ASH 2021 | Latest news in myeloma: MRD, BiTEs, and CAR T-cells

Hi, I’m Mohamad Mohty from the Sorbonne University in Saint- Antoine Hospital in Paris. I’ve been asked today to give a sort of an overview about the hottest myeloma data and impact on the future clinical practice. Well, what I can say that during this ASH 2021 annual meeting in Atlanta, it was a hybrid meeting, very exciting meeting. We had 4,140 abstracts being presented either oral sessions or posters. Among these 4,140 abstracts, we have 879 abstracts dedicated to multiple myeloma. So as you can see among the whole hematology field, whether malignant hematology, benign hematology, multiple myeloma by itself as a single disease is occupying 20 or 25% of the whole communication at that ASH meeting. So this clearly highlights the excitement but also the major advances we are seeing in this disease. And the natural history of myeloma is definitely changing. And the treatment landscape is being revolutionized progressively.

So it could take me hours and hours to go through the 800 plus abstracts. So, I’ll maybe focus on three aspects. First of all, MRD measurable or minimal residual disease, it looks like according to the data presented at this ASH 2021 meeting that MRD is becoming now the endpoint, the goal to achieve. MRD today is becoming what CR or even VGPR used to be in the past. And actually this is now something within reach. We have the GRIFFIN Phase II randomized trial. We’ve seen an update about the results of this trial. This is a trial testing DARA-VRd, daratumumab bortezomib lenalidomide dexamethasone, versus VRd in the transplant setting. And now with longer follow up, we can see that not only DARA-VRd is superior to VRd in terms of stringent CR but also in terms of achieving MRD negativity.

And this is translating towards now a trend of a PFS benefit progression-free survival benefit, which wasn’t seen at time of the initial follow up a time of the Blood paper publication about this trial. And we have also a similar story in the German Multiple Myeloma Group HD-7 trial, which was presented for the first time during this meeting. And interestingly, this trial had MRD after induction as a primary endpoint. So a very brave approach, I would say. And in this trial, the authors, the investigators led by Dr. Goldschmidt and colleagues tested the combination of VRd and isatuximab which is another anti-CD 38 monoclonal antibody versus VRd. And the primary endpoint was met with more than 50% MRD negativity after induction, and the hazard ratio is in favor at 1.8 versus VRd. And of course the speculation, the expectation is that if we are able to achieve sustained MRD in these patients, this is going to translate towards a longer survival and long term outcome.

Last but not least, we’ve seen the update of the MASTER trial. So this is about the use of daratumumab and KRd, carfilzomib, lenalidomide, dexamethasone. Very strong potent combination, quadruplet combination and here of course, I’ll not go into the details because now the paper has just been published a few hours ago in the Journal of Clinical Oncology. It was about guiding the treatment through MRD. And again, what is really very important is about in patients with MRD negativity, whether we can stop treatment. And we know that for the patient, discontinuing the treatment and having some long treatment free interval is crucial for the quality of life but also from a pharmacoeconomic perspective. And this MASTER trial, which has been masterly done/performed by Dr. Costa and colleagues for the so-called commit consortium in the United States has clearly established the proof of concept.

When you use such potent combination with transplant for instance, you can push the boundaries of MRD negativity beyond 80%. So lots of excitement about MRD, the use of quadruplet and it is likely in my opinion, that some significant proportion of these patients will be cured in the long term. The other two major topics which were crucial in my opinion, during this annual meeting were about the bi-specific antibodies but also again, the CAR-T cells. And now we have a huge number of different bi-specific antibodies T-cell engages. So a very smart way of immune therapy, trying to enhance, to use in vivo the T-cells to guide them into the tumor. So we had updated presentations about the teclistamab bi-specific antibody targeting BCMA, talquetamab GPRC5D, cevostamab, the elranatamab, the regeneron bi-specific antibodies. And it can take me hours to go through all of these details.

But the key message is that using these bi-specific antibodies in a population, which is refractory more than five or six lines, medium, five or six lines of prior therapies. The response rate is above 60%. So the bar is now very high. Remember in the past, when we used novel agents in relapse, refractory multiple myeloma, the bar in terms of response was around 30%. Now the bar is higher around 60%. And another key message is that when it comes to the safety profile, especially as a cytokine release syndrome, the incidence is quite high, but actually these are mainly grade one and two CRS. And for the time being with the limitation of the relatively short follow up, we don’t see major safety signals. And of course, these are very easy to use, they’re off the shelf. And my best guess is now to move these bi-specific antibodies into earlier lines, but also in combinations with other drugs.

And we’ve seen also already during this ASH 2021 combinations of talquetamab with daratumumab or talquestamab with daratumumab and so on. And last but not least when it comes to this field of immune therapy, we cannot skip the CAR-T cells. And I think the biggest highlight in the field of myeloma from ASH, in my opinion, is the confirmation of the longer follow up of the results of the CAR-T cell construct cilta-cel. So Dr. Martin presented the update of the CARTITUDE-1 results. And now we are talking in a relapse refractory population, median of six lines of prior therapies. We’re talking about more than two years of median PFS. So really very impressive results. And this is now paving the way I think, to different trials, looking into the use of CAR-T cells in different and earlier disease stages, but why not challenging the use of autologous stem cell transplantation as it has been done in lymphoma.

And that was another, I think, highlight of this ASH 2021 with the ZUMA-7 trial, TRANSFORM trial, but also the BELINDA trial. But going back to CAR-T cells in multiple myeloma, the progress continues there because we’ve seen further refinement of the BB 2121 construct namely ide-cel. This is the bb21217, and actually with further refinement of the quality of the immune factors. When you generate the CAR- T cell, you can further improve the efficacy and the results presented by Dr Noopur Raje were really very good compared to the original KarMMa data. Of course, we need to be cautious and avoid comparing across trials, but I think definitely these are important. We’ve seen also the use of gamma secretase inhibitors. And again, this is a most welcome junction I would say, or combination with CAR-T Cells and last but not least, I really liked the presentation by our Spanish colleagues from Barcelona who actually performed the study using academic autologous CAR-T cells directed against BCMA.

And the results are also similar to what you achieve for instance, with the commercially available product ide-cel. But what’s really interesting, it means also that through collaborative and academic efforts, you can also allow access to these innovations. And I believe this is extremely important because on one hand, it is crucial to make advances to improve the survival of these patients and try to find the optimal combinations of the different available drugs and tools. But also it is crucial to make all of these innovations and advances accessible, available, and affordable to the vast majority of myeloma patients across a globe. And I think the myeloma community is committed to achieve this goal and it is really a very exciting era for all of us. And it’s bringing a lot of hope to patients and families.