Correlation of immune fitness with response to teclistamab in relapsed/refractory multiple myeloma in MajesTEC-1.

Teclistamab, an off-the-shelf B-cell maturation antigen (BCMA) × CD3 bispecific antibody that mediates T-cell activation and subsequent lysis of BCMA-expressing myeloma cells, is approved for the treatment of patients with relapsed/refractory multiple myeloma (RRMM). As a T-cell redirection therapy, clinical outcomes with teclistamab may be influenced by patient immune fitness and tumor antigen expression. We correlated tumor characteristics and baseline immune profiles with clinical response and disease burden in patients with RRMM from the pivotal phase 1/2 MajesTEC-1 study, focusing on patients treated with 1.5 mg/kg of teclistamab (N = 165). Peripheral blood samples were collected at screening and bone marrow samples were collected at screening and cycle 3. Better clinical outcomes to teclistamab correlated with higher baseline total T-cell counts in the periphery. In addition, responders (partial response or better) had a lower proportion of immunosuppressive regulatory T cells, T cells expressing co-inhibitory receptors (CD38, PD-1, PD-1/TIM-3), and soluble BCMA, and a T-cell profile suggestive of a more cytolytic potential, compared with nonresponders. Neither frequency of baseline bone marrow BCMA expression nor BCMA receptor density were associated with clinical response to teclistamab. Improved progression-free survival was observed in patients with a lower frequency of T cells expressing exhaustion markers and immunosuppressive regulatory T cells. Overall, response to teclistamab was associated with baseline immune fitness; nonresponders had immune profiles suggestive of immune suppression and T-cell dysfunction. These findings illustrate the importance of the contribution of the immune landscape to T-cell redirection therapy response. This trial was registered at www.ClinicalTrials.gov, NCT03145181/NCT04557098.

Teclistamab Improves Patient-Reported Symptoms and Health-Related Quality of Life in Relapsed or Refractory Multiple Myeloma: Results From the Phase II MajesTEC-1 Study.

INTRODUCTION: Patients with relapsed or refractory multiple myeloma (RRMM) report significantly lower HRQoL compared with patients with newly diagnosed MM and experience further deterioration in HRQoL with each relapse and subsequent treatment. Therefore, consideration of the impact of treatment on HRQoL in addition to clinical outcomes is vital. PATIENTS AND METHODS: In the phase I/II MajesTEC-1 (NCT03145181, NCT04557098) study, patients with RRMM who received teclistamab, an off-the-shelf, T-cell redirecting BCMA × CD3 bispecific antibody, had deep and durable responses with manageable safety. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire core 30-item and the EuroQol 5 Dimension 5 Level descriptive questionnaire. Changes over time from baseline were measured with a repeated measures mixed-effects model. Proportions of patients with clinically meaningful improvement after starting treatment and time to clinically meaningful worsening were assessed. RESULTS: Compliance was maintained throughout the study. Compared with baseline, positive changes were observed for pain, global health status, and emotional functioning with treatment; other assessments were largely unchanged from baseline. Post hoc analysis showed patients with deeper clinical response generally reported improved HRQoL outcomes. Following an initial decline in HRQoL in some scales, the proportion of patients reporting clinically meaningful improvements increased, while the proportion reporting clinically meaningful worsening decreased over time. Clinically meaningful improvements in pain were reported in ≥40% of patients at most assessment time points. CONCLUSIONS: These results complement previously reported clinical benefits and support teclistamab as a promising therapeutic option for patients with RRMM.

Population Pharmacokinetics and Exposure-Response with Teclistamab in Patients With Relapsed/Refractory Multiple Myeloma: Results From MajesTEC-1.

