January 10, 2023
Fast Durable Responses to Bi-Specific Antibody Therapy In Heavily Pre-Treated Multiple Myeloma
Ajai Chari MD, Associate Professor of Medicine and Director of Clinical Research in the Multiple Myeloma Program at Mount Sinai School of Medicine in New York, USA.
NEW ORLEANS, USA—The bispecific antibody talquetamab, classed as a “T-cell redirecting therapy” achieved high response rates in the phase one/two multi-national MonumenTAL-1 study investigating 288 patients who had heavily pre-treated refractory multiple myeloma.
Findings reported at the American Society of Hematology 2022 Annual Meeting showed that nearly three-quarters of patients treated had “complete” or “very good partial” responses within one or two months, and median response durations of around nine months.https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.16_suppl.8015
“Remarkably in this unmet need we saw response rates of 73 to 74 per cent. The responses were maintained in triple-class refractory patients, penta-drug refractory patients, ISS (International Staging System) three high-risk disease,” said Ajai Chari MD, Associate Professor of Medicine and Director of Clinical Research in the Multiple Myeloma Program at Mount Sinai School of Medicine in New York, USA.
“The median time to response was one month—which is outstanding. And the median time to “best response” was slightly over two months—which is great, because it means that these patients who had explosive disease (these are not CAR-T cherry-picked patients with really indolent progression) were benefiting in high percentages—and quickly, and deeply,” Chari told the Audio Journal of Oncology.
Although patients with extra-medullary disease had fared slightly less well, their responses had still been good, he said. “Even there, there was an impressive 50 per cent response rate.”
Talquetamab was an off-the-shelf bispecific antibody, that binds to both T cells and multiple myeloma cells, said Chari. This facilitates an immune response to destroy myeloma cells by bringing T cells to the cancer. Its twin targets were the CD3 T-cell receptors and the cancer cell surface receptor known as G protein-coupled receptor family C group 5 member D (GPRC5D).
“[Previously] we only had naked antibodies. And a bispecific antibody is different. Like with all antibodies it has the Y-shaped structure, but unlike typical antibodies it binds two different targets. One target is the T cell—with CD3; and the other target is GPRC5D, which is a novel target in myeloma. It’s over-expressed particularly on malignant plasma cells, less so on normal plasma cells, and—importantly—not on the hematopoietic stem cell compartment—Which we think is a favorable finding,” said Chari.
“You basically can engage the patient’s own T-cells to try to attack the myeloma. And it’s a little surprising how remarkable this whole approach has been: Because patients with myeloma who are entering these studies have typically five to six lines of therapy over six years, are usually in their late sixties [or] early seventies, and you wouldn’t think that their T-cells would even be robust, and fit, and present, enough to generate results—let alone the outstanding results we’re seeing,” he said.
In the MonumenTAL-1 study, patients with relapsed/refractory multiple myeloma, were treated with either of two recommended dosing regimens: 0.40 mg/kg of talquetamab subcutaneously at weekly intervals, or 0.80 mg/kg every other week.
Patients in the weekly and bi-weekly dose regimens (equivalent in overall dose intensity) had similar outcomes in terms of response rates and toxicities. Nearly a third of patients had complete responses. More than half had “very good” partial responses. The responses deepened with time, and continued to a median of nine months duration. Median progression-free survival was 7.5 months.
The median time to a measurable response was approximately 1.2 months with either dosing regimen, and the median duration of response was 9.3 months in the patients treated with the weekly dosing.
“This means that three-quarters of these patients are looking at a new lease on life,” said Chari. “We’re hoping that this will soon become available so that patients can benefit.”
Side effects were relatively frequent, but mild in most patients. About three-quarters experienced cytokine release syndrome (immune activation—typically causing a fever). More than half of the study cohort had skin-related side effects such as rash. About a half reported dysgeusia (taste changes), and a similar proportion of study subjects had nail disorders. Only one in twenty patients discontinued talquetamab treatment early due to side effects.
