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Is It Time to Stop Calling Multiple Myeloma Incurable? Highlights from IMS 2026
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Released: October 29, 2026

Joshua Richter
Joshua Richter, MD

Is It Time to Stop Calling Multiple Myeloma Incurable? Highlights From IMS 2026

Joshua Richter, MD: Welcome to Hematology Highlights, brought to you by Decera Clinical Insights. I'm your host, Dr Joshua Richter from Mount Sinai, and today we're going to be giving you an update from the 2026 International Myeloma Society (IMS) annual meeting that we just got back from in Glasgow, Scotland.

And we're going to hit a couple of really high-level areas of where the myeloma field is going. So number one, right off the bat, myeloma now has a definition for cure, and technically speaking, is no longer considered an incurable malignancy for all. And the current definition is described as an aspirational definition, because we're not going to achieve this for everyone, but this is where we feel that the field is going.

It requires patients to have 5 years off of all therapy, be in a complete remission, minimal residual disease (MRD) negative, and during that time, 4 consecutive measurements of MRD negativity by next-generation sequencing or next-generation flow, as well as some type of functional imaging like positron emission tomography or diffusion-weighted magnetic resonance imaging. And this can apply to newly diagnosed or relapsed or refractory patients.

And note that this comes from the CARTITUDE-1 study, with the 5-year follow-up from Carvykti given to late-line patients. In 5-year follow-up, we have approximately one-third of those patients who fit these criteria and may in fact be cured of their myeloma. So we're starting to evolve and really starting to look prospectively at who we can cure. Are there features of the disease, and is it finally time to stop calling myeloma incurable for all? Stay tuned, because there's more on the way.

The second big thing that came out of the IMS meeting was updates from the MajesTEC-3 study. MajesTEC-3, as a reminder, was the combination of daratumumab and teclistamab in early relapse myeloma versus the standard-of-care options. And one of the crazy things was that the survival curve was not actually a curve. It was pretty much a flat line. Now, at the 36-month follow-up, we see that for around 84% of patients, the progression-free survival (PFS) equals the overall survival (OS), and they appear to be in long-term remission, if not, question, functional cure.

So not cure in the sense that we just described, but maybe by keeping them on chronic therapy, we can prevent them from ever relapsing. So functional cure, unclear. Remember that this type of therapy, because you're blocking CD38 and B-cell maturation antigen (BCMA), does require extra attention to preventing infections, so the administration of anti-infectives as well as monthly intravenous immunoglobulin.

But the question is: Can we not give this forever? Is there a fixed duration for this type of approach that will yield similar results? We need more data to find out.

PERSEUS, the upfront quadruplet of Dara-RVd plus an auto transplant plus Dara-Rev maintenance into eventually lenalidomide monotherapy maintenance, continues to show us long-term data that may provide functional cure without T-cell redirection, as we have estimated survivals of 17 years. This is really blowing everyone's mind, and the data presented at IMS shows a 6-year PFS of 81% and a 6-year OS of 86%. This is really where the field is at the moment for newly diagnosed patients. And if we think about this data, there are many older patients who will still get this type of therapy who will never relapse of their disease, and we may be able to functionally cure them with standard approaches at the moment.

So this is creating the new bar that needs to be beat for moving T-cell redirection like bispecific antibodies and chimeric antigen receptor (CAR) T-cell therapy to the frontline setting.

Talking about bispecific antibodies, the CERVINO study, Cervino if you're not Italian, looked at etentamig, the new BCMA bispecific antibody with altered affinity, compared to standard approaches. This was presented by Pete Voorhees. And the overall response rate of 74% versus 46%, with a hazard ratio of 0.4, really cementing the fact that in early relapse, BCMA-directed therapy is going to be better than the standard. Really exciting, as this joins the ranks of MajesTEC-3, MajesTEC-9, and MagnetisMM-5, looking at the role of bispecific antibodies in early relapse.

Now, what makes etentamig special is that given its altered affinity, they have lower rates of cytokine release syndrome and can actually go immediately to monthly dosing. So though this asset is not yet approved, we're really looking forward to the eventual approval of this therapy to help get some of those centers that have been reluctant to start treatment with bispecific antibodies because of the need for a step-up dosing period and weekly administration. Now we can go right to monthly with this type of drug. It's better than standard of care. It's really moving things to the front of the line very quickly.

