FDA Grants Breakthrough Therapy Designation to Talquetamab for Relapsed/Refractory Myeloma

The FDA has granted a breakthrough therapy designation to talquetamab for use as a potential therapeutic option in patients with relapsed or refractory multiple myeloma who received at least 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody.

The FDA has granted a breakthrough therapy designation to talquetamab for use as a potential therapeutic option in patients with relapsed or refractory multiple myeloma who received at least 4 prior lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody.1

The designation is supported by findings from the first-in-human, dose-escalation, phase 1/2 MonumenTAL-1 trial (NCT03399799; NCT04634552), in which the bispecific antibody was found to produce robust efficacy in heavily pretreated patients when administered at recommended phase 2 doses (RP2Ds) of 405 µg/kg weekly and 800 µg/kg every 2 weeks.2

At a median follow-up of 13.2 months (range, 1.1-24.0), those who received the agent at the weekly dose of 405 µg/kg (n = 30) experienced an objective response rate (ORR) of 70.0%. In triple-class refractory patients (n = 23), the ORR achieved with talquetamab was 65.2%; this rate was 83.3% in those who were penta-drug refractory (n = 6).

In those who received talquetamab at a twice-weekly dose of 800 µg/kg (n = 44), talquetamab induced an ORR of 63.6% at a median follow-up of 7.7 months (range, 0.7-16.0). In the subsets of patients who were triple-class refractory (n = 34) and penta-drug refractory (n = 12), the ORRs experienced with the agent were 67.6% and 75.0%, respectively.

“This breakthrough therapy designation marks an important step in the continued development of talquetamab, a first-in-class bispecific antibody T-cell engager using GPRC5D, a novel target for the treatment of patients with relapsed or refractory multiple myeloma,” Sen Zhuang, MD, PhD, vice president of Clinical Research and Development at Janssen Research & Development, LLC, stated in a press release.

To participate on MonumenTAL-1, patients needed to have multiple myeloma that was relapsed, refractory, or intolerant to established therapies; they needed to have measurable disease. Previous receipt of BCMA-targeted therapy was allowed. The key objective of part 1 of the research was to identify the RP2D of talquetamab.

The phase 1 portion of the trial included 130 patients with relapsed or refractory multiple myeloma who received subcutaneous talquetamab spanning a range of doses. Here, the maximum tolerated dose had not been reached. The collective safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) data supported 2 RP2Ds of the agent.

The key objectives of part 2 of the research include safety and tolerability at the selected RP2Ds, antitumor activity, PK, and PD.

At the 2022 EHA Congress, investigators shared updated findings from the trial, which had longer follow-up for those who received talquetamab at both RP2Ds, including additional patients having received the 800-µg/kg dose.

The median age in the subset of patients who received the agent at 405 µg/kg was 61.5 years (range, 46-80), and those in the group who received the agent at 800 µg/kg had a median age of 64.0 years (range, 47-84); 63.3% and 47.7% of patients, respectively, were male. Across the groups, most patients were White (83.3% vs 79.5%), had International Staging System stage II disease (44.8% vs 41.9%), and previously underwent stem cell transplantation (90.0% vs 75.0%).

Moreover, in the 405-µg/kg and 800-µg/kg cohorts, respectively, 20.7% vs 12.2% had 60% or higher of bone marrow plasma cells, 36.7% vs 34.1% had 1 or more extramedullary plasmacytomas, 11.1% vs 22.5% had high-risk cytogenetics, and the prior lines of therapy received were 6 (range, 2-14) vs 5 (range, 2-17).

In the 405-µg/kg cohort, all patients were triple-class exposed, 80.0% were penta-drug exposed, and 30.0% previously received a BCMA-targeted therapy; 16.7% of patients received an antibody-drug conjugate (ADC) and 13.3% received a CAR T-cell therapy. Moreover, 83.3% of patients were refractory to a PI, 93.3% were refractory to an IMiD, and 100% were refractory to an anti-CD38 monoclonal antibody. Notably, 76.7% of patients were triple-class refractory, and 20.0% were penta-drug refractory.