Since response rates observed in the early-phase MonumenTAL-1 study had been, higher than with most currently accessible therapies, Chari suggested talquetamab could potentially be proven to be a viable option for patients with refractory multiple myeloma and offer the possibility of extending life.
Chari told the Audio Journal of Oncology he regarded bispecific antibodies as an alternative T-cell redirection strategy comparable to chimeric antigen receptor therapy (CAR-T)—that had achieved notable successes in hematologic malignancy in certain academic centers of excellence recently. But bi-specific antibodies could potentially be more universally available, because off-the-shelf agents could more easily be distributed to a wider range of patients—without the need to individualize the therapeutic agent in each case. “There’s every reason to hope that these could be brought to the community oncologist near you so you don’t have to keep going to these academic centers,” he said.
157 Talquetamab, a G Protein-Coupled Receptor Family C Group 5 Member D x CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM): Phase 1/2 Results from MonumenTAL-1Clinically Relevant Abstract
Program: Oral and Poster Abstracts
Session: 653. Myeloma and Plasma Cell Dyscrasias: Prospective Therapeutic Trials: Bispecific Monoclonal Antibodies in Myeloma
Hematology Disease Topics & Pathways:
Biological therapies, Research, Clinical Research, Plasma Cell Disorders, Diseases, Therapies, Lymphoid Malignancies
Saturday, December 10, 2022: 12:00 PM
Ajai Chari1*, Cyrille Touzeau2*, Carolina Schinke3, Monique C. Minnema, MD, PhD4, Jesus Berdeja, MD5, Albert Oriol6*, Niels WCJ Van De Donk, MD7, Paula Rodriguez Otero8*, Elham Askari9*, Maria-Victoria Mateos, MD10, Luciano J. Megala Costa, MD, PhD11, Jo Caers, PhD12, Leo Rasche, MD13*, Amrita Y. Krishnan, MD, FACP14, Deeksha Vishwamitra15*, Xuewen Ma15*, Xiang Qin15*, Katharine S. Gries, PhD, PharmD16*, Michela Campagna17*, Tara Masterson15*, Brandi Hilder15*, Jaszianne Tolbert15, Thomas Renaud18*, Jenna D. Goldberg18*, Christoph Heuck15*, Jesús San-Miguel, MD, PhD19 and Philippe Moreau, MD20*
1Mount Sinai School of Medicine, New York, NY
2Centre Hospitalier Universitaire de Nantes, Nantes, France
3Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR
4University Medical Center Utrecht, Utrecht, Netherlands
5Sarah Cannon Research Institute, Nashville, TN
6Hospital Germans Trias I Pujol, Barcelona, Spain
7Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
8University of Navarra, Pamplona, Spain
9Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain
10University Hospital of Salamanca/IBSAL/CIC, Salamanca, Spain
11University of Alabama at Birmingham, Birmingham, AL
12University of Liege, Liege, Belgium
13University Hospital of Würzburg, Würzburg, Germany
14City of Hope Comprehensive Cancer Center, Duarte, CA
15Janssen Research & Development, Spring House, PA
16Janssen Global Services, Raritan, NJ
17Janssen-Cilag, Madrid, Spain
18Janssen Research & Development, Raritan, NJ
19Universidad de Navarra, Pamplona, Spain
20University Hospital Hôtel-Dieu, Nantes, France
Introduction: G protein-coupled receptor family C group 5 member D (GPRC5D) has limited expression in normal human tissue but is highly expressed on malignant plasma cells, making it a promising immunotherapy target for patients (pts) with multiple myeloma (MM). Talquetamab is a first-in-class, off-the-shelf, T-cell redirecting bispecific antibody targeting both GPRC5D and CD3 receptors. MonumenTAL-1 is a phase 1/2 trial (NCT03399799/NCT04634552) of talquetamab in pts with RRMM. In phase 1 of MonumenTAL-1, collective safety, efficacy, pharmacokinetic (PK), and pharmacodynamic (PD) data supported selection of 2 recommended phase 2 doses (RP2Ds) for talquetamab: 0.405 mg/kg subcutaneous (SC) weekly (QW) and 0.8 mg/kg SC every other week (Q2W). Here, we report results for pts treated at these RP2Ds in phase 1 and 2 of MonumenTAL-1.