The EXCALIBER study, or excal-IBER if you want to put the emphasis on the wrong syllable, looked at some of the updated data from EXCALIBER, which was a head-to-head phase 3 study comparing the triplet of daratumumab, iberdomide, and dexamethasone versus the CASTOR regimen of daratumumab, bortezomib, and dexamethasone (DVd).

Remember that this was the first US Food and Drug Administration (FDA)-approved myeloma therapy based on accelerated approval from MRD analysis, and we saw an improvement in MRD-negative complete response (CR) rates from 21% with DVd up to 41% with Dara-iber. We don't yet have PFS data, as the FDA mandated that this wait until median readouts to not alter the outcomes of the study.

But to give an idea of how impressive this data is, the current most frequently prescribed regimen in the second line for myeloma is daratumumab, pomalidomide, and dexamethasone, based on the APOLLO trial. That is given in about 10% to 14% of all second-line prescriptions in the US and has an MRD-negative CR rate of about 9%.

However, iberdomide is a new class called cereblon E3 ligase modulators, or CELMoDs. In my mind, these are really super IMiDs. That combination of a pill once a day for 3 weeks in a row and 1 week off, along with standard-of-care daratumumab, gives you a 41% MRD-negative CR rate. This is really blowing our minds. And on top of that, we have some excellent data from centers like ours that CELMoDs may augment T-cell activity, such that if you give somebody iberdomide and then follow this with a CAR T, you may be collecting a far better and more agile T cell. So this may be the great kind of bridge therapy from a relapse patient who ultimately wants to go on to T-cell redirection like CAR T.

Now, we've been talking a lot about bispecifics, but what's better than two? Three. And trispecific data is being thrown out left, right, and center. We're seeing a lot of different drugs, like ISB 2001, targeting BCMA, CD38, and CD3, or a number of drugs that are targeting BCMA, G protein-coupled receptor class 5 member D (GPRC5D), and CD3, like ramantamig, IBI3003, and SIM0500, with ramantamig being the most mature data to date, as we're now seeing data from evolving studies in early relapse and upfront, including Trilogy-4, -5, -6, and -7. This is following data from later relapse still showing a 100% response rate to this asset.

So we are extremely excited about this drug, and given the fact that the drug doesn't spend the entire time focusing on GPRC5D but bounces back and forth between the different target antigens, so far, we're seeing lowered on-target, off-tumor toxicity compared to the GPRC5D-targeting talquetamab.

So ultimately, the next big step, and a little bit of a teaser, it's going to be in our next episode: How do we sequence therapy? We have to think about myeloma like a chess game. So the question is that first relapse. We're seeing a lot of data emerge, not just from standard approaches, but from bispecific antibodies, CAR Ts, CELMoDs, and antibody-drug conjugates (ADCs).

What are we going to give in second line, and how does that impact what we do in third line? So the question is, do we go for the gusto, so maybe the patient never relapses, or do we tailor the response anticipating a subsequent relapse that we have optimized options for? So in our next episode, we're really going to dig into the sequencing of therapies in great detail.

And ultimately, what does this mean for our practice today? It really means that we need to go above and beyond what we've done in the standard approach. I think CD38-based therapy in early relapse, like Dara-Pom-Dex, Isa-Pom-Dex, and Isa or Dara plus carfilzomib, has been the standard for several years now. However, I think data is now emerging that BCMA-based assets, whether they're CAR Ts, bispecifics, ADCs, and in the future, trispecifics, need to come into play not at the end of the road, not as a last-ditch effort, but as forward-thinking therapy in the early relapse setting, and in the future, this is going to be part of the upfront setting.

So I think what this means for our community practitioners is either start to get these into your lexicon now and be able to prescribe, or work with your local tertiary or quaternary center to figure out how to jointly manage these, because these are going to lead to functional cure for some and potentially true cure for even more.

And with that, I'm Dr Joshua Richter. Thanks for spending time with me today on Hematology Highlights.

This transcript was generated by AI and lightly edited.