Second Myeloma Relapse and Beyond: Upcoming Strategies

Amrita Krishnan, MD, FACP: Our goals of therapy for patients who have multiple relapsed disease have changed in a good fashion, because we have better drugs available for them. For example, looking back now at least 5 or 6 years, when pomalidomide came on board, we were very excited because at that era, if you had failed lenalidomide or progressed on it, we didn’t have a lot of good options. So, pomalidomide had about a 30% response rate in combination with dexamethasone, had a median PFS of about 3.9 months, and we were happy with that. At least we had something to offer. But things have gotten even better beyond that now. For example, daratumumab came along. So, it’s a next step. Once you failed pomalidomide, we didn’t have a lot of good options. But then we had daratumumab, and that was for patients who had 3 prior regimens or double-refractory disease. We saw a response rate—again, with a single agent—about 30%, median PFS of about 6 months. We were very excited about that because, again, we had something else to offer.

Now we’ve moved even beyond that and said, “How do we give other combinations or newer types of drugs that can, for the multiply relapsed patients, offer longer PFS and deep responses?” And 1 of those options is immunotherapy, and that can be with antibody-drug conjugates. And there is an anti-BCMA antibody-drug conjugate that has shown high responses, about 60%, in patients who have advanced disease, including daratumumab progressors. And at ASCO this year, we heard about an update on CAR T-cell therapy with bb2121, a CAR T cell against BCMA. And those were very advanced patients.

Dr. Raja presented about the expansion cohort of this trial, which was patients who were required to have had daratumumab. And, in fact, 86% of those patients were daratumumab refractory. And we saw that with treatment with adequate doses of these CAR T cells, we could get responses in 95% of patients and a median duration of response of about 10 1/2 months—and remembering that these patients had a median of 8 prior regimens. So, speaking to this multiply relapsed patient and getting those kinds of duration of responses was very promising.

And so, my personal feeling is that immunotherapy is going to form a big backbone of our treatment. The other part of her presentation that should be noted was the toxicity. As it is a learning curve with CAR T cells, myeloma doctors were lucky in the sense that we came later to the CAR T cell than lymphoma and leukemia, so we were able to learn from them in terms of management of cytokine release, how to detect it early, and how to intervene early. And so, in the bb2121 trial, there was about a 60% incidence of cytokine release, but it was of a low grade, with just 2% of patients getting grade 3 or greater—so, suggesting that CAR T cells can achieve durable responses, high remission rates in patients who have multiply relapsed disease. And even more surprisingly, we’re able to see the patients become MRD-negative.

Targeted therapy is one of our goals for any cancer treatment, and we’re getting excited now in myeloma that we do have targets and approaches for certain subgroups of patients. For example, patients who have the 11;14 translocation, those patients tend to be high BCL2 expressors. And we have a targeted drug, venetoclax, that’s approved in CLL and is an inhibitor of BCL2, which can enhance cellular apoptosis. So, Luciana Costa presented data at ASCO this year looking at a phase I trial using escalated doses of venetoclax in combination with escalating doses of carfilzomib given weekly in patients, both 11;14 translocated, as well as nontranslocated. Importantly, in this trial, patients were carfilzomib-naïve, but patients could be exposed to other proteasome inhibitors. And, in fact, about 40% of those patients were refractory to other proteasome inhibitors.

And the results were certainly promising in that we saw response rates of about 80% in patients, including patients who were proteasome inhibitor refractory. And albeit it a very small number of patients…the response rates in the patients who were 11;14 translocated were 100%, suggesting that certainly this targeted approach for those 11;14 patients really, I think, is going to become a future staple regimen. Ultimately, we need venetoclax approved for myeloma, so that we are able to offer it to more patients, because that remains a challenge outside of a clinical trial setting. But I think that was a very exciting step forward for us—certainly for the 11;14 patients.