ASH 2020 【Expert connection】| Discussion among Prof. Shaji Kumar and Prof. Liang Wang: focus on relapsed/refractory multiple myeloma drug resistance and research progress
Dr. Liang Wang: As we all know, the treatment of relapsed or refractory multiple myeloma still remains a big challenge for now. In 2020 ASH meeting, are there any notable advances about RRMM? Would you please talk about this from the aspect of different types of agents?
Dr Kumar: Absolutely. There are a lot of new data coming out at ASH related to how we manage relapsed and refractory multiple myeloma disease. There are a lot of new drugs that have become available for patients over the past ten to fifteen years, but particularly the proteasome inhibitors, immunomodulatory drugs, and more recently, the monoclonal antibodies. Clearly, patients are getting these drugs and the myeloma are starting to breakthrough, and as the disease becomes refractory to these agents, we have to start developing new drugs or new modalities that work by different mechanisms of action. I would broadly classify three different groups of drugs. One represents the improvements over existing classes of drugs. There are new proteasome inhibitors coming through. We have new immunomodulatory drugs, especially the so-called CELMoDs. We saw some follow-up data from the iberdomide CC-220 of a new CELMoD that is quite effective even in patients who are refractory to lenalidomide and pomalidomide. There is some basic science work related to the mechanism of action of iberdomide as well. Then there are new anti-CD38 monoclonal antibodies that are being developed like the MOR202 and TAK-079. All these are anti-CD38 targeting but monoclonal antibodies that might represent an improvement over the current generation of anti-CD38 monoclonal antibodies. But I think the most exciting are the new small molecules and the immunotherapies. Among the new classes of drugs we have some data for venetoclax which seems effective - a BCL-2 inhibitor that is effective in translocation (11;14) patients. We have more data pertaining to the tyrosine kinase inhibitors, especially the targeted NIK agents. Nearly half of myeloma patients have mutations involving KRAS or NRAS, and this class of drugs might have a significant role to play in this disease as well. Then there are some data going back to the group of improved existing classes with melflufen. This is a new alkylating agent that also has some data from clinical trials being presented at ASH. But I feel that the major improvement is going to come from the immunotherapeutic approaches. There are two main groups. One is the CAR T-cell therapy, and then the bispecific molecules. The other exciting data from both classes of drugs being presented at ASH is the long-term follow-up for bb2121. The KarMMa trial results clearly showed there is durability of response. The majority of patients (70-80%) treated with the bb2121 respond to therapy, and the median duration of response appears to be roughly a little over a year, and the median PFS 9-10 months. We were hoping that the responses would last even longer, but even this durability of response is quite something considering these patients had a median of 5-6 prior lines of therapy and were refractory to the current lines of drugs. So these new therapies are getting close to FDA approval. We saw data from cilta-cel, the original molecule from Legend, now being developed by Janssen. With over 100 patients, there was almost a 100% response rate, and very deep responses. We don’t have a median PFS, but based on what we are seeing so far, it appears that will probably exceed a year-and-a-half, again in a heavily pretreated group with a median of six prior lines of therapy. These are also promising responses. We also saw data from some newer CAR T-cell therapies that are being developed, including the CT053 being developed by CARsgen, and also from UC San Francisco, which was interesting because it uses a different mechanism from previous lentivirus-based techniques to produce the CAR T-cells. That could alleviate some of the problems associated with lentivirus, or at least the potential for problems which require these lentivirus vector-based T-cell patients to be followed for up to 15 years. Hopefully this new platform for delivery will make long-term follow-up easier and safer. Another exciting aspect of CAR T-cell technology was the introduction of allogeneic CAR T-cells. We saw the results of ALLO-715, an allogeneic off-the-shelf CAR T-cell, which based on the initial group of patients who were treated, appears to be effective. They have seen responses and some of those responses have been lasting. We haven’t seen any significant toxicity, particularly graft versus host disease, which is something we were worried about. One thing that is common amongst all these CAR T-cells is that all patients get some degree of cytokine-release syndrome (CRS), but that can be very easily managed. Serious CRS of grade 3 and 4 seems to be rare. Neurotoxicity is something we worry about. Most of these agents appear to have very low rates of neurotoxicity, usually grade 1 and 2, although we did see some delayed neurotoxicity with ciloleucel which certainly needs further study to better understand. The other group of immunotherapies are the bispecifics. We saw updated data from the Amgen (AMG) 420 and AMG 701 molecules. This was one of the earliest bispecifics to be tested in myeloma and the results still seem to be quite promising. We saw some newer BCMA-targeting bispecifics, especially teclistamab from Janssen. Again, over 100 patients, very high response rates up to 80%, manageable CRS, nothing specific for neurotoxicity. There is obviously a significant risk of infection which we need to get a better understanding of. We also saw a bispecific against BCMA from Teneobio, TNB-383B, that also seems to be quite effective. We saw newer targets being targeted using bispecifics, especially talquetamab which is targeting GPRC5D, also the FCHR5 CD3 bispecific, that are showing early results which appear to be quite promising. Finally, there is a new antibody drug conjugate, MEDI228, a BCMA-targeting antibody drug conjugate that has good activity, but high toxicity, that is being worked through as well.
