ASH 2020: Targeted therapies in r/r multiple myeloma

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Published: 8 Dec 2020
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Prof Marivi Mateos, Prof Meletios Dimopoulos, Prof Meral Beksaç, Dr Shaji Kumar

Prof Marivi Mateos (University of Salamanca, Spain) chairs an expert discussion with Prof Meletios Dimopoulos (University of Athens, Greec)Dr Shaji Kumar (Mayo Clinic, Rochester, USA) and Prof Meral Beksaç (Ankara University, Turkey) on the latest in targeted therapy for multiple myeloma from ASH 2020.

They discuss all the updates from this year’s ASH conference regarding targeted therapies for R/R multiple myeloma including the FORTE, APOLLO, IKEMA, ICARIA-MM and MAIA studies.

They also touch on the latest in newly diagnosed multiple myeloma and discuss the use of immunotherapy and CAR-T cells.

ecancer's filming has been kindly supported by Sanofi through the ecancer Global Foundation. ecancer is editorially independent and there is no influence over content.


MM: Good morning, good afternoon, good evening, depending on where you are. Welcome to this ecancer round table discussion on multiple myeloma after ASH 2020 in which we will have the opportunity to discuss about multiple targeted therapies with all the information we have just come in from the end of the ASH 2020. My name is Marivi Mateos from Salamanca in Spain and I would like to welcome to the experts that will be joining with me today in this meeting – Professor Beksaç from Ankara University in Turkey, Professor Kumar from Mayo Clinic in Rochester, Minnesota, US and Professor Dimopoulos from Athens University. Welcome to all of you and let’s evaluate the relapsed and refractory situation which is becoming a bit challenging in clinical practice. I think in the near future most patients at first relapse will be exposed to proteasome inhibitor, to IMiDs, and I would say that almost all of them will be in principle lenalidomide refractory and in the future, not in the near future, will be also refractory maybe to the anti-CD38 monoclonal antibody.  But if we focus on relapsed and refractory myeloma patients in the first relapse, anti-CD38 monoclonal antibody naïve, Dr Dimopoulos, what is the best option or how do you plan to make the right choice, especially after the presentation you did at ASH coming from the APOLLO study with daratumumab, pomalidomide and dexamethasone? But we have also updates coming from KD plus daratumumab, KD plus isatuximab.

MD: Yes, thank you. Although the APOLLO trial was designed for patients who have received two or three prior lines of therapy, there was 10% of the patients who received this combination as second line, as we mentioned, after exposure to VRD. At this point, especially taking your point that most of the patients will be progressing on some kind of lenalidomide maintenance, in my mind the most appealing combinations that we have are the combinations of carfilzomib, dexamethasone with one of the two anti-CD38 monoclonal antibodies. CANDOR has a longer follow-up and we see that for lenalidomide refractory patients we have a median PFS exceeding two years which is, in my mind, the best data that we have seen. We expect similar data to see in the IKEMA trial where isatuximab was used with carfilzomib and dexamethasone. So I believe if I have to choose, I think one of those combinations could be preferable for treatment of these patients. Of course it is important that in the APOLLO trial for the first time the combination of subcutaneous daratumumab with pomalidomide and dexamethasone was used as second line treatment. I think this is also a useful regimen for patients who have been exposed to frontline treatment such as VRD.

MM: Perfect, thank you very much. Professor Kumar, I have a million questions for you. Is there any special difference between the two monoclonal antibodies targeting anti-CD38, daratumumab and isatuximab? And do you have any preference by one or the other in any specific population?

SK: No, we have seen no difference in terms of the activity. Now we have almost two sets of trials – we have the CANDOR and the IKEMA, we also have the ICARIA and the APOLLO trial which are [?] similar designs with similar combinations. We have seen quite comparable results between the two monoclonal antibodies. Even when you look at the early data with the single agent isatuximab and single agent daratumumab the results were very similar in a similar patient population. So, to me, both drugs are pretty much interchangeable in terms of its purpose. Now, the question is which one would you choose in any given setting. Clearly the pomalidomide combination and the carfilzomib combinations, either of them would be appropriate based on the four phase III trials that have been done. What a particular institution might end up doing might depend on what is available in the formulary. Having said that, the subcutaneous formulation with daratumumab certainly changes the equation, there is certainly a convenience to getting a subcutaneous injection with daratumumab and some patients and some institutions and providers may prefer to use that for logistical reasons, again, because the [?] might be different in different countries.

