Non-BCMA-Targeting Bispecifics in Multiple Myeloma: Talquetamab
Switching its focus to non-BCMA-targeting therapies, a panel of experts consider the clinical data behind talquetamab in patients diagnosed with multiple myeloma,
Transcript:
Amrita Krishnan, MD: As I mentioned, things are going to get even more complicated because probably this year we’re going to have a non–BCMA-targeting bispecific approved, talquetamab. Dr Garfall will fill us in on those data.
Alfred Garfall, MD: Thank you very much. It’s very exciting to have some new cell surface targets here in GPRC5D, and as we’ll hear later, FCRH5. Now that we know myeloma is so tractable to this T-cell redirection approach from the experience with anti-BCMA CAR [chimeric antigen receptor] T cells and bispecific antibodies, and loss of the BCMA target in some cases, it is really appealing to have tools in the toolkit that target other cell surface antigens. In the case of these agents we’re going to talk about, these are completely novel cell surface targets for cancer immunotherapy, so it’s exciting to see there are new safe targets. There’s always a question with the new cell surface antigen, what is the safety, what is the specificity when we’re talking about these very potent immunotherapies? It’s very gratifying to see a couple of new targets that are pretty far along in clinical development now, and not showing any major safety signals in terms of off-target toxicity that would prohibit their safe administration.
The MonumenTAL-1 study is a phase 1/2 study of talquetamab, which is a bispecific antibody directed against the GPRC5D target. Again, this is a completely new target in immunotherapy. This was similar to the MajesTEC-1 study, which throughout the study tested different dosing schemes but settled on recommended phase 2 doses. A couple of different recommended phase 2 doses: one a weekly subcutaneous administration and another a Q2 [every 2]-week subcutaneous administration. Importantly, patients were permitted on this study if they had previous therapies targeting BCMA, and in some cohorts, even prior therapies that entailed anti-BCMA T-cell redirection, so prior CAR T cells and bispecific antibodies. It certainly gives us some of the first systematic looks at the sequencing of these T-cell redirecting therapies.
You see here impressive response rates of 73% or 74% in patients getting either of these 2 recommended phase 2 subcutaneous dosing schedules, the 0.4 mg/kg every week or the 0.8 mg/kg every 2 weeks. There were indistinguishable response rates, and most of these responses being deep responses greater than or equal to very good partial response. In patients with prior T-cell redirection therapy, the response rate is 63%, which is really impressive. That I think addresses some of the sequencing questions we were asking in the prior session, that patients progressing on prior T-cell redirection may not be resistant to T-cell redirection per se, but may just need another target. It’s amazing to see such high responses. That population is also an intrinsically quite advanced population. Patients who were exposed to prior T-cell redirection therapy are inherently a very refractory patient population with very few palatable treatment options available. To see response rates with a single agent of 63% is remarkable. The duration of response is also very favorable. After a median follow-up in the 0.4 mg/kg dosing schedule of 14.9 months, the median duration of response has still not been reached. Likewise in the 0.8 mg/kg Q2-week cohort, with a shorter median duration follow-up, still the median duration of response had not been reached. So if you’re fortunate enough to respond to one of these agents, you can anticipate having a very durable response, which is also very impressive in patients in such a late line of therapy.
With this brand new cell surface target, I raised the question of safety in the introduction. On the left here you see the hematologic toxicities that are very consistent with what we expect with any bone marrow targeted agent, similar to what we see with the BCMA bispecific antibodies, and so, a fair amount of high-grade cytopenias. Importantly, there was a very low rate of discontinuation due to adverse events, and that suggests that these are manageable with supportive care and dose holds, and that’s very encouraging. We do see cytokine release syndrome as we did with teclistamab, 70%-plus rate of cytokine release syndrome, which is consistent with the response rate, basically patients who respond are very likely to have some cytokine release syndrome. Reassuringly, this was almost entirely low grade, and that indicates it is a manageable toxicity and confined to the early doses, and so not an ongoing concern once you get beyond those first few doses.
With GPRC5D, we do see this new class of adverse effects [AEs] that speak to the expression of GPRC5D on certain keratinized surfaces, and so skin- and nail-related AEs, and dysgeusia. This is thought to be due to expression of GPRC5D in salivary glands and taste buds. You see that while these are low-grade toxicities, grade 2 dysgeusia, these are things that do affect patients’ quality of life. So again, I point to the fact that there is a low rate of discontinuation due to these AEs as evidence that they were manageable. But still in my experience with a few patients getting talquetamab, they can be quite frustrating and affect quality of life. They do seem to abate over time for some reason, and so the most difficult part of this is early in dosing, and patients who respond and are doing well can anticipate some improvement over time.
Transcript edited for clarity.