Dr. Liang Wang: Nowadays, BCMA is the key target for CAR-T therapy towards multiple myeloma. In this ASH meeting, you presented one study evaluating efficacy and safety of CT053 in heavily-treated RRMM patients, the efficacy is very impressive. would you please talk about this study?
Dr Kumar: The study we are doing is a phase 1b with a planned phase 2 expansion with CT053, the BCMA-targeted CAR T-cell from CARsgen Therapeutics. There were two presentations at ASH - data from the LUMMICAR-1 study being conducted in China, and the LUMMICAR-2 study from the US. LUMMICAR-1 had 24 patients. LUMMICAR-2 had 20 patients. Both trials showed an overall response rate in the range of 80% to >90%. In LUMMICAR-2, 17 of the 18 response-evaluated patients had a response. Interestingly enough, 10 of those 17 had a very good partial response or better. In 14 of the 18 patients, their bone marrow had already become MRD-negative despite having seven levels of M-protein. Efficacy is clearly good so far. The phase 2 trial is enrolling with the recommended phase 2 dose of 250-300 million CAR T-cells. In terms of toxicity, we saw mostly grade 1 or 2 CRS. There was one grade 3 neurotoxicity, but overall, this was easily managed. Most of the toxicity appeared to be cytopenias related to lymphodepletion. We saw a couple of patients with some delayed thrombocytopenia and neutropenia, which we believe is related to the CAR T-cell itself. This was a very heavily pretreated group of patients - almost three-quarters of the patients were triple-refractory, and half of the patients were penta-refractory. Nearly half the patients had high-risk cytogenetics and one-quarter had extramedullary disease. With the treatment, we saw that by four weeks, all patients had clearance of their bone marrow. By four weeks, most of the light chains had normalized in patients with measurable light chain levels. Patients with a M-spike of more than a gram, saw a profound reduction in the M-spike level in the setting of CT053 treatment. Lymphodepletion was pretty standard. Fludarabine and cyclophosphamide were given as outpatients. Patients were hospitalized for a week after the infusion of CAR T-cells primarily for observation, bearing in mind that we didn’t have much of a problem with grade 1 CRS. Overall, the safety profile is interesting and the responses are quite encouraging, so this trial is moving ahead.
Dr. Liang Wang: in the era before daratumumab, four-drug combination in newly diagnosed MM patients is not recommended due to toxicities. In recent years, daratumumab-based four drug combinations could provide deep and durable responses. So do you think we are ready to step into the era of four-drug combination in first-line setting? If so, what kind of patients would you prefer to use four-drug combination?
Dr Kumar: The data for the quadruplets are still emerging. We have data from the GRIFFIN trial looking at the daratumumab, lenalidomide, bortezomib, and dexamethasone showing a progression-free survival advantage for the four drugs compared to three drugs. We don’t have any overall survival data yet. The important question that comes up is can the fourth drug be used later on instead of using all four drugs at the same time? Similarly, the GRIFFIN trial with daratumumab plus VRd clearly shows deep responses before going to an autologous transplant. We also have data from the ALCYONE trial where daratumumab was added to VRd in the non-transplant setting and showed improved overall survival as well. I think there is clearly a role for introducing daratumumab in the upfront setting whether it is part of a triplet or a quadruplet. We still need to wait for the long-term data for daratumumab with VRd before we can say that a four-drug regimen should be the standard induction therapy for these patients. There are clinical trials ongoing looking at adding the fourth drug based on the depth of response. One of the pieces of data we need to have is whether we can use these four drugs together as compared to using maybe two triplets containing similar drugs back-to-back. Those are the things we need to be looking forward to right now.
