VIDEO: Recent advancements in multiple myeloma

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There are multiple exciting new developments in myeloma this year, and I think the most recent and the most exciting include, in my opinion, two approvals for so-called bispecific T-cell engagers. And the first one, talquetamab [Talvey, Janssen] — talc, we call it for short. So talquetamab is a really exciting antibody. It targets a thing called GPRC5D, which is a different marker to BCMA on a myeloma cell. And in really lovely work led by Dr. Ajai Chari and colleagues, this bispecific T-cell engaging antibody has been shown to be very active in the setting of relapsed/refractory disease where multiple classes of other therapies have failed the patient, including prior BCMA exposure. And I think that’s a very remarkable finding in this work that Ajai has lead. And so as a result of that, talquetamab for, you know, broadly achieved around a 70% response rate with acceptable tolerability features, manageable side effects, manageable toxicity — recognizing the antibody still requires, you know, hospitalization. You have to be very careful about a thing called cytokine release syndrome. Infections, of course, are an issue, although perhaps possibly less so than they are for the BCMA-targeting bispecific antibodies. And obviously, with all those caveats, the excitement around talquetamab is that we’ve got a new bispecific T-cell engaging antibody that goes after a different target to BCMA. It’s an exciting development and it’s wonderful to see an accelerated approval, which I think is just so important for patients. We need all hands to the pumps in myeloma, and accelerated approvals, in my view, are such an important way of getting early access for patients in exquisite unmet medical needs. So, the availability of talquetamab as a result of the FDA’s decision I think is a really great step forward. And I think the hope is that, obviously, this will lead to approval elsewhere. And it’s my understanding this will be happening in Europe and so forth for talquetamab accordingly.

Now the next big news of just literally within the last 24 hours was the second bispecific approved against BCMA, specifically elranatamab [Elrexfio, Pfizer]. Now this is obviously hot on the heels of another bispecific called teclistamab [Tecvayli, Janssen] that was approved last year. Both of these bispecifics target ... And at the same time they seem to have, obviously, similar constructs in the way that they’re designed to work as T-cell redirecting antibodies that help target the myeloma cell and bring the T cells in to do their work against the myeloma. But they may have differences in some of their features. Again, one has to be very careful because cross-trial comparisons are an area where I think, you know, you have to be cautious about overinterpreting differences. But I have to say that with elranatamab there’s evidence that not only is there this strikingly high response rate, but at the same time there’s what’s called an MRD-negative rate seen in the relapsed/refractory studies that have been presented to date that seems to be quite impressive to me. And I think that, again, this whole construct around tolerability is very important. And there is of course, cytokine release syndrome. There are infections. These are an important problem with BCMA-targeting approaches of the bispecific or CAR-T variety, perhaps less so with the antibody-drug conjugates. But nonetheless, the tolerability profile does appear manageable.

And whilst of course these antibodies do require hospitalization, I think, you know, in the longer term they don’t. And I’m very excited to see another bispecific made available for patients. Again, exquisite unmet medical need, patients with triple-class refractory disease in whom other treatments have failed them, o, a very important next step forward for treatment. And these are what we call accelerated approvals. So, the confirmatory trials are coming, and I’m very hopeful that those confirmatory trials will support the approval first of teclistamab, which was last year, elranatamab, which we call elra for short. And then of course we have talquetamab of last week, which I think will have confirmatory trials to support it into the bargain. So, you know, three major antibody classes.

But I think it’s important to note whilst we have these immune therapies, there is really a consideration here that has to be borne in mind. They do, at the moment, require hospitalization. They do, at the moment, generate side effect profiles that can be quite challenging for older and frailer patients — recognizing that, again, that’s all a matter of appropriate supportive care, excellent nursing care and physician care to get patients through the potential side effects they might run into. But at the same time, I think it’s terribly important that we have other drugs available for our patients with relapsed/refractory myeloma because, whilst obviously the excitement right now is palpable — I mean, we’ve had the tremendous results of cilta-cel [Carvykti; Janssen, Legend Biotech] in the so-called CARTITUDE-4 study led by Dr. Jesus San-Miguel, published in The New England Journal [of Medicine] and presented recently at the ASCO meeting in Chicago in June. And what you can see in that trial is that bringing cilta-cel earlier in these patients with relapsed/refractory disease performed very well, and better than the control patients in the study that they evaluated.

What they did here was to offer patients with relapsed/refractory disease either cilta-cel, or two control regimens. One was daratumumab [Darzalex, Janssen], bortezomib and dexamethasone. The other one was pomalidomide, bortezomib and dexamethasone. These are so-called triplet therapies that some years ago were really considered state-of-the-art, and certainly are, to this day, standards of care in certain health care jurisdictions. I think the challenge is that the field’s moving so quickly that now in the relapsed/refractory space, we have other triplets and quadruplets that are really effective. So, I think one has to just interpret some of the CARTITUDE-4 results with a little bit of caution to say, fabulous results. The cilta-cel is performing exceptionally well. But just to bear in mind that the control group, in other words those patients assigned to quote unquote “standards of care” perhaps has already become a little less up-to-date, as it were, than we might be now.

With all the caveats, though, that obviously one’s not looking to hold back the advance of an exciting new therapy. I think we just have to realize that these therapies brought earlier are probably much more effective, less toxic and, therefore, really offer great opportunity for our patients. But also to recognize that, you know, multiple myeloma is multiple diseases and multiple patient characteristics, you know, from younger, very fit athletic patients to older, frailer patients in whom intensive treatments that may be CAR-T based, or bispecific, or so on and so forth, may be actually impossible for them to do. And so with that in mind I think it’s very important to recognize some of the other advances that are coming.

I think, honestly, an area that is really important to appreciate is the unmet need of frailer, older patients, which are the majority of our patients. Remember, the median age of this disease is around 70. So that means your younger patients are there, of course, and these newer therapies are very promising. But for older patients and a significant number of our patients in their 70s are well enough, fit enough, to easily tolerate and benefit from these exciting new cellular therapies or T-cell redirecting strategies. But in your 80s and late 80s, you know, this is not quite the same. And I think that, therefore, we always need to bear in mind that it’s, like I say, it’s not one versus the other. It’s we need all the tools that are available to us because myeloma really does remain, actually, sadly, for the majority of our patients, incurable. And whilst I think there’s an increasing fraction of younger patients in whom long-term disease control with quote unquote “functional” cure may be becoming closer to reality, I think we mustn’t underestimate the significant number of patients, particularly in communities that are less well-served … importantly, and in that contra-category I would include minority populations, we need to be very aware of how important it is to have everything available for those populations of patients so they too can benefit from the armamentarium that we have.