MM: Yes, so an excellent answer. Professor Beksaç, we receive sometimes many questions and even if we are faced with patients in the relapsed situation, in challenging situations, especially patients with renal impairment as well as sometimes patients with extramedullary disease. We know that these patients usually are not basically included in the clinical trials. So sometimes we can’t do formal recommendations but at ASH 2020 I think that you are the author of one abstract involved in this specific subgroup of patients – patients with renal impairment or extramedullary disease receiving pomalidomide, dexamethasone plus isatuximab. Do you want to comment something about that in order to give a clear message to the audience about the potential use of this combination in this population?

MB: Yes, thank you so much. Certainly for patients who have renal impairment, among the IMiDs pomalidomide is the most safest one. So with a monoclonal antibody and a pomalidomide combination it certainly works and with an effective regimen there is also the potential to circumvent the renal impairment. Regarding the extramedullary disease, in this congress there have been a couple of abstracts including one of the faculty members, Kumar has also another abstract with another combination excluding a monoclonal antibody. Extramedullary disease constitutes only a minority of patients. For newly diagnosed it’s about 10% and in the relapsed setting it’s even more. But in the ICARIA study among 300 patients there were 34 patients who had [?] and extramedullary disease, so they are combined together, and 24 of those patients were in the experimental arm. We were able to compare the efficacy of this triplet in extramedullary disease and both the response rate and the PFS were two times more for the response and three times more for the PFS. So it is an advance but for advanced patients it’s not the curative approach.

MM: Yes, sure. And now we have to dedicate just some minutes to the new modalities, the BCMA targeted therapy, but not only BCMA because we had the opportunity to see new targets in multiple myeloma. If we focus on the BCMA targeted therapy where we had the opportunity to see, I would say, a long list of CAR Ts as well as T-cell engagers targeting BCMA. Professor Kumar, any general thoughts about all these BCMA targeted therapies in terms of cell therapy? So T-cell engagers or CAR T-cells, do you want to pick up one of these as the favourite or the most relevant for you?

SK: You mean CAR T versus bispecifics?

MM: Yes, for example.

SK: I think 2020 ASH is going to be remembered as probably the inflection point in immunotherapy. We’ve been talking about the promise of immunotherapy for a long time but now we have accumulated data showing that this is really going to be the future. My feeling is that CAR T has most data in terms of durability of response so far. The bispecifics appear to be quite effective, based on the results that were presented, with three different targets now. But we don’t have a good sense of the durability of the bispecifics yet and also what could be the toxicity associated with the long-term administration. The advantage of autologous CAR T is the fact that it is a one-time thing. The disadvantage, obviously, is that it’s not off the shelf so you have to prepare the patients for it. So it’s really hard to know which one is really going to take off. My feeling is that both of them are going to play a role, maybe the CAR T more in the setting of maybe earlier lines of therapy and the bispecifics maybe in the later lines of therapy, especially in the relapsed setting where patients are more likely to be taken care of closer in their community which makes it easier to do a non-cellular therapy approach.

MM: Okay, thank you very much. Well the last question will be for Professor Dimopoulos. I was quite surprised but in a positive way about the median overall survival reported in ide-cel because Professor Kumar previously alluded to the lack of data in terms of durability of the response for the T-cell engagers. But three years of median overall survival after bb2121 in heavily pre-treated myeloma patients was surprising for me. Is it the same feeling for you and can you comment on this data because the median PFS was approximately nine months but the overall survival extended up to almost three years?

MD: Yes, I think these results are very, very interesting and we need to find an explanation on how these patients may respond to subsequent therapies in view of the short median PFS. So I believe that CAR T-cells should not only be viewed as a modality that is associated with a median PFS of 10-14 months but also as a modality that may give the opportunity to the patient at the time of relapse maybe to respond again to several lines of therapy. So I believe there are several things that we need to know and definitely modulation of the immune system is playing a very important role in the management of myeloma.

MM: And let’s go to a discussion about the newly diagnosed myeloma patients. If we focus first on the transplant eligible, I think that we have had the opportunity to listen to some abstracts in which the role of autologous stem cell transplantation in this population is, I would say, under debate. I would like to ask Professor Dimopoulos what is your perspective in terms of autologous stem cell transplantation? Do you consider that continues being the standard of care or maybe this hot topic of debate will continue ongoing for the coming years?

MD: Yes, thank you Professor Mateos. I think that in this ASH meeting we saw data which supports that early autologous stem cell transplant is associated with an improved PFS and also in some of the studies that have a longer follow-up with improved survival as well. So I believe that early autologous stem cell transplant remains as a standard of care. Of course we know that historically each time we have new drugs or new approaches this is a question that we pose. So far it seems that high dose therapy for myeloma is resistant and is here to stay. We don’t know in the future, however, I believe that it should be included in the standard of care today.

MM: Okay, Professor Beksaç, would you agree to conduct clinical trials in which maybe the risk status together with the minimal residual disease status will be incorporated into the treatment algorithms in order to plan again the role of autologous stem cell transplantation?

