Considering Sequence of Talquetamab and BCMA Therapy in Multiple Myeloma

Patients with relapsed/refractory multiple myeloma are now being treated with several different therapies targeting B-cell maturation antigen (BCMA), including chimeric antigen receptor (CAR) T-cell therapies, bispecific antibodies, and antibody-drug conjugates, but repeat targeting of BCMA may be less effective. The GPRC5DxCD3-targeted bispecific antibody talquetamab (Talvey) presents an alternative for BCMA-exposed patients, as was discussed in a live Case-Based Roundtable event in Minneapolis, Minnesota moderated by Shaji Kumar, MD, professor of medicine and research chair in the division of hematology at the Mayo Clinic in Rochester, Minnesota. Kumar reviewed the trial data for talquetamab and evaluated how this information guides sequencing to maximize the efficacy of targeting BCMA and GPRC5D.

Register today to join a Case-Based Roundtable near you.

Targeted Oncology: Could you discuss the background of the MonumenTAL-1 trial (NCT04634552)?

Shaji Kumar, MD: This was the phase 1 trial…that eventually led to the approval for talquetamab.¹ These are patients with more than or equal to 3 prior lines of therapy. They have been all exposed to a proteosome inhibitors immunomodulatory agent,, and anti-CD38 agent. There were 2 different dosing strategies that were explored, the 0.4 mg/kg weekly, and the 0.8 mg/kg every other week. There was a smaller cohort of patients who have previously been exposed to a T-cell redirection [TCR] therapy. Looking at the baseline characteristics, this is a heavily pretreated patient population with a median of 5 prior lines of therapy. A good number of patients have been exposed to all the classes of drugs. The third group had previous TCR therapy as well. About 33% had bispecific antibodies [and] 73% of them had a CAR T, with 6% having had both of them.

This is the response rate to talquetamab: the overall response rate [ORR] is about 65% to 70%,¹ and interestingly enough, if you take any bispecific antibody, the ORR is somewhere in that 60% to 70%. That tells you that the mechanism of action is probably more important than the antigen that you’re targeting for somebody who hasn’t seen a bispecific before. The median progression-free survival [PFS] with the 0.4 mg/kg was 7.5 months [and the median duration of response was 9.5 months], and for 0.8 mg/kg every 2 weeks, PFS was 11.2 months and the median duration of response was about a year and a half.² If you look at the median PFS, [the prior TCR group had] quite a bit lower than the [0.8 mg/kg group (7.7 months]]. The duration of response is only for the people who responded, so [the duration of response was 19.2 months, although] the ORR is a bit lower in this patient population.

How do you decide whether to give talquetamab once a week vs every other week?

The caveat here is the response rates were similar. [The every-other-week group] had a slightly deeper responses. Personally, I always use every other week because it’s convenient. Again, these studies were not designed to actually compare them head-to-head. There are differences in the patient populations. The weekly dosing group was a little bit more heavily pretreated compared with the every-other-week patient population. Even though the response rates were similar, the PFS was different.

What other efficacy findings stood out from this trial?

[Looking at] the overall survival curve, they’re not supposed to be compared, [but] every other week, seems to be a better option overall.² That’s part of the reason why most of us tend to use every other week.

They also looked at the high-risk patient population subgroups, and the ORR appears to be quite comparable, except for those patients with extramedullary disease.³ The PFS, looking at the cytogenetic risk, is not that different.¹ But the extramedullary disease makes a difference. That seems to be the case with all these immune therapies. Extramedullary disease is one place where things really tend to drop, especially the PFS. The response rates are still maybe good enough, but the PFS doesn’t seem to be that good in that patient population.

We have some data with teclistamab [Tecvayli] plus talquetamab in that patient population, and compared with everything we have seen so far in those patients with extramedullary disease, it has better outcomes.⁴ That’s one of the combinations we have been using in the clinic for those patients. With the patients with extramedullary disease, I think at least in my practice, I often tend to give them maybe a cycle or 2 of VDT-PACE [bortezomib (Velcade), dexamethasone, thalidomide, cisplatin, adriamycin, cyclophosphamide, etoposide] to debulk it a little bit, and then go in with immunotherapy, because when it’s [bulky] disease, it’s sometimes hard to get it under control.

How do the data inform sequencing of talquetamab?

