Relapsed & Refractory Myeloma: What’s Changing and What’s Next Rahul Banerjee, MD, FACP

Hi everyone.

Thank you for listening. My name is Rahul Banerjee.

I'm an assistant professor of medicine and a myeloma specialist at the Fred Hutchinson Cancer Center in Seattle, Washington.

I'm here at the 2025 American Society of Hematology, or ASH meeting in Orlando.

It's always an exciting meeting to hear about new developments in myeloma and talk about, you know, what has changed, how far we've come as a field, but how far we have left to go.

The right now we're talking about relapsed refractory multiple myeloma. What is new in 2025 and what is coming.

So I think I'll break into two categories in terms of what is new now, in terms of things that are practice changing a practice and forming now for you and your doctors and your providers.

I would say Car-T therapy right now is the default and should be the default for early relapses.

There were data presented earlier today that for patients with cilta-cel, brand name carvykti, which is a commonly used Car-T therapy that's approved for one prior line in patients who've gotten a proteasome inhibitor like bortezomib, carfilzomib, and an IMiD like lenalidomide.

We already knew that patients, on average, got about three years of mileage out of it. You know, the relapse setting, probably more than three years, to be honest.

And then we have a factory setting here. They found that basically for patients with standard risk cytogenetics, you know, or patients where, you know, the myeloma doesn't have some of these known high risk features like deletion 17p and so forth.

These patients often 80, 90% of them were at the two year, three year mark. And alive and disease still remains in remission.

The reason this matters is that there tends to be a belief, and I've been guilty of it, too, that all we should save earlier line Car-T for the patients who are sicker or have more aggressive myeloma or something along those lines.

And to an extent, that is true for patients with functional high risk myeloma, which is defined as early relapse. Depends how you define what that number is. We used to say 18 months after frontline therapy.

There's another, abstract Luciano Costa here saying that for someone who gets a quad, if you have a relapse within three years of transplant, that is still considered functional high risk early relapse.

For those patients, Car-T should absolutely be the norm.

And we've kind of historically said, oh, Car-T at first relapse is a big gun. Save it for patients who have early relapse or high risk of genetics.

One could argue the data we see here show that, well, maybe the risk patients actually do the most of it. And you could argue that everybody should have access to Car-T therapy. A first relapse should be discussion.

So that's where we stand now.

And certainly, you know, a lot of research is happening here on strategies to make Car-T safer for patients because there is but cilta-cel, this risk of nerve palsy is parkinsonism, enterocolitis, which can be diarrhea.

So delayed nerve like neurological toxicities and GI toxicities. We're trying to figure out and a lot of researchers how to make that better.

The biggest abstract of ASH 2025. If you were to ask you the myeloma doctors can't agree on anything. But if you were to ask us, probably 80% of us would agree that the biggest abstract in relapsed myeloma is a MajesTEC-3 trial or teclistamab plus daratumumab in relapsed myeloma not approved yet, but almost certainly will be approved later.

This was a study of teclistmab, brand name Tecvayli, which is a BCMA bispecific antibody.

Again, a bispecific antibody grabs a myeloma cell with one arm. Grab the T cell with one arm. It squishes them together.

There's no genetic modification involved. Unlike with Car-T therapy, it is off the shelf. You could just start someone on to teclistamab.

They combine it with daratumumab, which many of you are familiar with that brand name Darzalex. CD38 monoclonal antibody.

In patients with relapsed myeloma, only about 5% of the patient with dara was exposed. So just to be clear, it's not as directly, relatable to the U.S. population today.

But to be fair, many of my patients are not there to remember refractory, you know, patients I've been on there are daratumumab. They stop the daratumumab go on just lenalidomide something along those lines. When the myeloma comes back.

What if we try to use teclistmamab plus daratumumab.

And basically the MajesTEC-3 study compared that combination teclistmab plus daratumumab versus dara, pom, dex or dara, bortezomib, dex.

And again this arm blew this arm out of the water.

