Are there any trial results that you anticipate coming out this year that might inform CAR T therapies for MM?
Dr Chari: There is great interest in more mature data from the allogeneic CAR data, fully humanized CAR constructs, and alternative cell types, for example NK cells. Getting longer follow-up from the CARTITUDE studies to show what is the median PFS and overall survival will be important. Finally, data for earlier relapse will be important, as there are a lot of clinical trials going on, particularly in high-risk and early-relapse patients. High risk remains an unmet need and the question is, “Can CAR T change the natural history here?”
Is there a particular area of unmet need that should constitute a key focus for drug development and research efforts in 2021?
Dr Chari: Multidrug-refractory disease has historically been an unmet need and is currently characterized as disease refractory to immunomodulatory agents, proteasome inhibitors, and CD38 inhibitors. However, potentially in the not-too-distant future, it could be anti-BCMA-refractory disease. Other unmet needs include molecular high risk, extramedullary disease, frail elderly, those with persistent renal failure, or central nervous system myeloma that could potentially benefit from novel therapeutics. Many of these subgroups are underrepresented or outright excluded from clinical trials. Studying these groups requires multisite collaborations to attain an adequate sample size.
Has there been any recent progress toward curative regimens in MM?
Dr Chari: “The median overall survival has been gradually increasing and something not frequently discussed is that we are curing approximately 10% to 15% of patients with MM. We need to understand what it is about these patients that leads to cure. We know that the vast majority have undergone autologous stem cell transplants. Many are eager to abandon transplant, but it has also been the basis of the improvements in the overall survival of younger patients more so than older ones. So, I think we need to know more about how and when transplant is best implemented and how it is sequenced with other therapies.
Up to now, the patients who we have typically cured are those who have historically been low-risk patients with transplant-based approaches. There has been an unprecedented response rate of these T-cell redirection therapies in heavily treated patients, keeping in mind that not only are these patients heavily treated, but we know that as patients go through these sequences of therapies, even when there is an adequate number of T cells, the T cells are exhausted. There’s great interest in what happens when these move earlier. “Might you be able to get deeper, more durable responses?”
Another unanswered question involves the mechanisms of relapse of all of therapies we currently have approved. The translational science is really important, as often clinical development precedes our understanding of disease and treatment biology. Figuring out why these regimens stop working is essential to answering questions about sequencing and rational combination strategies. For example, what is it about lenalidomide refractory disease that makes these patients have worse outcomes even when you are using non cross-resistant drugs? If we are really going to understand the disease, and cure MM in greater numbers of patients, it is imperative to develop all these exciting novel therapeutics and at the same time iteratively learn from those who aren’t being cured. This requires understanding not only MM but also its genomic and immunologic milieu.
This interview has been edited for style and clarity.
Disclosure: Dr Chari has served as an advisor or consultant for and has received grants for clinical research from numerous pharmaceutical companies.
- Sebag M, Bahlis N, Venner CP, et al. A randomized phase ii, open label, study of daratumumab, weekly low-dose oral dexamethasone and cyclophosphamide with or without pomalidomide in patients with relapsed and refractory multiple myeloma. Presentation at: 62nd ASH Annual Meeting and Exposition; December 5-8, 2020. Abstract 413.
- Chari A, Berdeja JG, Oriol A, et al. A phase 1, first-in-human study of talquetamab, a G protein-coupled receptor family C group 5 member D (GPRC5D) x CD3 bispecific antibody, in patients with relapsed and/or refractory multiple myeloma (RRMM). Presentation at: 62nd ASH Annual Meeting and Exposition; December 5-8, 2020. Abstract 290.
- Cohen AD, Harrison SJ, Krishnan A, et al. Initial clinical activity and safety of BFCR4350A, a FcRH5/CD3 T-cell-engaging bispecific antibody, in relapsed/refractory multiple myeloma. Presentation at: 62nd ASH Annual Meeting and Exposition; December 5-8, 2020. Abstract 292.