ASCO 2024 | Linvoseltamab versus teclistamab for TCE RRMM and the sequencing of bispecifics with CAR-Ts

So I’m here to present the matched indirect adjusted comparison between linvoseltamab and teclistamab. Teclistamab is already approved in patients who have triple class exposed and relapsed refractory myeloma. In the same population a clinical trial of a new drug linvoseltamab was also conducted, and we then compared the results of linvoseltamab with the drug teclistamab to see whether it is comparable, whether the outcomes are similar. And in our findings, we find that when we balance doing the match adjusted indirect comparison, we use the most important prognostic factors that was identified by Doctor Kumar in a publication which are important. So we use the top six important prognostic factors and match them between linvoseltamab and the teclistamab clinical trial outcomes. And when we did that, we found out that the linvoseltamab really did do well. There was improved overall response rate, complete response rate, and improved progression free survival and time to next treatment. Then we also compared again with all the prognostic factors that was identified by Kumar and again tried to adjust the two populations which meet those criteria. And again, we found that overall, the linvoseltamab did well when it was compared to teclistamab.

The adverse events of linvoseltamab is comparable to all the 2 or 3 other bispecifics which have been approved and are available. All the bispecific antibodies as a class have CRS as their side effect but usually the CRS are grade one and two, rarely grade three, and occasionally there can be neurological symptoms called ICANS, and it is also very low with these bispecific antibodies. So bispecific antibodies as a class have done better in their side effect profile compared to Car-T cell therapy in terms of severity of CRS as well as the ICANS.

Now the sequencing is become an important question. As a matter of fact, in this ASCO meeting, there was a talk on sequencing in the educational portion by my colleague, Doctor Samir Parekh. What we note is that is patients who receive Car-T cell therapy, it is a one and done deal. After the Car-T cell administration they are not on any ongoing therapy. So patients who relapse after Car-T cell therapy, they have been not on any maintenance therapy. So they have had a time away from any treatment. So their immune system is much more robust and they respond very well to subsequent bispecific treatment. Not only that, the two currently approved Car-T cells in myeloma or BCMA specific, and most of the patients when they relapse, over 90% do express the BCMA so they can receive a BCMA directed bispecific, as well as a GPRC5D directed bispecific antibody. Now, on the other side, when a patient does relapse on a bispecific, the way the bispecifics are administered currently is they are given continuously until progression. So they are actually most of the patients are relapsing on therapy. And because the bispecific is being administered, one of the way they escape and relapse is either by downregulation of the antigen or mutation in the antigen or the T cells become anergic or there is upregulation of T regulatory cells. So it is kind of not so easy to transition directly from a bispecific to a Car-T cell, it is better to give some time off so that the T-cell function improves, so you can generate a good Car-T cell therapy and you don’t have failure. And also to give an interim therapy before you take them on to Car-T cell therapy. And also, if the patient was on a BCMA bispecific, you know, the reason they are progressing could have been down modulation of the antigen expression of the BCMA or mutation in BCMA. So they may not do as well on Car-T. So there is a subtle difference. You can sequence them, but you need to know how. But the future is getting brighter because there is also Car-T cell against GPRC5D in clinical trial. So other modalities are coming. But one thing that was made clear during the educational session is the best salvage after a T cell redirection therapy is another T cell directed therapy.