Prof. Nikhil Munishi: High-throughput gene analysis has brought new methods for diagnosis and prognosis assessment, and immunotherapy is setting off a new wave of MM therapy
Q1：High-throughput Genomic Analysis provides a new way of researching pathogenesis and molecular diagnosis of MM. At this ASH meeting, your team’s study aims at evaluating High-throughtput Genomic Analysis in diagnosis of low-risk smoldering MM(SMM),could you talk about it?
Dr Munshi: In this study, we have evaluated patients with smoldering myeloma and we have tried to highlight those who may have a good risk. What we have is a very unique set of samples. We have patients who have not progressed from smoldering myeloma to myeloma for five years or more. Then we have patients who progressed for whom we have paired samples - samples collected when they had smoldering disease (SMM) or monoclonal gammopathy of undetermined significance (MGUS), and then a sample from when they had active myeloma. Using high throughput genomics, both whole genome sequencing as well as RNA sequencing, we tried to analyze what predicts the non- progressor group. In this abstract, we identified that there are certain significant differences observed in the coding regions. If we look at patients in the MGUS stage, the number of mutations is lower compared to active myeloma and the progressor group. We observed very low NRAS (3%) and BRAF (3%) in non-progressing SMM. That is an important finding. And we did not observe driver mutations in FAM46C, TTN, CYLD, etc., in this patient population. So we had differences in mutation patterns that predict for outcomes. We also looked at what we described recently in a paper in the Journal of Clinical Oncology as genomic scar score (GSS). GSS is low in the non-progressing SMM (3) compared to progressive myeloma (11). So GSS could help identify patients who are likely to remain smoldering compared to others. We have done additional sequencing to see if there are any specific patterns that predict outcomes. We are beginning to describe some of these patterns. The progressor patients have already acquired certain signatures of aggressiveness that may be enriched in MYC target, DNA repair gene, and mTOR pathways, and that may predict progressors over non-progressors. We have also seen that certain signatures of mutations such as APOBEC are also important in this patient population. To summarize, in this abstract, we found the differences between smoldering patients who are not progressing for long periods (5 years and more) compared with those who have progressed, and identified the mutational patterns, the signatures of the mutations, and we have looked at expression profile and pathway activation that differentiates this group. This is the first such effort from which we can begin to develop a genomic-based algorithm for identifying good-risk patients, and then the rest could be considered higher risk patients.
Q2：A study of your team aims at evaluating resistance mechanism to venetoclax,could you talk about it?
Dr Munshi: Venetoclax is an important drug that targets BCL2. It has been approved for other lymphoid malignancies, but in myeloma, we have evaluated it and found it to be effective especially in combination with bortezomib. It’s effective in patients with t(11;14) where cyclin D1 is upregulated when BCL2 is upregulated. This is where it is being utilized. However, patients relapse, and we are beginning to study the markers for resistance to venetoclax. In our study, we first looked at extrinsic resistance, where we took the two cell lines, treated with venetoclax and induced resistance over time. We then identified individual clones. What we find on this study is that the resistance process appears to be heterogeneous (and that is important to keep in mind) and we have identified pathways that may be activated in the resistant clones that we studied. The ERK inhibitor leads to additional killing of clones. Then we tried to correlate with intrinsic pathways. We found that cell lines with intrinsic resistance do not have a similar pattern to what we found with extrinsic pathways of resistance. ERK was not super-significant in this group. It is known that changes in MCL1 and BCL-XL are the drivers if the ratio of one to the other is high. This has been evaluated in other malignancies as well, and what we have now observed in myeloma. We have identified and reported that one of the genes, GOS2 is reduced and may be important in intrinsic resistance, and we need to understand its role further as we move forward. So we have provided evidence in this abstract of the molecular mechanisms of acquired resistance to venetoclax with activation of the ERK pathway as one of the prime targets. That will now begin to give us molecules that can be combined with venetoclax, such as an ERK inhibitor on one hand, but also MCL1-targeting molecules that are already in the clinic for synergistic activity.
Q3：BCMA CAR-T shows great efficacy in relapsed and refractory multiple myeloma, obtain great response rate. So, could you talk about latest advances of BCMA CAR-T?
Dr Munshi: BCMA CAR T-cells are very exciting. At this ASH meeting, there are many studies being presented by various groups including from the US, Europe and China, with many CAR T-cell products targeting BCMA. There are data from larger studies like KarMMa study, the Johnson & Johnson/Legend study, and then other investigators presenting to show how BCMA-targeting T-cells work. Almost all of these studies show similar data, which are that response rates are very high (75-95%) and toxicity is limited. The main toxicity ends up being cytopenia because of lymphodepletion. CRS (cytokine release syndrome) happens in almost everybody, but the severity is low, grade 1 or 2. Grade 3 is seen rarely (5-7%). Very importantly, different from lymphoma, neurotoxicity is not a common issue with these patients. Concerns that remain relate to PFS. Even though responses are very high and deep (half of patients who get CR or PR have MRD-negativity, sometimes even higher), PFS remains around 8-12 months. Patients still relapse. There is great excitement though because patients being treated are very late in their disease, 5th and 6th lines of treatment and beyond. Even then there are these good responses. The effort now has been to improve PFS. Many things are being planned, and some of them are already in the clinic. For example, using CAR T-cells in second-line, and in some high-risk patients, in first-line. Also strategies to prolong PFS by using maintenance treatment. There are studies using two CAR T-cell treatments being infused over a certain period of time, or they can be combined with immune modulating agents. But there is great excitement around the efficacy of CAR T-cells, and they are being used in earlier stages of disease. Stay tuned for more data for their use in the clinic in the very near future.
Q4：could you enlighten us with other latest advances of RRMM treatment regardless of CAR-T?
Dr Munshi: If I had to summarize this ASH meeting, immune therapy has drawn the greatest focus so far,and immunotherapy in multiple forms, not just as CAR T-cell therapy as I have been describing, for instance. Immunotherapy utilizing different targets. Immunotherapy utilizing other mechanisms, including bispecific molecules. We have to keep all these new treatment options that are becoming available in mind. For example, BCMA is a wonderful target, but besides that, there are two other targets that are currently being analyzed. One of those targets is GPRC5D. This is a very exciting target because it is expressed predominantly on myeloma cells, in the early studies using bispecifics, there was a really good response with minimal toxicity. So GPRC5D is an important new target for CAR T-cells and for bispecifics. There is another target called FCRL5. That also is expressed predominantly on myeloma cells on 1q or subtype specific. In early bispecific studies again, it shows good responses. So we have two new targets besides BCMA for immune targeting. We know CAR T-cells are very effective using BCMA-targeting as well as these new targets connected through bispecific antibodies. Bispecifics show very good efficacy, and good tolerability with minimal toxicity. I think the most important part of this ASH meeting was the immune-based therapies, the efficacy of CAR T-cells moving forward, and the BCMA and other novel targeting bispecific agents that can provide deep and durable responses in this patient population. In this ASH meeting, immunotherapy for multiple myeloma has been most important and the antibody-based therapies will be of great significance and interest to us in coming years.