Where should bispecific antibodies be positioned in RRMM?

Where should bispecific antibodies be positioned in relapsed refractory multiple myeloma? Well, at the moment, both teclistamab and then elranatamab, the BCMA bispecific. And talquetamab, the GPRC5D bispecific are only approved for patients who have had formal prior therapies. On July 2nd, 2025, Linvoseltamab received FDA accelerated approval as a BCMA targeting bispecific antibodies.

So that limits our ability to deliver these therapies early in the treatment course. That's probably going to change in the next year or two, I think, given that the CAR-Ts have been approved for second line and there's more data being generated in second, third line therapy that we're going to see some label changes to allow second, third line therapy. But until that's accomplished with the FDA, clinical trials are our best option.

So there's a number of clinical trials ongoing, better looking at these, using bispecific either as monotherapy or in combination in early lines of therapy. And it just so happens like, MRRF just launched a platform trial called Horizon One for relapsed refractory multiple myeloma. This is deployed in the Multiple Myeloma Research Consortium. And the control arm in that study is single agent teclistamab. And so this is available for patients who've had 1 to 3 prior lines of therapy. So this is one example of a clinical trial where bispecific had been used earlier in therapy.

When considering a bispecific antibody as a treatment, does the target matter? There's a lot of considerations into the choice of bispecific antibodies. So the two targets, BCMA and GPRC5D, both are highly expressed on myeloma cells, and they're very good targets. They have very different side effect profiles. And BCMA is targeted both by bispecific and also by the current crop of CAR-T sources. So if you're looking ahead to the entire treatment course of the patient, you have to think about what your target choices are and how are you going to put those together?

Because right now we talk about sequencing therapies and unfortunately we're talking about sequencing therapies for failure. Right. So if somebody is on one therapy for x amount of time and then they relapse, what's the next therapy we're going to give them? And so in that context your choice of target GPRC5D versus BCMA. Are you going to use a CAR-T first or bispecific first? Those kinds of choices factor into your decision. Hopefully we're looking towards a future where we're sequencing for success, where we're putting together our best therapies, either in combinations or in sequences or both.

We don't necessarily want to give the same therapy all the time. We may want a certain therapy to start, for example, an immune response. And then another set of therapies to make sure that that immune response remains effective and strong. And so that sequencing of therapies may ultimately confer durable remissions. And that's what we're looking for—cures. So we don't want to sequence for failure. We want to sequence for success.

Why is BCMA a target of so many bispecific antibodies? The reason BCMA is such a good target is because it's really primarily only on myeloma and plasma cells. We have learned with really effective BCMA targeted therapy. It's on some neurologic cells that can explain some of the neurologic side effects that happen with really potent BCMA targeted therapies.

When would you choose a bispecific antibody as opposed to a CAR-T cell in later lines of therapy? Bispecific antibodies, I like to choose to use bispecific antibodies in those patients whose myeloma is progressing somewhat rapidly, because we can very quickly initiate bispecific antibody therapy, in contrast to what we're able to do with CAR-T cells.

We know just like almost every other drug that we've studied in myeloma, teclistamab and other bispecific antibodies are going to be moved earlier in the course of disease. And there's currently studies looking at teclistamab as a second line therapy with combinations as consolidation. There are bispecific antibody studies that are going to look at the going to be used as maintenance therapy. Could it be used as initial therapy? We're even having discussions. Can this be used to help prevent myeloma progression in patients with smoldering myeloma?

So just because it's approved right now in greater than four lines of therapy, as we study it more, we're going to learn the optimal place, which will be earlier in the course of the disease. As of 2025, two additional BCMA-targeting bispecific antibodies, elranatamab and linvoseltamab, and one GPRC5D-targeting bispecific antibody have received FDA approval. Currently, all FDA-approved bispecific antibodies are indicated for use after four prior lines of therapy.

Well, I think that we're going to find out now that we have potentially more bispecifics available. At the moment, we're using them for people who have relapsed after a CAR T-cell, or for people who we can't get a CAR-T cell slot for early enough. And they need some immediate therapy, we're using in those two situations. I think with more research and more studies, we may in fact be moving the bispecifics much earlier, even as early as frontline therapy. It's good. I can imagine daratumumab, teclistamab, talquetamab, induction. I mean, that's further off, but I can imagine something like that. Three shots, minimal toxicity, deep remissions, maybe cure. Who knows, but I can I can see them moving earlier and earlier and earlier.