This is exciting data about the efficacy and safety of talquetamab and teclistamab, which are two bispecific therapies targeting one is GPRC5D and the other one is targeting BCMA bispecific, in use in patients who have relapsed/refractory multiple myeloma. That was updated data on the phase II results from the RedirecTT [??] study with an extended follow-up.

What was the study design?

It’s a good question because this is a single-arm study where we are trying to answer what happens to these extramedullary disease multiple myeloma patients who are not typically enrolled in the clinical trial. In this study we have taken into certain aspects in the context. Number one is what is called the EMD. So we defined the EMD and extramedullary myeloma which is not really attached to the bones. So we defined them into organ EMDs and non-organ EMDs like multiple myeloma involving the liver, multiple myeloma involving the kidneys, lungs and the lymph nodes and other soft tissues. So we actually were able to separate them into these cohorts, like what the extramedullary involvement is.

Patients who were refractory to PI, which is a proteasome-based regimen, daratumumab-based therapy or immunomodulatory agents were included in this study who have EMD. In addition to that we also included patients who do not have a measurable disease – they don’t have M spike, they don’t have measurable light chains but they have a disease. So these are the populations which are typically excluded from the clinical trials and in our clinical practice we do see these types of patients more frequently nowadays, especially with the novel agents. So there is an unmet need of how we address these patients because historically these patients have a poor outcome and have a poor prognosis.

What were the results of this study?

After the eligibility criteria that the patients met, we actually used these agents together in combination. We divided the results into two sections, one is the efficacy results, the other one is the toxicity results. In terms of efficacy results the objective response rates, which are almost close to 80%, these are quite exciting to hear that because these responses we don’t expect them from extramedullary disease patients. We see more of these responses who have organ EMD versus the non-organ EMD but the responses have been seen across the board. So that is a very important finding.

The second thing is we have not hit the overall survival yet. Many of these patients are still alive and more than 50% of the patients are still getting the treatment. The third important part was that up to a year we still have not hit the median and the patients are still living longer on the treatment. So we had a better objective response rate, impressive PFS data as well as overall survival.

The second question to come up, OK, we are combining these two agents together, what are the toxicities? Is it feasible to be used? Since this is an extension study, it’s a phase II study. So toxicities are one of our major interests.

We did notice the rates of infection rates are higher, however, we also have to acknowledge that this study was done at a time when we were recovering from COVID and there were still quite a lot of patients developing COVID. So infection is something that we have to be very, very vigilant with this. The infection rates are higher but they were mostly grade 1 and grade 2. Some patients do get the grade 3 opportunistic infections, however, with the period of time what we have learned is that with these bispecifics, these are not new to see these types of effects but having IVIG on the board, proper antibiotic use, having supportive care, is actually helping to mitigate many of these side effects.

Also, interestingly, what we have seen in this study, that we use this bispecific twice-weekly, every other week. We use them up to four months and patients who have a deep response rate, they’re in vgPR, we de-escalate the treatment to once a month. When we did that we also have noticed that the infection rate subsequently comes down. So de-escalating the therapy after achieving a sufficient response is another important finding that what we have seen. Because of that we have been seeing the patients who sustained these effects, they’ve been living longer.

So overall you can see that we had 90 patients in this study and the median age was around 64.5. Cohorts already well balanced, median lines of therapy was 4. So it’s quite a heavily pre-treated population. Knowing how dismal their prognosis is, this is, I would consider, one of the practice-changing results for our patients.

What is the clinical significance of these results and what is next for this study?

That’s a very good question. At the moment it’s important that we see what the real-world data actually looks like when these patients have been treated as other than the clinical trial. But we also have to accept the reality that these patients have nothing; these patients do not do well. Those who treat myeloma, they know that patients who have extramedullary disease, oligosecretory myeloma, they have a dismal outcome. This is the light at the end of the tunnel. We are seeing amazing results here and combining the two bispecifics can be a very effective strategy, provided we can manage the toxicities.

Now, we have been using the bispecifics for some time now and we are using them in the relapsed/refractory setting who have received four lines of therapy. So it’s not like this is new for our oncologists, how you manage them, but combining the two with a different strategy is something new and an innovative approach because these plasmacytomas have a lot of resistance and they can have these variable expressions on GPRC5D and BCMA so dual targeting could be very exciting.

I would see the next thing from here is that, OK, we do these therapies and we have some results but we also have seen the patients that fail and we were trying to figure out what to do next. So what to do next is a very important question. Now in this ASH we have been using the CELMoD therapy, immunomodulatory agents in combination or immunotherapy in combination, trying to enhance our bispecific functionality. I think this is an important thing to see how we combine together in a safe way and what we do at the time of relapse. Should we do CAR-T, different agent, different trials or using the CELMoD? That is a question up in the air and the future data will tell us how we will move forward from here.

Is there anything else you would like to add?

I would say that those who are interested in reading more about that, so I would say the results have been published in The New England Journal of Medicine and I would like our audience and our colleagues to please review those results, see how the patient populations were enrolled and how they have seen it. I can tell you, these are the real-world experiences I have, these are tough patients to enrol in the study and you can see that many of these patients were drop-out for many reasons. Because of aggressive disease you need to treat it early. Having these types of therapy, if it’s available for our patients, it can be a game changer and would be very beneficial for our patient population.