At IMS 2024 I had the opportunity to provide an overview of the landscape of chimeric antigen receptor T-cell therapies in the relapsed multiple myeloma setting. I was able to review some of the data for the late-line approvals such as data from the original pivotal KarMMa study as well as the CARTITUDE study which showed that for patients with at least three prior lines of therapy and triple class exposure, in fact many of the patients being triple-class refractory, chimeric antigen receptor T-cell therapies targeting B-cell maturation antigen have truly revolutionised the field.
We have seen progression free survival of 8.8 - 35 months using the two different products that are currently FDA approved, which is idecabtagene vicleucel as well as ciltacabtagene autoleucel, and this has really been a remarkable improvement from PFS that was under 5 months previously for these patients. So that led to their approval, FDA approval, in March of 2021 for ide-cel as well as February of 2022 for cilta-cel. In the last year we have seen the data for anti-BCMA CAR T-cells in earlier lines of disease in the KarMMa-3 trial wherein idacabtagene vicleucel was studied in patients with 2-4 prior lines of therapy with significant improvement of standard therapies with a median progression free survival that was 14 versus 4 months for patients with triple class exposed disease. This was really a very impressive landmark for these patients. As well as we have seen the use of ciltacabtagene autoleucel in early lines of therapy in the CARTITUDE-4 trial wherein we saw almost a 74% risk of progression or death with the use of ciltacabtagene autoleucel in earlier lines of disease when compared with standard of care daratumumab, pomalidomide and dexamethasone and pomalidomide, Velcade and dexamethasone. In fact, at this congress we saw an improvement in overall survival that now favoured ciltacabtagene autoleucel.
So we’re seeing that BCMA-directed CAR T-cells are really revolutionising the field of relapsed myeloma. Earlier this year the FDA approved both cilta-cel and ide-cel in early lines with slightly different FDA approvals in terms of their indications. However, we are routinely using these now in clinic.
The next steps will be how we can incorporate these CAR T-cells in even earlier line, including newly diagnosed settings as well as how can we improve the access, persistence and availability of these CAR T-cells for patients with relapsed disease. So those are some important areas of ongoing investigation.
Why is CAR T-cell therapy a better treatment option for RRMM?
CAR T-cell therapy is a very important new treatment avenue for patients with relapsed myeloma. The most important factor that comes in is the fact that it has transformative efficacy, really hands down improving overall survival, progression free survival, compared to standard approaches as early as second-line myeloma as well as late-line multiple myeloma. So, first of all is its transformative efficacy.
Additionally, CAR T-cells are typically a ‘one and done’ type therapy where patients go through this procedure and then are followed with active surveillance. So this has in numerous studies shown improvement in quality of life over ongoing standard treatment options. And patients really enjoy the treatment break as well as improvement in quality of life that comes with these therapies.
So I would say that for both of those reasons this frequently is a preferred strategy for deep, durable remissions without additional therapies which is what our patients need. Of course it’s not without toxicities and there are some unique toxicities but I think we are developing a better understanding of how to identify, mitigate and treat some of these toxicities.
Where does it stand in treating frail patients?
Autologous stem cell transplant is a modality in treatment of myeloma that has long been a strategy that has mostly benefitted patients who are fit. With the advent of CAR T with better development of patient selection strategies as well as mitigation and treatment of some of the toxicities, this has become accessible to more patients who were traditionally not candidates for autologous stem cell transplant. The very frail may still be excluded in most efforts but overall CAR T-cells have the ability to reach far more number of patients in terms of their eligibility than autologous stem cell transplant.
One of the greatest bottlenecks, though, remains in terms of access to these therapies because, much like autologous stem cell transplant, these are mostly available at larger transplant programmes. However, I do feel that a significantly higher number of patients will now be CAR eligible that may or may not previously have been autologous transplant eligible. So I do think that with right patient selection this can be carefully offered to a select number of frail patients.
What are some of the challenges in this treatment?
There are several unique challenges that need better understanding. We are doing much better with our understanding and treatment of cytokine release syndrome with high-grade cytokine release syndrome and immune effector cell associated neurotoxicity affecting first of all a small number of patients and then we’re developing better treatment approaches, early identification for these things.
However, the areas where we continue to struggle remain ongoing delayed cytopenias. We continue to struggle additionally with on-target, off-tumour toxicities as well as delayed neurotoxicities which we understand poorly. Additionally, treatment options for these delayed neurotoxicities are largely unsuccessful and patients continue to deal with certain types of neurotoxicity events for a prolonged period of time which deeply impacts their quality of life. Luckily, with movement of these therapies into earlier lines, with better bridging strategies, with better education about identification and mitigation of some of these toxicities, we are doing better but there is still a lot that we don’t understand.
The other aspect that will need further study is the risk of secondary malignancies, in particular haematologic toxicities. For the longest time it has been felt that many of the patients who receive CAR T-cells have been very heavily pre-treated with prior autologous stem cell transplants but this risk seems very real, as high as up to 10% of the patients in some of the original studies. As these therapies move into early lines particularly, newly diagnosed where patients may or may not go to autologous transplant, those larger randomised studies will help us understand if there is a clear signal and if we can identify a patient phenotype or subset where this is more likely to happen so we can select our patients much better.
