VIDEO: ‘Exciting’ approvals for multiple myeloma over the last few years

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In the past years, there have been a few very exciting approvals, and I have already incorporated in my practice and we will be using those medications more and more in the myeloma community. And I am talking about bispecific T-cell engagers. The first drug to come on the market was teclistamab [Tecvayli; Janssen]. It was approved in October of 2022. So, we have been using this drug for over a year now. It is a BCMA-targeting bispecific T-cell engager. And as that was followed in August of last year by elranatamab [Elrexfio, Pfizer], which is also a BCMA/CD3 bispecific T-cell engager, and — very exciting — talquetamab [Talvey; Janssen], which has a different target on myeloma cell, it is a GPRC5D/CD3 b-specific T-cell engager. And so, this drug, having a different target, is a very valuable salvage option for patients who have already progressed through BCMA-directed therapies.

So those drugs are all approved currently in patients who had at least four prior lines of therapy, which, of course, is extremely refractory, extremely heavily pretreated population, and those patients prior to those approvals had very limited options. And response rates for both teclistamab and elranatamab are around 60%, again, in patients who have failed already three classes of myeloma drugs, [immunomodulatory drugs (IMiDs)], proteasome inhibitors and CD38 antibodies.

Responses are very durable. We have not very long follow up. We have around 1 year and a half, 2 years follow-up from the studies, but they can already tell us that patients who have achieved response are maintaining this response for over a year and may be approaching 2 years. So, as a class of drugs, really changed how we are treating patients with heavily pretreated and multiple refractory myeloma. Now [unintelligible] drug in the class talquetamab, then GPRC5D bispecific antibody actually has close to 70% overall response rate in, again, triple-class-refractory myeloma patients, and it does have over 40% rate in patients who have been previously treated with BCMA-directed bispecific antibodies and even high response rate in patients who were treated with other BCMA-directed therapies such as [chimeric antigen receptor T-cell therapy (CAR T)] or antibody-drug conjugate.

Now, logistically, there are challenges in giving these therapies. The main side effect we are worried about is cytokine release syndrome and neurotoxicity at the initiation of these drugs. We are very familiar with those toxicities from CAR T therapies. The bispecifics, the toxicities are, on a smaller scale, lower rate compared to CAR-T and also lower rates. However, it is still very significant, and those toxicities have to be addressed very promptly. Fortunately, those toxicities are happening in the pretty narrow window after initiation of the drug. To mitigate them, all three drugs are given in a step-up dosing approach and patients need to be very closely monitored in the first week or so of the first cycle. Based on how the studies that led to approval were designed, FDA label actually recommends inpatient observation for a certain number of days after each dose and that leads to — potentially, with a high volume of eligible patients — it creates burden on the health system, a burden in terms of inpatient beds that are already stretched.

So, there are ways to give this medications outpatient. Our institutional experience at Fox Chase and other institutions were already presented at recent meetings and with appropriate close outpatient follow-up, these drugs can be given very safely. However, it still requires a lot of resources. It requires very close monitoring, it requires the ability to admit a patient immediately if complications arise, and it requires the staff to be trained, and it requires availability of tocilizumab [Actemra; Genentech] on site. So, all these resources may not necessarily be available in the community, but they're definitely available at the tertiary centers, very easily at the centers that are already treating patients with CAR-T. So right now, I think the biggest goal is to push this really daily practice change of therapies to the community and make some available for as many eligible patients as possible. And collaboration is critical here, because patients can be safely initiated on therapy at the referral centers and safely transitioned back to the primary oncologist close to home for continuation of therapy. And again, we are talking about over a year of doing well on this treatment.

Now there are, of course, long-term toxicities outside of the immediate toxicities of CRS and neurological toxicities, and those are mainly infections. Infectious risk is increased, because BCMA-directed therapy is an immunosuppressive therapy. We know now how to mitigate those risks. There is supportive care that's quite simple. Patients should be maintained on regular hive agent infusions, patients should be on PCP prophylaxis, of course, on viral prophylaxis, and patients need to be monitored. But this is really, really, very doable and I think more and more patients will be benefiting from these amazing drugs.