Talquetamab Shows High Response Rates in BCMA-Pretreated RRMM

Jonathan L. Kaufman, MD

David Bankes Glass Multiple Myeloma Professorship

Professor, Department of Hematology and Medical Oncology

Emory University School of Medicine

Medical Director and Section Chief, Ambulatory Infusion Centers

Winship Cancer Institute of Emory University

Atlanta, GA

Targeted Oncology: Please describe the significance of the MonumenTAL-1 study (NCT03399799/NCT04634552) of talquetamab (Talvey) for patients with relapsed/refractory multiple myeloma (RRMM).

JONATHAN L. KAUFMAN, MD: This was the accelerated approval branch, which means it's based on efficacy compared with toxicity, not a phase 3 study against standard of care. There was a phase 1 study, then a phase 2 study in patients with [at least] 3 prior lines of therapy with ECOG performance status [PS] of 0, 1, or 2, so [the eligibility] was looser than what we saw with CAR [chimeric antigen receptor] T cells since it did include those with PS of 2. [The arms consisted of] subcutaneous weekly dosing, every-other-week dosing, and then a third cohort treated with prior T cell therapies. Prior anti-BCMA [B-cell maturation antigen] therapy…was allowed in this third cohort; they could have had prior CAR T cell or bispecific antibody as well.

Is it becoming typical for multiple myeloma therapies to be introduced without phase 3 data?

They’ve done that, but we have 2 drugs off the top of my head that were taken away for lack of a phase 3 study. Melflufen flufenamide [Pepaxto] was taken away for [excess deaths in] a phase 3 study,¹ and belantamab mafodotin [Blenrep] was taken away for lack of a positive phase 3 study,² whereas all these other drugs historically, going back to bortezomib [Velcade] followed up with a positive phase 3 randomized study.

What were the patient characteristics in the MonumenTAL-1 study?

About one quarter of the patients had had extramedullary disease.³ One quarter to one third of the patients had high-risk cytogenetics. Everybody was triple-class exposed, [approximately 70%] were penta-drug exposed, and 70% to 80% were triple-class refractory. One quarter to 40% of patients [were] penta-drug refractory. Almost all patients were refractory to the last line of therapy, except in the third cohort, which had [some] patients who weren't refractory to CAR T-cell therapy because the refractory definition says a patient has to progress within 30 days.

What efficacy was seen in this trial patients with RRMM?

What we [saw] in the patients who were not exposed to prior BCMA-targeted therapy, with a median of 5 prior lines of therapy was an overall response rate [ORR] of 74%.^3,4 Here you have median progression-free survival [PFS] of 7.5 months and 14.2 months, [respectively, for the weekly and every-other-week dose groups]. The duration of response was 9 months and not reached [in these respective cohorts]. The [BCMA-pretreated cohort]…was a sicker group of patients, with [a median of] 6 prior lines of therapy, and more patients [84%] had triple-class refractory disease. The ORR was a little bit lower in the prior CAR T cell [patients] at 75% vs prior bispecific at 44%. The issue is that the PFS was lower [5.1 months], but the duration of response was maintained [11.3 months]. If you can get that response, the duration of response looks pretty good.

What toxicities were observed in the MonumenTAL-1 trial?

The cytokine release syndrome [CRS] rate was still high overall [79%, 75%, and 77% across the weekly, every-other-week, and BCMA cohorts, respectively], but the serious CRS rate was low [2%, 0.7%, and 2.0%, respectively].^3,4 Infections were not low [59%, 66%, and 73%, respectively] but a were little bit lower [than other cell therapy trials]. Immune effector cell–associated neurotoxicity syndrome [ICANS] was uncommon and rarely serious.

There is a group of toxicities we see with talquetamab that we don't see with [other] bispecifics that leads to asking the question, can somebody with a ECOG performance status of 2 who can't get around [tolerate] this drug? These include dysgeusia, the terrible taste in the mouth [where] everything tastes bad or metallic or salty, [in approximately] 70%. There was some skin toxicity in between 50% and 70% of patients, [but] rarely is it serious. Nail dystrophia and nail toxicities [occurred] in more than half the patients, [roughly] 50% to 60%. Dose reductions happened [in 14.7%, 8.3%, and 9.8% of the 3 respective cohorts]; discontinuations happened in [4.9%, 8.3%, and 7.8% of the respective cohorts]. It's generally rare that they're discontinued for these toxicities, but dose delays are common.

For right now, all of the first dosing is done at your academic centers, but I know that our center…I am working very hard to figure out how your patients don't need to come to my site to start these drugs. I think in a year, we're going to have protocols where [community oncology practices] are going to be able to do this safely in your community, in your office.

With that said, your system is going to have to know to manage and recognize CRS, and how to manage and recognize ICANS. Hematologic toxicity is common. We use growth factor support when the patient’s neutrophils are low. For this on-target, off-tumor toxicities [like] the hypogammaglobulinemia, we can use IVIG [intravenous immunoglobulin] when the immunoglobulins go below 400 mg/dL. There is topical medications for the skin changes. Dose interruptions [may be needed] for severe adverse events, and systemic steroids [can be used] in the setting of rash. From an infection standpoint, IVIG is critical, granulocyte colony–stimulating factor is critical. [You can also give] varicella and herpes simplex virus prophylaxis and pneumocystis Jirovecii pneumonia prophylaxis with [trimethoprim/sulfamethoxazole; Bactrim] or pentamidine…whatever you're able to give.

_References:

_{1. Oncopeptides provides update on Pepaxto US marketing authorization. News release. Oncopeptides AB. December 7, 2022. Accessed November 29, 2023. https://cisn.co/3iywZgL}

_{2. GSK provides an update on Blenrep (belantamab mafodotin-blmf) US marketing authorization. News release. GlaxoSmithKline. November 22, 2022. Accessed November 29, 2023. http://bit.ly/3gniPi1}

_{3. Touzeau C, Schinke C, Minnema M, et al. PIVOTAL phase 2 MonumenTAL-1 results of talquetamab (TAL), a GPRC5DXCD3 bispecific antibody (BsAb), for relapsed/refractory multiple myeloma (RRMM). HemaSphere. 2023;7(S3):e5955094. doi:10.1097/01.HS9.0000967676.59550.94}

_{4. Chari A, Touzeau C, Schinke C, et al. 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. Blood. 2022;140(suppl_1):384-387. doi:10.1182/blood-2022-159707}