In the 800-µg/kg cohort, 97.7% of patients were triple-class exposed, 68.2% were penta-drug exposed, and 27.3% had previously received a BCMA-targeted therapy, with 18.2% having received an ADC or bispecific antibody and 9.1% having received a CAR T-cell therapy. Moreover, 84.1%, 95.5%, and 95.5% of patients in this cohort were refractory to a PI, an IMiD, and an anti-CD28 monoclonal antibody, respectively. Notably, 77.3% of patients were triple-class refractory and 27.3% were penta-drug refractory.

Treatment at both dose levels was found to result in durable responses that deepened over time, even in patients who were highly refractory to prior therapies. The median duration of response in the 405-µg/kg cohort was 10.2 months (95% CI, 3.0–not estimable [NE]) and 13.0 months (95% CI, 5.3-NE) in the 800-µg/kg cohort.

Both doses were found to have comparable PK profiles, with antidrug antibodies detected in 17.6% of evaluable patients (n = 74); these were noted to be generally low titers and did not appear to affect safety, efficacy, or PK. Moreover, peripheral induction of PD-1–positive T cells was noted at both dose levels, and both levels were linked with consistent induction of several key cytokines.

Overall, the most common toxicities experienced with talquetamab at the 405-µg/kg and 800-µg/kg dose levels, respectively, were cytokine release syndrome (CRS; 76.7% vs 79.5%), skin-related adverse effects (AEs; 66.7% vs 72.7%), and dysgeusia (63.3% vs 56.8%). Dysgeusia was managed with supportive care measures, and sometimes with dose adjustments.

Regarding CRS, the median time to onset in the 405-µg/kg and 800-µg/kg cohorts, respectively, was 2 days (range, 1-22) and 2 days (range, 1-5); the median duration was 2 days (range, 1-3) and 2 days (range, 1-5). All CRS effects were grade 1 or 2, with the exception of 1 grade 3 event. These effects were largely confined to the step-up doses and the first full dose of the agent.

In the 405-µg/kg cohort, 76.7% of patients received supportive measures for their CRS event; 63.3% of patients received tocilizumab (Actemra), 3.3% were given steroids, 3.3% received oxygen, and 3.3% received single vasopressor. In the 800-µg/kg cohort, 79.5% of those with CRS received supportive measures, which included tocilizumab in 54.5% of patients, steroids in 6.8% of patients, and oxygen in 4.5% of patients.

Cytopenias were mostly confined to step-up and cycle 1 and 2 doses; these effects were generally found to resolve within 1 week. Notably, infections were reported in 46.7% of those who received talquetamab at a dose of 405 µg/kg vs in 38.6% of those who received the agent at 800 µg/kg; grade 3 or higher infections were experienced by 6.7% and 9.1% of patients, respectively.

Notably, no patients died because of treatment-related AEs.

“Despite the therapies available for patients with relapsed or refractory multiple myeloma, new targets and treatments are needed because of the heterogeneity of the disease, which can impact a patient’s response to treatment,” Zhuang added in the release. “We are resolute in our commitment to advance science and develop new therapies and regimens for patients with the goal of delivering the best possible outcomes while driving toward cures.”


  • Janssen announces US FDA breakthrough therapy designation granted for talquetamab for the treatment of relapsed or refractory multiple myeloma. News release. The Janssen Pharmaceutical Companies of Johnson & Johnson. June 29, 2022. Accessed June 29, 2022. https://bit.ly/3nnpKHQ
  • Minnema MC, Krishnan A, Berdeja JG, et al. Talquetamab, a G protein-coupled receptor family C group 5 member D X CD3 bispecific antibody, in relapsed/refractory multiple myeloma: updated efficacy and safety results from MonumenTAL-1. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract S182. https://bit.ly/3NDAZqo