BACKGROUND: Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, is approved in patients with relapsed/refractory multiple myeloma (RRMM) who have previously received an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody. OBJECTIVE: We report the population pharmacokinetics of teclistamab administered intravenously and subcutaneously (SC) and exposure-response relationships from the phase I/II, first-in-human, open-label, multicenter MajesTEC-1 study. METHODS: Phase I of MajesTEC-1 consisted of dose escalation and expansion at the recommended phase II dose (RP2D; 1.5 mg/kg SC weekly, preceded by step-up doses of 0.06 and 0.3 mg/kg); phase II investigated the efficacy of teclistamab RP2D in patients with RRMM. Population pharmacokinetics and the impact of covariates on teclistamab systemic exposure were assessed using a 2-compartment model with first-order absorption for SC and parallel time-independent and time-dependent elimination pathways. Exposure-response analyses were conducted, including overall response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and the incidence of grade ≥ 3 anemia, neutropenia, lymphopenia, leukopenia, thrombocytopenia, and infection. RESULTS: In total, 4840 measurable serum concentration samples from 338 pharmacokinetics-evaluable patients who received teclistamab were analyzed. The typical population value of time-independent and time-dependent clearance were 0.449 L/day and 0.547 L/day, respectively. The time-dependent clearance decreased rapidly to < 10% after 8 weeks of teclistamab treatment. Patients who discontinue teclistamab after the 13th dose are expected to have a 50% reduction from Cmax in teclistamab concentration at a median (5th to 95th percentile) time of 15 days (7-33 days) after Tmax and a 97% reduction from Cmax in teclistamab concentration at a median time of 69 days (32-163 days) after Tmax. Body weight, multiple myeloma type (immunoglobulin G vs non-immunoglobulin G), and International Staging System (ISS) stage (II vs I and III vs I) were statistically significant covariates on teclistamab pharmacokinetics; however, these covariates had no clinically relevant effect on the efficacy of teclistamab at the RP2D. Across all doses, ORR approached a plateau at the concentration range associated with RP2D, and in patients who received the RP2D, a flat exposure-response curve was observed. No apparent relationship was observed between DoR, PFS, OS, and the incidence of grade ≥3 adverse events across the predicted exposure quartiles. CONCLUSION: Body weight, myeloma type, and ISS stage impacted systemic teclistamab exposure without any clinically relevant effect on efficacy. The exposure-response analyses for ORR showed a positive trend with increasing teclistamab systemic exposure, with a plateau at the RP2D, and there was no apparent exposure-response trend for safety or other efficacy endpoints. These analyses support the RP2D of teclistamab in patients with RRMM. CLINICAL TRIAL REGISTRATION: NCT03145181 (phase I, 09 May 2017); NCT04557098 (phase II, 21 September 2020).

Plain language summary of the MajesTEC-1 study of teclistamab for the treatment of people with relapsed or refractory multiple myeloma.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of a phase 1-2 clinical trial called MajesTEC-1. This trial tested the cancer drug teclistamab in people with relapsed or refractory multiple myeloma, a cancer that forms in a certain type of white blood cells known as plasma cells. Most participants who took part in the study had at least 3 prior treatments for multiple myeloma before their cancer came back. HOW WAS THE STUDY IN THIS SUMMARY CONDUCTED?: A total of 165 participants from 9 countries were included in this study. All participants were given teclistamab once per week and monitored for side effects. Once participants started taking teclistamab, they were checked regularly to monitor if their cancer had no change, improved (responded to treatment), or worsened or spread (known as disease progression). WHAT WERE THE RESULTS OF THE STUDY?: After approximately 14.1 months of follow-up (from 2020 to 2021), 63% of participants who were given teclistamab had a decrease in myeloma burden, meaning that they responded to treatment with teclistamab. Participants who responded to teclistamab lived without their myeloma coming back for approximately 18.4 months. The most common side effects were infections, cytokine release syndrome, abnormally low white and red blood cell counts (neutropenia, lymphopenia, and anemia), and low platelet cell counts (thrombocytopenia). Approximately 65% of participants experienced serious side effects. WHAT DO THE RESULTS OF THIS STUDY MEAN?: Overall, more than half of the participants (63%) in the MajesTEC-1 study responded to treatment with teclistamab despite previous myeloma treatment failures. Clinical Trial Registration: NCT03145181, NCT04557098 (ClinicalTrials.gov).

Detailed overview of incidence and management of cytokine release syndrome observed with teclistamab in the MajesTEC-1 study of patients with relapsed/refractory multiple myeloma.

