VIDEO: Looking to the multiple myeloma pipeline for future treatment options

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There are a few very exciting developments in the pipeline that I'm really looking forward to. And one drug I would like to mention is actually a comeback of an older drug. And I'm talking about belantamab mafodotin [Blenrep; GSK]. So, this drug is pretty unique. It's a BCMA antibody toxin conjugate, and it received approval based on the results of a phase 2 study called DREAMM-2. And the timing of this drug coming out to the market was before the approval of bispecific antibodies, and at the time of very limited availability of CAR-T, so the need was huge. It was also approved in the fifth-plus line of therapy, and in the registration study, it showed 30% response rate in a highly refractory population, which is not as impressive as the novel immunotherapies we are talking about now, but responses were actually very, very durable. The approval was accelerated, and it was conditioned on the results of confirmatory phase 3 study DREAMM-3, which compared belantamab to pomalidomide [Pomalyst; Bristol Myers Squibb]-dex control arm. And the study was designed to show superiority, and it failed to achieve the primary endpoint of superiority. So also, it did confirm decent response rates and really, really prolonged responses with belantamab. Not meeting primary endpoint led to belantamab being taken off the market. So, there are two more phase 3 studies that are currently ongoing — DREAMM-7 and DREAMM-8. We do not have much update from DREAMM-8 right now, but we do have a press release from DREAMM-7. We don't have actual results yet. They will be presented at ASCO Plenary in February, but an announcement just cme out of positive results for PFS. The study looked at a combination of belantamab with bortezomib [Velcade, Millennium/Takeda] and dex, with control arm of daratumumab-bortezomib-dex, and I have to say, control arm is really good control arm, so it's not easy to beat. And we have superior PFS with belantamab-bortezomib-dex combination, which is very exciting and which, hopefully, will bring this drug back.

So now BCMA space is quite crowded again. We have two bispecifics, we have two CAR-T products, we have multiple, multiple options. We are in completely different situation now, but this drug still has its niche, because unlike all the immune-engaging drugs, it doesn't have the dreaded CNS toxicity. It does not require monitoring. It can be easily given in the community. All it requires is a follow up due to unique toxicities of keratopathy. But it's really, really very doable, and we now know reduce those frequency results, and maintain efficacy but less toxicity. So, again, the drug is becoming more manageable now compared to the initial approval, and it's otherwise minimally toxic. It can be given to really older and frail patients, and so I think this drug will be very beneficial for a patient population.

So, another not quite new but new thing that I'm looking forward to come is moving up CAR T therapies to earlier line. So, we now have two excellent BCMA CAR-T products, cilta-cel [ciltacabtagene autoleucel, Carvykti; Janssen, Legend Biotech] and ide-cel [idecabtagene vicleucel, Abecma; Bristol Myers Squibb, 2seventy bio], that are both approved in patients who had four prior lines of therapy. And, again, meeting this criteria of four prior lines of therapy is becoming more and more difficult these days, as we are putting now all our best drugs together in the front-line, and, really, patients can be triple-exposed after front-line therapy, and they can easily be triple-class refractory at the time of second relapse. It's getting harder and harder to get patients to meet the FDA level for the novel immunotherapies. And moving these therapies to earlier line is really, really important. So, both CAR-T products, the application is being reviewed by the FDA based on two positive studies, CARTITUDE-4 for cilta-cel and KarMMa-3 for ide-cel. Both studies used CAR-T in second-plus line for cilta-cel, and third-plus line for ide-cel, and they're very positive in those randomized control studies. So really looking forward to be able to use CAR-T earlier.

So, a couple of products that are truly in pipeline and we don't have access yet. So first is another CAR-T product — really exciting. That's GPRC5D CAR-T. It is the same target as for the bispecific antibody, docartamab??, and GPRC5D is widely expressed on plasma cells, and it has very limited expression in the healthy tissues — particularly skin and nails. Toxicities of GPRC5D therapy include skin and nail toxicities, and also very unique oral toxicity, mainly dysgeusia, or losing taste, which can be really uncomfortable for patients. Those toxicities, interestingly, are noted less with CAR-T compared to bispecific drug, possibly because of continuous exposure to the bispecific drug versus time-limited exposure to CAR-T and response rate was over 80% — again, of course, in highly refractory population. And toxicities in terms of CRS and [immune effector cell-associated neurotoxicity syndrome (ICANS)] were very comparable to other CAR-T products, and against this drug because of different target can be used in a post-BCMA space, which is where our unmet need now is and will be.

And lastly, another novel class of therapies soon to be approved is CELMoDs. CELMoDs are cereblon E3 ligase modulators and those are drugs that are very similar to in mechanism of action to IMiDs, but more potent. More potent in terms of cellular mechanisms, more potent in terms of immunomodulatory effect. We currently have two exciting drugs in the pipeline, iberdomide [Bristol Myers Squibb] and mezigdomide (Bristol Myers Squibb). For both drugs, we have phase 1/2 studies as monotherapy, or I would rather say in combination with dexamethasone, already published. So, studies were done of course in highly refractory population. And so specifically with mezigdomide, we have an overall response rate of 41% in triple-class-refractory patients. And I think it's very, very impressive because all these patients were refractory to IMiDs, and some of them were refractory to both lenalidomide and pomalidomide. And the mechanism of the drug is really similar. However, it was able to salvage 41% of already refractory patients, and iberdomide had 26% overall response rate in triple-class-refractory population. Both drugs, in terms of toxicity profile, again, somewhat similar to IMiDs, main toxicity is neutropenia. It is mostly manageable. Other toxicities such as skin and drug toxicities actually seem to be even less compared to IMiDs. So those are going to be really, really important, practice-changing drugs. And currently, there are multiple, multiple combinational studies ongoing, and there is a post-stress maintenance study of iberdomide run as compared to lenalidomide standard. So, I'm really looking forward to more results from the studies and eventually approval.