Plain language summary of the MonumenTAL-1 study of talquetamab in people with relapsed or refractory multiple myeloma.

WHAT IS THIS SUMMARY ABOUT?: This plain language summary describes the results of a phase 1 research study (or clinical trial) called MonumenTAL-1 published in the New England Journal of Medicine in December 2022. A phase 1 study is an early clinical trial where researchers evaluate how safe a medicine is at different doses in a small number of people. In the MonumenTAL-1 study, researchers looked at a new medicine under development called talquetamab, for people living with multiple myeloma (a type of blood cancer) who did not respond (refractory), stopped responding (relapsed), or who had difficulty dealing with their previous treatments. HOW WAS THE STUDY CONDUCTED?: The phase 1 MonumenTAL-1 study was performed in 2 parts. Safety was the main focus of Part 1 in which side effects, and how serious they were, were assessed. The results of Part 1 were used to identify doses of talquetamab that were well tolerated, without a need to stop treatment or reduce the doses, for further study in Part 2. Part 2 of the study examined how well talquetamab worked to decrease signs of the cancer and what side effects, and their severity, people experienced at the doses identified in Part 1. WHAT WERE THE RESULTS?: In Part 1 of the study, researchers identified 2 doses of talquetamab for further study: 405 micrograms for every kilogram of body weight (µg/kg) given weekly and 800 µg/kg every other week. All participants experienced at least one side effect of treatment at these 2 doses. Less than half of participants (43% at 405 µg/kg weekly dose and 34% at the 800 µg/kg every other week dose) experienced serious side effects which are those side effects that led to hospitalization, death, or permanent or life-threatening damage). The most common side effects at both doses were a condition known as cytokine release syndrome (CRS); changes in blood cell levels (where different types of cells in the blood were measured); changes in skin such as itching, dry skin, eczema, ulcers or shedding; changes in nails such as discoloration or ridging (lines or dents); and changes in sense of taste such as food tasting sour or metallic. CRS is caused by the overactivation of the immune system (the body's natural defense system) and can result in fever, feeling sick (nausea), being tired (fatigue), low blood pressure, low blood oxygen levels and body aches. Most cases of CRS, as well as most other side effects, were mild or moderate. Most common serious events were CRS, fever and bone pain. Most people had fewer signs of the cancer after taking talquetamab, and the response was similar between the 2 doses. The median duration of response at the 2 identified doses was 8-10 months. WHAT DO THE RESULTS MEAN?: Most of the side effects people experienced when taking talquetamab were mild or moderate. Most people who took talquetamab responded to the treatment even though they hadn't responded or stopped responding to previous multiple myeloma treatments or stopped taking those treatments because they were unable to tolerate them. These results demonstrate the potential of talquetamab as a treatment option in people who have used up other available therapy options. The 2 doses of talquetamab identified here are being examined in a larger group of participants to further test for safety and to test how well people respond.

Talquetamab, a T-Cell-Redirecting GPRC5D Bispecific Antibody for Multiple Myeloma.

BACKGROUND: G protein-coupled receptor, family C, group 5, member D (GPRC5D) is an orphan receptor expressed in malignant plasma cells. Talquetamab, a bispecific antibody against CD3 and GPRC5D, redirects T cells to mediate killing of GPRC5D-expressing myeloma cells. METHODS: In a phase 1 study, we evaluated talquetamab administered intravenously weekly or every other week (in doses from 0.5 to 180 µg per kilogram of body weight) or subcutaneously weekly, every other week, or monthly (5 to 1600 µg per kilogram) in patients who had heavily pretreated relapsed or refractory multiple myeloma that had progressed with established therapies (a median of six previous lines of therapy) or who could not receive these therapies without unacceptable side effects. The primary end points - the frequency and type of dose-limiting toxic effects (study part 1 only), adverse events, and laboratory abnormalities - were assessed in order to select the recommended doses for a phase 2 study. RESULTS: At the data-cutoff date, 232 patients had received talquetamab (102 intravenously and 130 subcutaneously). At the two subcutaneous doses recommended for a phase 2 study (405 µg per kilogram weekly [30 patients] and 800 µg per kilogram every other week [44 patients]), common adverse events were cytokine release syndrome (in 77% and 80% of the patients, respectively), skin-related events (in 67% and 70%), and dysgeusia (in 63% and 57%); all but one cytokine release syndrome event were of grade 1 or 2. One dose-limiting toxic effect of grade 3 rash was reported in a patient who had received talquetamab at the 800-µg dose level. At median follow-ups of 11.7 months (in patients who had received talquetamab at the 405-µg dose level) and 4.2 months (in those who had received it at the 800-µg dose level), the percentages of patients with a response were 70% (95% confidence interval [CI], 51 to 85) and 64% (95% CI, 48 to 78), respectively. The median duration of response was 10.2 months and 7.8 months, respectively. CONCLUSIONS: Cytokine release syndrome, skin-related events, and dysgeusia were common with talquetamab treatment but were primarily low-grade. Talquetamab induced a substantial response among patients with heavily pretreated relapsed or refractory multiple myeloma. (Funded by Janssen Research and Development; MonumenTAL-1 ClinicalTrials.gov number, NCT03399799.).

Translational Modeling Predicts Efficacious Therapeutic Dosing Range of Teclistamab for Multiple Myeloma.