MB: Yes, I think so. Today the importance of personalised medicine and patient-based decisions are becoming more and more important and we have come to notice that there are some long-term survivors, even without transplant, and with transplant they can survive in remission more than ten years. So the question for these patients is transplant still valid for those. On the other hand patients who achieve, let’s say, MRD negativity prior to transplant and after transplant MRD is negative, it is still questionable to pursue because the question is is MRD once enough or is a sustained MRD more important? In this setting I think there is a need for future trials although there might be not so much interest in the audience. But the thing is, transplant is important but for some subsets maybe there are other modalities. The EMNO2/HOVON trial has shown the importance of consolidation. So on top of transplant the role of consolidation is also very important.

MM: Excellent, and a quick question to all of you: standard of care for this transplant eligible, newly diagnosed myeloma patient – RVD or VD plus anti-CD38 monoclonal antibody or maybe VTD plus daratumumab? Shaji?

SK: I think, for us, the combination of VRD is still the standard of care. We tend to use the four drug combinations only in the setting of high risk disease because of the deep MRD that has been seen, or high rates of MRD that have been seen, with the quadruplets and data showing that getting to be MRD negative is probably the most important thing for the high risk patients. The transplant still continues to be an important part and the FORTE trial data confirms that the transplant still has something to offer even when you use a combination like KRD.

MM: Professor Dimopoulos?

MD: Yes. As you know, in Europe we cannot still administer daratumumab in the frontline setting outside clinical trials. However, we have the possibility of VTD plus daratumumab; now, whether VTD plus daratumumab is better than VRD remains to be seen. I believe that one of those induction regimens are appropriate for the treatment of myeloma and, as Professor Kumar mentioned, I believe that in the future a quadruple combination including anti-CD38 monoclonal antibody may be of benefit, not only in the high risk patients which clearly may be indicated but also in standard risk myeloma patients because we still want to increase the percentage of such patients that may achieve MRD negativity even after induction.

MM: Professor Beksaç?

MB: Based on the approvals in our country, VCD and VDTR [?] are the ones and in some countries as well but VRD is certainly better than these. The role of the quadruplet, adding daratumumab, has been shown that even in high risk patients it decreases the gap but it doesn’t overcome the high risk feature. So, for this purpose the debate is still ongoing.

MM: Thanks, and now let’s move on to the transplant ineligible population. I would like to ask Professor Kumar because he presented an update of the MAIA study and I think that this study will result, from my point of view, in the best result so far reported in the transplant ineligible population. Do you consider that daratumumab/lenalidomide/dexamethasone should be the standard of care in the upcoming phase III clinical trials?

SK: I completely agree, I think daratumumab/lenalidomide/dexamethasone certainly, especially with the updated data now with the PFS probably projected to go beyond 55-60 months is the best that we have seen in the context of newly diagnosed myeloma in the transplant ineligible population. Obviously we cannot compare across clinical different trials but I think the data would support certainly the use of DRd as an initial therapy for this group of patients. Whether it should be used over and above VRD is a little harder to say in the absence of comparative data but our approach has been to use DRd in the standard risk and continue to use VRD in the high risk transplant ineligible patients, primarily because of data showing that there is benefit of using a proteasome inhibitor in the high risk setting. But one thing important to the follow-up data is now we see that both the high risk and the standard risk appear to benefit in a similar fashion with DRd which was not that evident with the early analysis.

MM: Yes, this is true and I think that this is the second time that the hazard ratio for patients with high risk is quite good. So definitely we need to have longer follow-up in order to evaluate from the numerical point of view the median PFS. Professor Beksaç, just a quick question about something to which Dr Kumar previously alluded to – three drug based combination RVD plus the anti-CD38 monoclonal antibody in this transplant ineligible because there at least two phase III clinical trials ongoing, RVD plus daratumumab, RVD plus isatuximab. Do you see any specific population in which we can potentially select this combination according to what Professor Kumar previously said?

MB: I think that even daratumumab-RD can be myelosuppressive and there is a need to reduce the lenalidomide dose in the elderly. But our experience with the ongoing IMRO [?] study, for instance, is extremely good. So in the elderly setting selected patients who have good performance status and who are in the fit range, they benefit from this quadruplet. But coming back to patients elderly and who have renal problems, in this setting maybe the [?] type of approach could be also kept in mind.

MM: Thank you very much. I think that this brings us up to the end of this meeting with a positive message because we are observing how the survival of our patients with multiple myeloma is clearly improving, basically thanks to the incorporation of new options of therapy, new targets. So thank you very much to all of you and I hope you are enjoying this ecancer round table discussion after ASH 2020. I am looking forward to seeing you after ASH 2021 but maybe in a physical way. Thank you very much.