trial were to identify the RP2D for each treatment combination and characterize the safety of each regimen at the selected doses. Additional end points of interest included antitumor activity, pharmacokinetics, pharmacodynamics.

The median age of enrolled patients across all 3 cohorts was 67 years (range, 51-79), and 54.1% were female. Moreover, 24.3% of patients had at least 1 extramedullary plasmacytoma and 25.9% had high-risk cytogenetics. The median time since diagnosis was 6.7 years (range, 0.7-14.2), and the median prior number of therapies received was 5 (range, 2-16). Additionally, 73% of patients underwent prior stem cell transplantation. Additionally, 75.7% had previously been exposed to anti-CD38 therapies, 75.7% were triple-class exposed, and 59.5% were penta-drug exposed.

Additional data showed the median time to first confirmed response across all groups was 1.0 month (range, 1.0-2.8). The ORR was also found to have improved with the addition of daratumumab vs the RP2D of 1.5 mg/kg of teclistamab monotherapy. At a median follow-up of 6.5 months (range, 1.2-12.9), 92.6% of responders were still on treatment.

Peripheral T-cell activation was noted with teclistamab/daratumumab, which was shown by the upregulation of CD38-/CD8-positive T cells. The proportion of CD38-/CD8-positive T cells declined after initial daratumumab dosing on day 1 of cycle 1, and teclistamab administration resulted in the induction of CD38-positive T cells after cycle 1 day 2, despite concurrent daratumumab treatment. After teclistamab dosing in the presence of daratumumab, the induction of pro-inflammatory cytokines was observed. The pharmacokinetic profile of teclistamab in the presence of daratumumab was consistent with the profile that was observed in the MajesTEC-1 trial.

No new AEs were observed vs when either agent was used as a monotherapy, and no toxicities resulted in treatment discontinuations. All CRS events were grade 1 or 2 in severity. One patient had grade 2 ICANS, which resolved in 5 days. Infections were experienced by 59.5% of patients, with 29.7% experiencing grade 3 or higher events.

Hematologic AEs neutropenia, anemia, and thrombocytopenia of any grade were reported in 51.4%, 45.9%, and 32.4% of patients, respectively. Grade 3 or 4 neutropenia, anemia, and thrombocytopenia occurred in 45.9%, 29.7%, and 32.4% of patients, respectively. The most common nonhematologic AEs of any grade were CRS (64.9%), diarrhea (35.1%), nausea (29.7%), asthenia (29.7%), fatigue (27.0%), pyrexia (24.3%), and headache (24.3%).

The data reported from all 3 cohorts of the trial support further exploration of the combination, according to the study authors.

To this end, the phase 3 MajesTEC-3 study (NCT05083169) will evaluate teclistamab plus daratumumab vs daratumumab, pomalidomide (Pomalyst), and dexamethasone, or daratumumab, bortezomib (Velcade), and dexamethasone.

“The combination of teclistamab and daratumumab [shows] preliminary efficacy [with] a promising ORR that could be even higher [than] the efficacy [achieved with] teclistamab as a single agent,” Rodriguez-Otero concluded. “It is the basis of an ongoing phase 3 study [called] MajesTEC-3, [which] is further evaluating the combination of teclistamab plus daratumumab in relapsed/refractory multiple myeloma.”

References

1. Rodriguez-Otero P, Dholaria B, Askari E, et al. Subcutaneous teclistamab in combination with daratumumab for the treatment of patients with relapsed/refractory multiple myeloma: results from a phase 1b multicohort study. Blood. 2021;138(suppl 1):1647. doi:10.1182/blood-2021-148723
2. Moreau P, Usmani SZ, Garfall AL, et al. Updated results from majestec-1: phase 1/2 study of teclistamab, a B-cell maturation antigen x CD3 bispecific antibody, in relapsed/refractory multiple myeloma. Blood. 2021;138(suppl 1):896. doi:10.1182/blood-2021-147915