[Looking at] the patients who got a prior BCMA-targeted therapy, whether it be CAR T cells or bispecifics, and the ORRs don’t look too bad. This is different than what you see if you were to be using a BCMA bispecific after BCMA CAR T or vice versa; you do see a quite a bit of a drop in the response rate. Whereas when you look at this patient population, you don’t necessarily see that bigger drop, which is the supporting evidence for trying to use talquetamab after BCMA-targeted therapy compared with going to BCMA after BCMA-targeted therapy.

[Among] patients who had a BCMA-targeted therapy, the ones with the CAR T seems to have better outcomes. But again, it’s so hard to say anything, because these are patient profiles that are more determined by what was available when those patients actually got the therapy. It may be very different when we start doing them routinely, when all 3 of them are available at the same time, and you’re trying to choose one vs the other.

Most of these trials, where they have looked at sequencing, it’s been late-line patients. You had one [therapy], the disease is relapsing, you go to the next one, and then you go to the next one. But in the future, that is not going to be the case. If you’re going to be treating a first-relapse patient with CAR T and you have a 3- or 5-year PFS, then those patients have not seen any treatment for quite a while, and they may be as good as a brand-new patient, as if they haven’t had the previous treatment.

I think that will make a lot of difference in terms of how the results might end up being. I would generally say anything more than a median PFS is usually a later one. So, with ciltacabtagene autoleucel [cilta-cel; Carvykti], for example, the median PFS with some of the studies is around 3 years. So, if somebody got less than 3 years, I would say, maybe think about it as if it’s suboptimal, especially if it’s less than 18 months. It’s probably not a durable response.

Can looking at BCMA expression show whether patients could receive repeat BCMA therapy?

The problem with the BCMA expression is there is no validated assay, and it’s very unusual for the cells to completely lose the expression for BCMA. There is no good way to create a threshold that you can apply in the clinic. What has been seen more than the expression is the mutations that happen in the BCMA antigen that seem to make a difference in terms of what binds and what cannot bind. So just looking for expression doesn’t seem to be very helpful.

All these studies have shown that the higher the level of soluble BCMA at the start of therapy, the worse the outcome is. But the problem is it’s also a measure of the tumor burden. We know with all these immunotherapies, the effector cell to tumor cell ratio is important. The interesting thing is, there is some anecdotal experience, as well as animal studies, where it shows that if you can get the tumor burden low and then give the bispecific antibodies, your responses are much longer lasting compared with if you just throw it at someone who’s got a very high tumor burden. These are scenarios that are probably not going to be that applicable in the future, when we’re going to start using this much earlier. We’re going to be using all of them when the patients are just starting to relapse vs when they are going to be in full relapse.

Register today to join a Case-Based Roundtable near you.

_{DISCLOSURES: Kumar previously reported receiving research support from AbbVie, Adaptive, Celgene, Johnson & Johnson, KITE, MedImmune/Astra Zeneca, and Takeda, and has been an advisory committee member for AbbVie, Adaptive, Celgene Johnson & Johnson, KITE, MedImmune/Astra Zeneca, Merck, Novartis, Oncopeptides, Roche, Sanofi, and Takeda}

REFERENCES

1. Chari A, Touzeau C, Schinke C, et al. Safety and activity of talquetamab in patients with relapsed or refractory multiple myeloma (MonumenTAL-1): a multicentre, open-label, phase 1-2 study. Lancet Haematol. 2025;12(4):e269-e281. doi:10.1016/S2352-3026(24)00385-5

2. Rasche L, Schinke C, Touzeau C, et al. Efficacy and safety from the phase 1/2 MonumenTAL-1 study of talquetamab, a GPRC5D×CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma: Analyses at an extended median follow-up. J Clin Oncol. 2025;43(suppl 16):7528. doi:10.1200/JCO.2025.43.16_suppl.7528

3. Rasche L, Schinke C, Touzeau C, et al. Long-term efficacy and safety results from the phase 1/2 MonumenTAL-1 study of talquetamab, a GPRC5D×CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma. Presented at: European Hematology Association 2024 Congress; Madrid, Spain; June 13-16, 2024. Abstract P915.

4. Kumar S, Mateos MV, Ye JC, et al. Dual targeting of extramedullary myeloma with talquetamab and teclistamab. N Engl J Med. 2026;394(1):51-61. doi:10.1056/NEJMoa2514752