BACKGROUND: Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, demonstrated an overall response rate of 63.0% in 165 heavily pretreated patients with relapsed or refractory multiple myeloma in the phase 1/2 MajesTEC-1 study. Cytokine release syndrome (CRS), a known manifestation of T-cell redirection, was observed in 119 of 165 patients (72.1%). METHODS: Patients received once-weekly teclistamab 1.5 mg/kg subcutaneously after two step-up doses (0.06 and 0.3 mg/kg). CRS was graded according to American Society for Transplantation and Cellular Therapy criteria and managed according to the study protocol, including use of tocilizumab and/or steroids. RESULTS: Most cases of CRS occurred during the step-up dosing schedule of teclistamab and were grade 1 (50.3% of patients) or grade 2 (21.2% of patients); a single case of grade 3 CRS was reported in a patient with concurrent grade 3 pneumonia. All CRS cases resolved and none led to treatment discontinuation. Overall, 33.3% of patients had >1 CRS event; CRS recurrence was reduced when tocilizumab was administered for the first CRS event compared with when it was not (20.0% vs. 62.2%, respectively). Baseline characteristics such as tumor burden and cytokine levels did not appear to predict CRS incidence or severity. CONCLUSIONS: Findings of this study support the need for preemptive planning and prompt management of CRS in patients treated with T-cell-engaging bispecific antibodies. Intervention with tocilizumab for CRS appears to decrease the likelihood of patients experiencing subsequent CRS events without compromising response to teclistamab. PLAIN LANGUAGE SUMMARY: Cytokine release syndrome (CRS), observed in 72.1% of patients treated with teclistamab in the MajesTEC-1 study, was mostly grade 1 or 2 and manageable, without requiring treatment discontinuation. Most CRS occurred during the step-up schedule, requiring vigilance during treatment initiation. Ensure fever is resolved and patients have no signs of infection before initiating the teclistamab step-up schedule or administering the next teclistamab dose, to avoid exacerbating CRS. Tocilizumab reduced the risk of subsequent CRS in patients receiving it for their first CRS event (20.0% vs. 62.2% in those not receiving it), without affecting response to teclistamab. No baseline characteristics, including tumor burden or cytokine levels, appeared to clearly predict for CRS occurrence or severity.

Teclistamab in Relapsed or Refractory Multiple Myeloma.

BACKGROUND: Teclistamab is a T-cell-redirecting bispecific antibody that targets both CD3 expressed on the surface of T cells and B-cell maturation antigen expressed on the surface of myeloma cells. In the phase 1 dose-defining portion of the study, teclistamab showed promising efficacy in patients with relapsed or refractory multiple myeloma. METHODS: In this phase 1-2 study, we enrolled patients who had relapsed or refractory myeloma after at least three therapy lines, including triple-class exposure to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. Patients received a weekly subcutaneous injection of teclistamab (at a dose of 1.5 mg per kilogram of body weight) after receiving step-up doses of 0.06 mg and 0.3 mg per kilogram. The primary end point was the overall response (partial response or better). RESULTS: Among 165 patients who received teclistamab, 77.6% had triple-class refractory disease (median, five previous therapy lines). With a median follow-up of 14.1 months, the overall response rate was 63.0%, with 65 patients (39.4%) having a complete response or better. A total of 44 patients (26.7%) were found to have no minimal residual disease (MRD); the MRD-negativity rate among the patients with a complete response or better was 46%. The median duration of response was 18.4 months (95% confidence interval [CI], 14.9 to not estimable). The median duration of progression-free survival was 11.3 months (95% CI, 8.8 to 17.1). Common adverse events included cytokine release syndrome (in 72.1% of the patients; grade 3, 0.6%; no grade 4), neutropenia (in 70.9%; grade 3 or 4, 64.2%), anemia (in 52.1%; grade 3 or 4, 37.0%), and thrombocytopenia (in 40.0%; grade 3 or 4, 21.2%). Infections were frequent (in 76.4%; grade 3 or 4, 44.8%). Neurotoxic events occurred in 24 patients (14.5%), including immune effector cell-associated neurotoxicity syndrome in 5 patients (3.0%; all grade 1 or 2). CONCLUSIONS: Teclistamab resulted in a high rate of deep and durable response in patients with triple-class-exposed relapsed or refractory multiple myeloma. Cytopenias and infections were common; toxic effects that were consistent with T-cell redirection were mostly grade 1 or 2. (Funded by Janssen Research and Development; MajesTEC-1 ClinicalTrials.gov numbers, NCT03145181 and NCT04557098.).