It did the holy grail of myeloma treatments. Patients were in remission for longer PFS was better.

Number two patients felt better. The patient for the outcomes were better.

And number three, they live longer. Overall survival was better.

So in remission for longer. Feeling better, living longer. There is nothing more I can ask for the myeloma treatment than that. And that was extraordinary.

If you had asked myeloma specialist two years ago about this exact same combination, we would have been terrified.

Two years ago, I remember vividly the discussion around combining BCMA bispecifics and, CD38 monoclonal antibodies, daratumumab was infection, infection, infection.

And one early study, there was a 25% risk of death, like fatal infections, primarily due to Covid 19.

We've come a very long way since then.

Teclistamab and daratumumab was much, much better in terms of infection risk compared to studies of the same drugs three years ago.

What's changed?

Covid 19 is part of it. As you're well aware, Covid 19 has evolved in many ways. Not as lethal as it used to be.

Number two, in this particular study teclistamab lined up with daratumumab. What do I mean by that?

Those of you who've been on daratumumab, know that dara typically goes from every one week to every two weeks to every four weeks. Most patients end up on once a month daratumumab here teclistamab.

They had them follow the exact same schedule. And I love that.

Many times in myeloma we end up combining different regimens together. And many of my patients are, you know, have days where they've come in for only one drug, not the other or this one now or both drugs, and doesn't make any sense because again, we just squishing two trials together without we critically, you know, merging them properly.

Here there are daratumumab and teclistamab are seamlessly merged together, less frequent teclistamab.

Now probably means T cells are less exhausted than normal plasma cells are being the hit less common the normal cells, not the myeloma cells, normal cells are being degraded less. So that probably helps a lot.

But most importantly, and I think the biggest takeaway for anyone I would say, is that if you are on a bispecific antibody, a BCMA bispecific antibody in particular, like teclistamab (Tecvayli), linvoseltamab (Lynovozyfic) or elranatamab (Elrexfio), you should be on IgG replacement therapy, for example, IVIG intravenous immunoglobulin.

This was not the norm a couple of years ago.

A lot of my research and my advocacy has been in the in this field as an essential safety step, where in the past 25% of people dying of infections is 25% too much.

And the reason is because, again, you knock down all the normal B cells, their T cells are distracted. They are phenomenally and fundamentally immunocompromised, even more so than with Car-T therapy, because Car-T therapy, the immunosuppression kind of happens like this and fades off.

But the bispecific like tec, dara are you're doing it again and again and again and again.

And so here they found that once they required intravenous immunoglobulin basically patients did much better much lower risk of infections.

There was only one fatal infection after the mandatory initiation of IVIG. Before there were many more.

There was another study being presented here that IFM 2021 study of teclistamab and daratumumab same combination newly diagnosed myeloma, where they implemented IVIG from the beginning and there again the infection rate is much lower, not just serious infections needing to go to the intensive care unit, but any grade infections.

Those of you listening who have been on bispecifics, I'm sorry many of you have had colds or Covid mild symptoms that lasts for like three weeks.

Even the grade one infections that are low grade and the doctor's like not a big deal for patients. They can be a very big deal.

IVIG can close that gap and knock all these infections down, not all the way to zero, but enough that patients could stay onto teclistamab, daratumumab for long enough that the drugs worked for long enough for them to be in remission for longer, feel better, and live longer.

So bring it all together again, I think in the future teclistamab and daratumumab this combo a BCMA bispecific plus a CD38 monoclonal antibody.

If done right. And when I say done right, I mean intravenous immunoglobulin. IVIG from the beginning is a game changer, truly a game changer, and will probably become the default for patients who are BCMA naive haven't had BCMA therapies going into relapsed myeloma.

Many unanswered questions remain because obviously, once that's approved, who should get teclistamab and dara with the BCMA bispecific and who should get BCMA Car-T therapy was cilta-cel, ide-cel, anito-cel in the future etc.

Ask me again in a couple of years. I don't know yet,

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