Dr. Liang Wang: In this ASH meeting, I noticed one interesting abstract presented by professor Samur from Dana-Farber Cancer Institute, and they concluded that High-Dose Melphalan Significantly Increases Mutational Burden in Multiple Myeloma Cells at Relapse. In the era of so many novel agents, which can put MM patients into deep remissions, do you think it’s time for us to reappraise the role of high dose melphalan?
Dr Kumar: That’s a question I think we will be asking more often as we get new therapies. At this point, myeloma remains incurable, even with the more effective therapies like CAR T-cells. We are not able to keep the disease under control for long. So I see no reason to throw away a very effective therapy like transplant that can keep the disease under control for 2-3 years. Just by itself, it can achieve deep responses, and even deeper responses in the context of these newer therapies. I think of it as just one element of the therapy that needs to be used in conjunction with the other treatments that we have. The presentation looking at the mutational profile of the myeloma cells at the time of relapse is certainly interesting. The caveats are that it is based on a very small group of patients and we don’t know what the implications are there in terms of actual clinical outcomes. So far, we know from the IFM 2009 trial with a very long-term follow-up looking at transplant early versus delayed transplant, that it does not show any difference in outcomes for these patients in terms of overall survival. There are also long-term follow-up data from the EMN02 trial, which compared transplant to VMP consolidation, being presented at ASH this year that shows there is improved overall survival for the transplant. So I don’t think we are ready to throw the transplant away at this point, but we certainly need to figure out how best to use transplant. Do we transplant patients when they get to minimal residual disease with the four-drug or three-drug induction therapy? Another important question is from the findings that were presented with the mutation load in the relapsing myeloma cells. If we did the transplant at the time when the myeloma is in minimal residual disease negativity stage, will that decrease the risk of additional changes happening if there are very few cells left behind at the time of melphalan administration?
Dr. Liang Wang: Concerning the basic researches, we all know the pathogenesis of multiple myeloma is extremely complicated, and tumor microenvironment is a key element in the process of development and relapse of MM. Therefore, would you please briefly talk about tumor microenvironment advances of MM?
Dr Kumar: It has been known for a long time that tumor microenvironment plays a role in this disease, but the initial focus had been in the context of drug resistance in that the microenvironment actually protects the myeloma cells from the various drugs we use. Over the years, we have come to understand that it has a major role to play not only in the development of disease and the progression from the precursor phase to active myeloma, but also the development of relapsed refractory disease. The major component of the tumor microenvironment that seems to be playing a role is the immune system. We know the immune system likely plays a major role in terms of the transformation from smoldering myeloma to active myeloma. There are several presentations at ASH this year looking at the immune microenvironment and it’s role during this transformation process. The second aspect is understanding the role of the immune system and how it is affected by the disease response to treatments given for myeloma. This has become of great interest because now we have all these newer therapies, some of which require collecting autologous T-cells for the manufacturing of CAR T-cells. The important questions being asked are, at what time point are the T-cells most competent? What type of influence will the myeloma cells have on these immune cells? And how can we actually modulate these immune cells in order to enhance the anti-tumor activity? A further aspect of the tumor microenvironment is bone disease. There has been a lot of focus on that in the past and we have bisphosphonates and anti-RANKL inhibitors, both of which seem effective in reducing bone disease. The impact of these measures on the disease itself is not really well-outlined, though we have seen some PFS advantage both for bisphosphonates and denosumab in phase III trials. A third aspect is the marrow stroma. We know that it seems to help the myeloma cells escape the therapy. We know there is increased angiogenesis in the tumor microenvironment of the bone marrow as the tumors evolve. We also know the tumor cells become more extramedullary as the disease becomes progressive. Plasmacytomas cause involvement of other organs and CNS. So the mechanisms by which the myeloma cells escape the tumor microenvironment are equally important as we follow our patients long-term. We need to continue to understand the biology better.