BACKGROUND: Teclistamab (JNJ-64007957), a B-cell maturation antigen × CD3 bispecific antibody, displayed potent T-cell-mediated cytotoxicity of multiple myeloma cells in preclinical studies. OBJECTIVE: A first-in-human, Phase I, dose escalation study (MajesTEC-1) is evaluating teclistamab in patients with relapsed/refractory multiple myeloma. PATIENTS AND METHODS: To estimate the efficacious therapeutic dosing range of teclistamab, pharmacokinetic (PK) data following the first cycle doses in the low-dose cohorts in the Phase I study were modeled using a 2-compartment model and simulated to predict the doses that would have average and trough serum teclistamab concentrations in the expected therapeutic range (between EC50 and EC90 values from an ex vivo cytotoxicity assay). RESULTS: The doses predicted to have average serum concentrations between the EC50 and EC90 range were validated. In addition, simulations showed that weekly intravenous and subcutaneous doses of 0.70 mg/kg and 0.72 mg/kg, respectively, resulted in mean trough levels comparable to the maximum EC90. The most active doses in the Phase I study were weekly intravenous doses of 0.27 and 0.72 mg/kg and weekly subcutaneous doses of 0.72 and 1.5 mg/kg, with the weekly 1.5 mg/kg subcutaneous doses selected as the recommended Phase II dose (RP2D). With active doses, exposure was maintained above the mean EC90. All patients who responded to the RP2D of teclistamab had exposure above the maximum EC90 in both serum and bone marrow on cycle 3, Day 1 of treatment. CONCLUSIONS: Our findings show that PK simulations of early clinical data together with ex vivo cytotoxicity estimates can inform the identification of a bispecific antibody's therapeutic range. CLINICAL TRIAL REGISTRATION: NCT03145181, date of registration: May 9, 2017.

A Phase 1 and 2 study of Filanesib alone and in combination with low-dose dexamethasone in relapsed/refractory multiple myeloma.

BACKGROUND: Filanesib (ARRY-520) is a highly selective inhibitor of kinesin spindle protein, which has demonstrated preclinical antimyeloma activity. METHODS: This open-label Phase 1/2 study determined the maximum tolerated dose of Filanesib administered on Days 1 and 2 of 14-Day Cycles in patients with multiple myeloma (MM) and included expansion cohorts with and without dexamethasone (40 mg/week). Patients in the dose-escalation (N = 31) and Phase 2 single-agent (N = 32) cohorts had received prior bortezomib as well as prior thalidomide and/or lenalidomide. Patients in the Phase 2 Filanesib plus dexamethasone cohort (N = 55) had received prior alkylator therapy and had disease refractory to lenalidomide, bortezomib, and dexamethasone. Prophylactic filgrastim was incorporated during dose escalation and was used throughout Phase 2. RESULTS: Patients in each cohort had received a median of ≥6 prior therapies. The most common dose-limiting toxicities were febrile neutropenia and mucosal inflammation. In Phase 2, Grade 3 and 4 cytopenias were reported in approximately 50% of patients. Nonhematologic toxicities were infrequent. Phase 2 response rates (partial responses or better) were 16% (single agent) and 15% (Filanesib plus dexamethasone). All responding patients had low baseline levels of α1-acid glycoprotein, a potential selective biomarker. CONCLUSIONS: Filanesib 1.50 mg/m2 /day administered with prophylactic filgrastim has a manageable safety profile and encouraging activity in heavily pretreated patients This study is registered at www.clinicaltrials.gov as NCT00821249. Cancer 2017;123:4617-4630. © 2017 American Cancer Society.

A phase 1 dose-escalation study of filanesib plus bortezomib and dexamethasone in patients with recurrent/refractory multiple myeloma.

BACKGROUND: Filanesib is a kinesin spindle protein inhibitor that has demonstrated encouraging activity in patients with recurrent/refractory multiple myeloma. Preclinical synergy with bortezomib was the rationale for the current phase 1 study. METHODS: The current study was a multicenter study with an initial dose-escalation phase to determine the maximum tolerated dose of 2 schedules of filanesib plus bortezomib with and without dexamethasone, followed by a dose-expansion phase. RESULTS: With the addition of prophylactic filgastrim, the maximum planned dose was attained: 1.3 mg/m2 /day of bortezomib plus 40 mg of dexamethasone on days 1, 8, and 15 of a 28-day cycle, with filanesib given intravenously either at a dose of 1.5 mg/m2 /day (schedule 1: days 1, 2, 15, and 16) or 3 mg/m2 /day (schedule 2: days 1 and 15). The most common adverse events (assessed for severity using version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events) were transient, noncumulative neutropenia and thrombocytopenia with grade 3/4 events reported in 44% (16% in cycle 1 with filgastrim) and 29% of patients, respectively. A low (≤11%) overall rate of nonhematological grade 3/4 toxicity was observed. With a median of 3 prior lines of therapy and 56% of patients with disease that was refractory to proteasome inhibitors, the overall response rate was 20% (55 patients), and was 29% in 14 patients with proteasome inhibitors-refractory disease receiving filanesib at a dose of ≥1.25 mg/m2 (duration of response, 5.2 to ≥21.2 months). CONCLUSIONS: The current phase 1 study established a dosing schedule for the combination of these agents that demonstrated a favorable safety profile with a low incidence of nonhematologic toxicity and manageable hematologic toxicity. The combination of filanesib, bortezomib, and dexamethasone appears to have durable activity in patients with recurrent/refractory multiple myeloma. Cancer 2016;122:3327-3335. © 2016 American Cancer Society.