Treatment Options for Frail Patients at Early Relapse | Paul Richardson, MD | IMS 2023

Hello everyone, it's a pleasure to have time with you today here at this amazing International Myeloma Society meeting, the 20th in fact, being held in Athens, Greece. I have the privilege of presenting today on options in frailer older patients in the context of early relapse, but focusing really on opportunities for patients and options specifically that lie outside of the classical bi-specific and cellular therapy approaches that are gaining so much excitement in the field, recognising that those approaches are obviously tremendously valuable to younger, fitter patients, but for frailer elderly patients these options may be less practical and less feasible in fact, but above all I think it's a matter of understanding that we need all the options in the management of this disease and very importantly as we think about multiple myeloma to understand that it truly is a disease of subgroups and in that context we have to have our treatment options both available on the one hand, but on the other hand have a rational approach to how we sequence and use them. So my session has really been looking at what do we do when we face lenalidomide and daratumumab refractory disease after first relapse, what options do we have and we recognise that re-challenging with CD38 based therapy can be sub-optimal in terms of responses and durability of response that we see, say for example if you've already had daratumumab a re-challenge with a daratumumab based platform may be less ideal. Interestingly you may be able to derive more benefit from an isotuximab based approach in combination with other strategies. For the frailer patient this obviously may be relevant if one thinks of isotuximab combined with pomalidomide for example, but above all you may also be thinking in terms of an opportunity such as elatuzumab and pomalidomide which is a very reasonable combination, well tolerated, but we also recognise some of the limitations of that approach so clearly newer strategies are needed. And in that context what I'm focusing on today is really what are they and what do they look like and we're discussing obviously the opportunities from other small molecules such as selenexor and XPO1 inhibitor which is an oral agent combined with others in particular and dosed at a low dose in combination can be really quite active. We're looking then at other opportunities like venetoclax and the translocation 1114 positive patients where this oral agent combined with other strategies such as proteosome inhibition and in particular bortezomib and then an appropriate patient in combination with carfilzomib can be very active so I think that there are important small molecule opportunities that are worth focusing on. Now the thing I wanted to touch on though is importantly in Europe there is the availability of melphlufen which is a peptide drug conjugate and this is very different in terms of its mechanism action to traditional cytotoxics and it works by a very targeted delivery system directly to the tumor cell and so leaves behind it a lot of the side effects that we typically associate with conventional chemotherapy and indeed with high dose chemotherapy so with that in mind melphlufen in Europe is approved and used typically with dexamethasone and recent combination trials have shown really exciting promise there when combined not only with proteosome inhibitors like bortezomib but also with daritumumab and then as we think beyond those opportunities and look to where we're going in terms of new directions I think it's important to recognize that we have a whole new space generated after both pomalidomide based strategies and linolydomide based strategies have failed and that lies with the so-called cell mods which I like to think of as degraders and these are highly targeted approaches which engage the cerebral and E3 ligase complex and trigger a rapid degradation of both icaros and allos these are key transcription factors that control not only plasma cell biology directly but activate the immune system against it I think these are particularly promising because we've shown pre-clinically that they're able to overdrive pomalidomide and linolydomide resistance and then when we've taken this to the clinic these agents have worked in patients in whom linolydomide has failed them and in whom pomalidomide has failed them and above all what we're seeing now in triple class refractory patients is promising activity from the most potent arguably of the cell mods namely mizigdomide. I should mention there's been data at this meeting on from iberdomide showing it to be very well tolerated and very active and we've also presented updates on our mizigdomide experience showing that not only is it active even just as a monotherapy without dexamethasone but especially combined with dexamethasone as we've published recently in the new england journal a few weeks ago when you combine it and you do so in patients in whom all three major drug classes have failed them you see a very solid response rate from just an oral agent of around 41 percent and these responses appear durable and sustained and what's very important also to note is we saw a response rate also in those patients who are bcma exposed in other words they could have had prior belantamab amaphodotin they could have also had prior car t therapy and bispecific therapy and in those group of patients we were able to see promising activity in federal response rate of 50 no less in those patients. Now in terms of the durability of these responses it's important to acknowledge that with the two drugs of just mizigdomide and dexamethasone the duration of response was around seven to eight months having said that when you combine this particular platform with other drugs like for example butezomib or carbrosimab or for that matter cd38 antibody these responses are dramatically larger they almost double in size and at the same time the durability is much longer so we see great promise for these approaches in the future. And then finally in terms of the other agents that we're discussing at my session today one of the focuses is on antibody drug conjugates namely belantamab amaphodotin and this is a bcma targeted approach which is not strictly a t-cell redirecting approach which obviously is a bispecific and certainly not a cellular therapy such as a car t but it does target bcma. Now obviously we've recognized the ocular toxicities associated with its use but this has proven much more manageable and as a result of bringing this toxicity down we've been able to show you can administer this drug every two to three months in combination with other drugs manage the ocular side effects actually remarkably well and from a patient perspective and then above all engender a response when you combine it with other drugs so we're very excited to have these other opportunities for our patients to complement the real revolution that we're seeing with the immunotherapies for those younger and fitter patients we're now seeing opportunities open for older frailer patients which we have to realize constitute in fact the majority of our patients with myeloma recognizing that the median age of diagnosis of this disease is 70. So with that being said it's been a very exciting meeting and it's been a privilege to be part of the faculty here presenting on these exciting opportunities for our patients. Thank you very much. you