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

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

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

peer reviewedWHAT 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

GPRC5D as a novel target for the treatment of multiple myeloma: a narrative review

Abstract Multiple myeloma is a genetically complex and heterogenous malignancy with a 5-year survival rate of approximately 60%. Despite advances in therapy, patients experience cycles of remission and relapse, with each successive line of therapy associated with poorer outcomes; therefore, therapies with different mechanisms of action against new myeloma antigens are needed. G protein–coupled receptor class C group 5 member D (GPRC5D) has emerged as a novel therapeutic target for the treatment of multiple myeloma. We review the biology and target validation of GPRC5D, and clinical data from early phase trials of GPRC5D-targeting bispecific antibodies, talquetamab and forimtamig, and chimeric antigen receptor T cell (CAR-T) therapies, MCARH109, OriCAR-017, and BMS-986393. In addition to adverse events (AEs) associated with T-cell–redirection therapies irrespective of target, a consistent pattern of dermatologic and oral AEs has been reported across several trials of GPRC5D-targeting bispecific antibodies, as well as rare cerebellar events with CAR-T therapy. Additional studies are needed to understand the underlying mechanisms involved in the development of skin- and oral-related toxicities. We review the strategies that have been used to manage these GPRC5D-related toxicities. Preliminary efficacy data showed overall response rates for GPRC5D-targeting T-cell–redirecting therapies were ≥64%; most responders achieved a very good partial response or better. Pharmacokinetics/pharmacodynamics showed that these therapies led to cytokine release and T-cell activation. In conclusion, results from early phase trials of GPRC5D-targeting T-cell–redirecting agents have shown promising efficacy and manageable safety profiles, including lower infection rates compared with B-cell maturation antigen- and Fc receptor-like protein 5-targeting bispecific antibodies. Further clinical trials, including those investigating GPRC5D-targeting T-cell–redirecting agents in combination with other anti-myeloma therapies and with different treatment modalities, may help to elucidate the future optimal treatment regimen and sequence for patients with multiple myeloma and improve survival outcomes. Video Summar

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.)