Methods: Eligible pts in phase 1 had measurable MM and had progressed on or were intolerant to standard therapies. Pts in phase 2 had received ≥3 prior lines of therapy (LOT), including ≥1 proteasome inhibitor, ≥1 immunomodulatory drug, and ≥1 anti-CD38 monoclonal antibody (ie, triple-class exposed). In phase 1, 0.405 mg/kg SC QW was a putative RP2D; this was modified to 0.4 mg/kg SC QW in phase 2 for convenience. Phase 1 and 2 data were combined for analysis. Step-up dosing was used to mitigate risk of severe cytokine release syndrome (CRS). Primary endpoint of phase 2 was overall response rate (ORR) per IMWG criteria based on independent committee review. Key secondary endpoints were duration of response (DOR), rate of very good partial response or better (≥VGPR), rate of complete response or better (≥CR), time to response, progression-free survival (PFS), and incidence of AEs. AEs were graded by CTCAE v4.03; CRS events were graded per ASTCT criteria. PD parameters were measured at baseline and through day 1 of cycle 2.
Results: As of May 16, 2022, 288 pts with no prior exposure to T-cell redirecting therapies had received talquetamab at the RP2Ds in phase 1 or 2. In 143 pts treated at 0.4 mg/kg QW (median time since diagnosis: 6.7 years), median age was 67 years (range 46–86), pts received a median of 5 prior LOT (range 2–13), 31.1% had high-risk cytogenetics, 23% had extramedullary disease, 19.6% had ISS stage 3 disease, 100%/74% were triple-class exposed/refractory, and 73%/29% were penta-drug exposed/refractory; median follow-up was 11.0 months (range 0.5+–26.1). Baseline characteristics were similar among 145 pts who received 0.8 mg/kg Q2W (median follow-up: 5.1 months [range 0.2+–17.9]).
In 143 pts treated at 0.4 mg/kg QW, ORR was 73% (≥VGPR: 58%; ≥CR: 29%). Responses were durable and deepened over time (Figure). Median time to response was 1.2 months (range 0.2–5.0). Median time to CR was 2.1 months (range 1.1–12.4). Median DOR was 9.3 months (95% CI, 6.6–20.2; range 1–23+). Median PFS was 7.5 months (95% CI, 5.7–9.2 [38% censored]). ORRs in pts who were triple-class refractory (72% [76/106]) and penta-drug refractory (71% [30/42]) were comparable to the overall population. Efficacy at 0.8 mg/kg Q2W will be presented at the meeting.
The most common AEs at 0.4 mg/kg QW/0.8 mg/kg Q2W were CRS (79%/72%; grade 3: 2%/1%; grade 4: 0%/0%), dysgeusia (48%/46%; grade 3/4: not applicable [NA]), and anemia (45%/39%; grade 3: 31%/25%; grade 4: 0%/0%]); skin-related AEs occurred in 56%/68% (grade 3: 0%/1%; grade 4: NA) and nail disorders in 52%/43% (grade 3: 0%/0%; grade 4: NA) of patients. Cytopenias, including neutropenia in 34%/28% (grade 3: 20%/17%; grade 4: 10%/6%) and thrombocytopenia in 27%/27% (grade 3: 10%/8%; grade 4: 10%/8%), were generally limited to the first few cycles. At 0.4 mg/kg QW/0.8 mg/kg Q2W, infections occurred in 57%/50% of pts (grade ≥3: 19%/13%); 4.9%/6.2% discontinued, 8.4%/13.8% had dose delays, and 14.7%/6.2% had dose reductions due to AEs. There were 2 deaths due to COVID-19 (1 patient at each RP2D).
Talquetamab exposure was comparable at the two RP2Ds. No clinically significant effect of anti-talquetamab antibodies on PK, efficacy, or AEs was observed.
