COMy 2021 | CARs & MAbs: broadening the myeloma armamentarium

You look at patients that have been exposed to IMiDs, proteasome inhibitors, CD38 antibodies. Those triple-class exposed patients have poor outcomes, especially when they are triple-class refractories or refractory to PI, IMiD, and a CD38 antibody is associated with an overall survival of only 12 months. So we need new agents for these patients.

The good thing is that we have now several drugs recently approved for these triple-class refractory patients. We have melflufen, we have selinexor, and the BCMA antibody-drug conjugate, belantamab mafodotin. This is a antibody with attached to the protein a warhead, in this case monomethyl auristatin F, which is a microtubule inhibitor. And in that way, the BCMA antibody can bring this toxic molecule to the tumor cell and kill the tumor cell. Belantamab mafodotin has a overall response rate of approximately 30% in triple-class refractory multiple myeloma, and a median PFS of also approximately three months. So this is an agent that we can now give in Europe and in United States in triple-class refractory myeloma.

Also recently approved is the first CAR T-cell product, ide-cel. This CAR T-cell product targets BCMA-positive tumor cells, and induces a much higher response rate, 70%, 80%, also with deep responses and a median progression-free survival of approximately 12 months. The big advantage of CAR T-cell therapy is that it is a single infusion after which the patient has a treatment holiday, which is very comfortable for the patient also when it comes to quality of life, because otherwise the patient has to come to hospital frequently. Toxicity of ide-cel is cytokine release syndrome at the beginning, mostly one day or two days after the infusion. And in some patients, some neurotoxicity, often coinciding with cytokine release syndrome. Infections can also occur in these heavily pretreated patients. And you have to be careful and treat the infections in a timely fashion.

Cilta-cel is another CAR T-cell product that’s very advanced in terms of clinical evaluation. It has a higher response rate, 90%, and also a higher rate of complete response. Its toxicity consists of cytokine release syndrome and some neurotoxicity, the classic neurotoxicity that coincides with cytokine release, but also with cilta-cel, it has been described that some patients experienced delayed neurotoxicity, which can consist of movement or cognitive disorders or neuropathy. And recently this type of delayed neurotoxicity has also been described for a patient treated with ide-cel.

And then, another important class of new agents is the class of the bispecific molecules. Bispecific antibodies bind to CD3 on the T-cell and, most of the time, to BCMA on the tumor cell and thereby T-cells are redirected to the tumor cell and the tumor cells are eradicated. BCMA bispecific agents are very effective with an approximately 70% response rate and also deep responses can be seen here. 20%, 30% of the patients achieve CR. A substantial number of patients have VGPR. Cytokine release syndrome is also often seen with bispecifics, but it’s typically less severe than what is seen with CAR T-cell therapy. And also you have to be careful here with, with infections, partly because these patients are very heavily pretreated. And partly because these patients develop hypogammaglobulinemia because also normal plasma cells are eradicated. The advantage of bispecific antibodies is that they are directly off the shelf available, which is very convenient for patients with the rapidly progressive disease for which the manufacturing of CAR T-cells can be cumbersome.

A disadvantage of bispecifics is that you have to give to them continuously often until progression. So many bispecific antibodies are targeting BCMA, like teclistamab, like the compound from Dana Bio and from Pfizer. But there are also a new bispecific antibodies that target other antigen such as talquetamab targeting GPRC5D and cevostamab targeting FcRH5, which is important because BCMA expression is heterogeneous, can be lost after BCMA-targeted therapy, and in those cases, other bispecific antibodies targeting other antigens can be effective and helpful for the patient.