It’s exciting to announce that our phase I portion of the study with talquetamab was actually just published in The New England Journal and at this year’s ASH meeting we presented the phase II portion. I can get into a little bit of the differences but basically talquetamab is a novel first-in-class agent that’s a bispecific antibody. So it engages CD3 on the T-cells and a novel target known as GPRC5D which stands for G-protein coupled receptor, family C, group 5, member D. This protein is over-expressed on myeloma cells preferentially, even more in malignant than normal plasma cells, and also generally is not very highly expressed in other human tissues with an exception, perhaps, of heavily keratinised tissue.

So in the phase I study in The New England we found that this drug worked very well, even in advanced myeloma patients – response rate around 70%. We had characterised a safety profile and here at ASH we updated both efficacy and safety at this meeting.

What was the design of the study?

Here there were three major cohorts. The first was getting a dose of 0.4mg/kg every week subcutaneously; the second was 0.8mg/kg every two weeks and the third cohort was either one of those doses but specifically in patients who had had prior T-cell redirection therapy. I should mention that some of the patients in the phase I study were included in this dataset but the majority of these patients were only for the first time presented at ASH. Also I would distinguish this study because in the phase I study we studied a variety of doses from very, very low to RP2D and higher, and we studied both IV and sub-cue formulations but here, in this study that is being presented, it’s only subcutaneous.

What were the key findings?

The findings, to put it into context, we just need to briefly review who the patients were. These were typically relapsed/refractory myeloma patients. There was a high representation of extramedullary disease, about 60%, be it by high risk cytogenetics, ISS-3 or extramedullary disease. In particular ISS-3 extramedullary had been known to be high risk even in their T-cell redirections which is CAR-Ts and bispecifics. Also these patients, approximately 95% were progressing on their last line of therapy and also, again, almost all patients were refractory to CD38 antibodies and about three-quarters were triple class refractory to PI, IMiDs and CD38. So heavily pre-treated – five lines of therapy over about six years.

In this population we found that the response rate was 73% and 74% in the two cohorts respectively and that response was maintained in triple class refractory, penta-drug refractory, ISS-3, high risk disease, pretty much all the subgroups except perhaps extramedullary disease. Those patients did respond very well but response rate was 50%. Also I would highlight that the time to response was quite rapid, around one month, and time to deepest response was actually also rapid, around two months.

So that was the first two cohorts and the other finding that would be important would be the third cohort which had a response rate of about 62% in the prior T-cell redirection.

We also did find some efficacy in terms of durability. We found that the PFS was about 8 months and 12 months in the 0.4mg/kg and 0.8mg/kg dosing respectively, and the median duration of response was 9.3 months and 13 months. For those patients who had CR or better we didn’t even had a median reached.

So, to summarise, what we find is that this a highly active agent, both by response rate of around 60-70%, depending on the cohort, and also deep and durable remissions.

To show where this drug might be heading we should also look briefly at the efficacy. So grade 3 and higher toxicities were uncommon, except hematologic and those were less than a third of the patients and typically early on. Also infections which have been plaguing some of the other bispecifics, particularly BCMA, we didn’t see high rates of grade 3 infections, only about 10-15%. Two COVID deaths and none in the phase I portion of the study in New England, compared to many more COVID deaths. We see good COVID antibody response to vaccine and also relatively low rates of IVIg.

But we did have some unique toxicities with this agent which included the CRS which has been reported with all the bispecifics, about 70% low grade. But the unique things are rashes, which are quite manageable in those early parts of the cycle, nail changes and loss of taste.

I bring up this safety in terms of future directions because we know that myeloma is very genomically and immunologically complex. These initial single arm studies with monotherapy are not always how we use the drug in the future. Because of the safety profile, this drug is readily combinable with other agents because there is lack of overlap. So it has been combined with all the standard myeloma backbone drugs, it can be combined with the other bispecific known as teclistamab and also with checkpoint inhibitors. Also confirmatory phase III studies going on with this agent in various combinations that are already accruing and, of course, there is great interest in moving these agents into earlier lines of therapy. But a lot of excitement about this novel MLA, novel target in myeloma.