PD changes were comparable at both RP2Ds and consistent with talquetamab activity, including T-cell activation, redistribution, and induction of cytokines.
Conclusions: Talquetamab demonstrated robust efficacy and manageable safety in pts with heavily pretreated RRMM. Additional phase 1 studies (NCT04586426; NCT04108195; NCT05050097) are evaluating talquetamab in combination with other agents in pts with RRMM.
ASH 2022 PRESS BRIEF:
Talquetamab Generates High Response Rate in Patients with Hard-to-treat Multiple Myeloma
157: Talquetamab, a G Protein-Coupled Receptor Family C Group 5 Member D x CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM): Phase 1/2 Results from MonumenTAL-1
In an early-phase trial, nearly three-quarters of patients who received talquetamab, a first-in-class experimental immunotherapy for multiple myeloma, saw a significant reduction in cancer burden within a few months. The study participants had all been previously treated with at least three different therapies without achieving lasting remission, suggesting talquetamab could offer new hope for patients with hard-to-treat multiple myeloma.
“This means that three-quarters of these patients are looking at a new lease on life,” said Ajai Chari, MD, of The Tisch Cancer Institute at Mount Sinai in New York. “We’re hoping that this will soon become available so that patients can benefit.”
Talquetamab binds to both T cells and multiple myeloma cells. This activates an immune response to destroy myeloma cells by bringing T cells to the cancer, a strategy that researchers described as “bringing your army to the enemy.” It also uses a different target than other approved therapies; in this case, the target is a receptor expressed on the surface of cancer cells known as GPRC5D.
Multiple myeloma is a blood cancer that forms in plasma cells. Several treatments are available, but the prognosis can be very poor and many patients survive less than a year if the disease doesn’t respond to therapy or returns after several different treatments.
The study enrolled a total of 288 patients who were unable to tolerate existing therapies or showed disease progression after at least three multiple myeloma therapies. After an initial phase generated encouraging results in terms of safety and efficacy, researchers began enrolling additional patients to assess the agent’s efficacy with two different dosing regimens—0.4 mg/kg weekly and 0.8 mg/kg every other week. Data from patients who had received these same dosing regimens in the first phase were included in the analysis for the second phase.
Seventy-four percent of those receiving 0.4 mg/kg of talquetamab weekly and 73% of those receiving 0.8 mg/kg every other week saw a measurable improvement of their cancer following treatment, the primary endpoint for the trial’s second phase. More than 30% of patients in both groups had a complete response (no detection of myeloma-specific markers) or better and nearly 60% had a “very good partial response” or better (indicating the cancer was substantially reduced but not necessarily down to zero). The median time to a measurable response was approximately 1.2 months in both dosing groups and the median duration of response is 9.3 months to date with weekly dosing. Researchers are continuing to collect data on the duration of response in the group receiving 0.8 mg/kg every other week and for patients in both dosing groups who had a complete response or better.
Side effects were relatively frequent, but typically mild. About three-quarters of patients experienced cytokine release syndrome (a sign of immune activation common with therapies that redirect T cells, typically causing a fever); 60% experienced skin-related side effects such as rash; about half reported taste changes; and about half reported nail disorders. Researchers said 5-6% of patients stopped talquetamab treatment early due to side effects.
The response rate observed in this cohort, which Dr. Chari explained is higher than that of most currently accessible therapies, suggests talquetamab could offer a viable option for patients with hard-to-treat myeloma, offering a chance to extend patient lifespans.
In a separate cohort, 51 patients who had previously received therapies that redirect T cells showed a response to talquetamab. In addition, several other studies are underway to assess the use of talquetamab in combination with other existing and investigational multiple myeloma therapies, which could allow patients to have similar or improved benefits, potentially in earlier stages of treatment.
This study was funded by Janssen Research & Development LLC.
Ajai Chari, The Tisch Cancer Institute at Mount Sinai, will present this study during an oral presentation on Saturday, December 10, 2022, at 12:00 noon in R02-R05.