TRiMM-2: Talquetamab + Daratumumab in Relapsed/Refractory Multiple Myeloma
In the context of other clinical trials for patients with relapsed/refractory multiple myeloma, Ajai Chari, MD, and Carolina Schinke, MD, review data from TRiMM-2.
Transcript:
Ajai Chari, MD, PhD: We’ve been talking a lot about talquetamab monotherapy in combination with teclistamab. There was actually other additional exciting data presented at ASCO [American Society of Clinical Oncology] and EHA [European Hematology Association] about combining talquetamab with daratumumab, the TRIMM-2 [trial; NCT04108195]. This data has been presented before, but what’s new is really the follow-up duration and think the rationale to do this combination is preclinical. When you do a combination CD38 with bispecific, there has been data suggesting more cell killing. We know that one of the things that CD38 monoclonal antibody does is leads to a clonal T-cell expansion, which might therefore work well with a bispecific that’s also activating T cells. So these were typical relapsed myeloma with at least 3 lines of therapy. Prior CD38 was allowed, but there was a 90-day washout, and it was the same doses of talquetamab that we heard in MonumenTAL-1 [NCT04634552], 0.4 [mg/kg] every week or 0.8 [mg/kg] every 2 weeks combined with standard subcutaneous daratumumab. And the goal here was again to identify to RP2D [recommended phase 2 dose] and its typical characteristics. About a quarter was extramedullary, about 10% to 15% were ISS [International Staging System] 3, and these were heavily treated with 5 to 6 lines of therapy over about 6 years.
When we look at the refractory status, 80% were refractory to CD38 in both cohorts and, interestingly, also about 20% to 30% were refractory to prior bispecifics and about 43% and 23% were refractory to tentative drugs, and three-quarters of the patients were progressing on the last line of therapy. We see an impressive response rate of 71% [and] 84%. I think one of the challenges, of course, is, how does this compare to monotherapy? I think it’s hard to answer that because there are always going to be differences between patient and disease characteristics. So the contribution of data is difficult to discern from these single-arm studies. We do see that the response rate was maintained even in CD38 refractory patients, 64% in the 0.4 [mg/kg] and 80% in 0.8 [mg/kg], and also encouraging responses with prior CAR T’s [chimeric antigen receptor T-cell therapies] and bispecific, about 67% and 80% for all patients. Even in prior bispecific 70%, 80% is just exciting to see. The median duration of response was not reached, even in prior T-cell redirection-exposed patients. At 12 months, 88.4% remained in remission.
I think that’s a very exciting and interesting signal. Even those who switched to less frequent dosing were able to maintain their responses. And over half the patients at data cutoff were maintaining their remission, about 60%. There were really no additional toxicities. Particularly notable is the relatively low rates of [hematologic toxicities], only about 28.6% of grade 3 and higher with 0.4 [kg/mg], and 28% in 0.8 [mg/kg]. And these, again, as with monotherapy, are limited to the first cycle or 2. Of course, infections are something that we’re concerned about with this population and these therapies. Here we do see modest infections, 57% and 73%, but primarily low-grade. Grade 3 and higher were only about 20%, and most of these occurred in the first 6 months. Opportunistic infections are relatively uncommon, about 11%, and the rate of hypogammaglobulinemia, less than 4 at 500, was about 35% at baseline. But as we know, with daratumumab monotherapy as well, that can go up to 75% with monotherapy, and here it was 86%. And about a third of patients received IVIG [intravenous immunoglobulin].
Interestingly, when they looked at B cell populations, the B cells were spared, these are typically CD19-positive cells, which may explain the partly low infection rate. I think what was particularly really exciting here was the median PFS was not reached with weekly dosing and 19.4 months with Q2-week dosing. Again, while we avoid direct cross-study comparisons, there are no apparent major differences in prior therapies or lines of therapy. And so, this PFS [progression-free survival] of not-reached or 19 months is really exciting. I think that that was the main take-home message of this update, which is really with additional follow-up, really the durability of responses. Carolina, thoughts on TRIMM-2? Were you excited as I was?
Carolina D. Schinke, MD: Yes, again, because it shows that we can combine bispecifics. Particularly talquetamab, as you previously mentioned, is probably the bispecific antibody that can be combined easier just because the BCMA [B-cell maturation antigen]-targeting ones just have already on their own such a high infection rate. Talquetamab doesn’t. S, obviously, it’s nice to see that there are opportunities for combination with talquetamab, and I think the infectious rate went up, or it seems a little bit higher than monotherapy, but still manageable. So I think that was very encouraging. Then, as you said, the efficacy in terms of response rate and duration of response is very impressive.
Ajai Chari, MD, PhD: I think between the monotherapy, but more importantly, both the RedirecTT-1 with teclistamab and here with CD38, I think talquetamab appears to be more promiscuous. It looks like the BCMA bispecifics are going to be more selective because of the neutropenia and infection signal. They’ll be harder to do in combination. I think as we try to move these earlier as well, we’re going to have to keep an eye on those infectious deaths where here we’re seeing really encouraging data. So it looks like both these are amazing choices to have, but talquetamab seems to have a bright future with its ability to move up. And again, I think to echo the comments from RedirecTT-1 when you have this much response in PFS, we may be able to back off on the dose intensity sooner to mitigate some of the dysgeusia. Wouldn’t you agree?
Carolina D. Schinke, MD: Absolutely.
Transcript edited for clarity.
