By Joshua Richter, MD
What is a Anti-CD38? And How can Anti-CD38 help patients with Relapsed/Refractory Multiple Myeloma (RRMM)? This study that we presented at this year's ASH (American Society of Hematology) meeting was entitled, Enduring Responses After One Year Fixed Duration Cevostamab Therapy in Patients With Relapsed And Refractory Of Multiple Myeloma Early Experience From A Phase 1 study.
Now, the bispecific antibodies are an exciting new field in myeloma, with the recent approval of Teclistamab and the recent filing of Talquetamab we recognize that they're gonna be an integral part of the way we manage relapse and refractory myeloma. However, the lion share of therapeutic approaches at this time with biospecifics is to treat until progression or intolerance.
And this could mean years of ongoing therapy, and potentially putting patients at increased risk for infections. So one of the really wonderful things about this study is that we gave patients Cevostamab, which is an FcRH5xCD3 bispecific for fixed duration. Patients received 17 cycles of therapy, and as the drug is given every 3 weeks, this comprised approximately 1 year of treatment.
At which point, regardless of where they were at, patients were stopped and observed off of therapy. Now at this time for the data cutoff there have been 18 patients who have been monitored post stopping after 17 cycles. And again, they're on no therapy, which is relatively unheard of in the relapse refractory myeloma world.
Currently, 14 out of 18 remain in remission. Some patients beyond 6 months, some beyond even 12 months off of all therapy, and anyone that was in a stringent CR (sCR) or better. At the time of completing the 17 cycles has not yet progressed. So this is hoping to really inform the future of how we use all biospecifics in myeloma.
So we get asked a lot of things about these studies. One is that what happens if while they're off of therapy, if they relapse? And the study allows for patients to be retreated with the same drug if they have had a disease-free interval after stopping treatment, there are a number of patients who have now relapsed a few of them and we're following them, although the date is quite early.
Another question that we're often asked is, what are the toxicities of this drug? And because this is a T-cells redirecting agent, the same type of toxicities that we see with other biospecifics and Car Ts are things that we do see with Cevostamab, including cytokine release syndrome and icons. However, there isn't any of the on target toxicity that we see with the GPRC5D agents. Where in those agents the two big ones that are out there right now, we see issues with rash and taste issues, dyscrasia and weight loss.
At the moment Teclistamab is the only FDA approved bispecific antibody. But again, with the recent filing of Teclistamab hopefully it will not be too far into 2023, where we have two bispecific assets at our disposal. Now the question is are we gonna just continue patients on treatment with these drugs? Until progression or intolerance. And I think we're starting to get a better understanding that there may be some biological endpoint that if you get people down deep enough, stringent CR (sCR) MRD negative or even better sustained MRD negative, we may be able to stop them on their therapy. And a improve quality of life for not having to get recurrent treatment. And B as we'll, stop redirecting some of those T-cells. We may mitigate some of the infectious risks that we see across the class of drugs. So I think this is gonna help guide us as we navigate the world of commercially available biospecifics.
We are moving forward with Cevostamab and the main things that we're looking for is how to optimize therapy from all standpoints. Number one, limited or fixed duration therapy, two at the same ASH (American Society of Hematology) meeting data was presented by Dr. Suzanne Trudel regarding the use of Prophylactic Tocilizumab to prevent CRS with step up dosing.
With these type of strategies, we can see market reductions in the incidence of CRS and right now with Teclistamab recommended by the FDA to admit patients to the hospital for greater than a week. The hope is that if we can offset much of the risk of CRS, we can give these drugs as outpatient and in the community to make the drugs more available to everyone.
Furthermore, there's ongoing studies, including the PLYCOM study, P L Y C O M, that's looking to combine Cevostamab with a number of other agents. Including the immunomodulatory drugs, the cell mods, and an anti-CD25 antibody to hopefully reduce the incidence of Tregs so that we maximize the T-cell response rate.
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A substance that forms bonds with CD38, a protein that is present on certain types of red blood cells and in high numbers on certain cancer cells, in particular myeloma cells. It is possible that anti-CD38 monoclonal antibody will block the CD38 protein and assist the immune system in its fight against cancer cells. The cancer of the plasma cells known as multiple myeloma can be treated with monoclonal antibodies directed against CD38. In addition, research is being done on their potential use in the treatment of various other types of cancer.
So the key takeaways are that bispecific antibodies are here to stay, and they're going to become part and parcel of the way that we manage patients with multiple myeloma. So just as a number of years ago, we went as hematologist and oncologist from the realm of classical chemo into having to learn to navigate the world of checkpoint inhibitors and the subsequent toxicities therein biospecifics are gonna be that next leap that we all have to become used to dealing with things like cytokine release syndrome, things like icons things such as the more atypical infections, including viral reactivations like CMV and EBV or even pneumocystis pneumonia. So really constructing a prophylactic approach, including judicious use of intravenous immune (cells) globulin for patients with significant Hypogammaglobulinemia. So it's really gonna usher in a new approach for all of us as hematologists and oncologists.
New medicines that are effective when administered for a fixed length and offer the possibility of a longer treatment-free period may help lessen cumulative toxicities and the burden of therapy on patients and healthcare systems. Cevostamab is an FcRH5xCD3 T-cell engaging bispecific monoclonal antibody that facilitates T-cell directed killing of multiple myeloma cells. It has demonstrated clinically meaningful activity and favorable toxicity when administered Q3W for up to 17 cycles (approximately 1 year) in an ongoing Phase I trial (GO39775; NCT03275103) in patients with heavily pre-treated RRMM (Trudel et al. ASH 2021). Here, we present preliminary duration of response data for individuals in GO39775 who completed 17 cevostamab therapy cycles and then discontinued treatment.
All patients had RRMM for which no established therapy was available, acceptable, or tolerable, and they had an ECOG performance level of 0–1. In order to mitigate cytokine release syndrome, intravenous infusions of cevostamab were provided in 21-day cycles with a step-up dose in Cycle 1 (C1). The treatment was administered for 17 cycles (roughly one year) unless PD or unacceptable toxicity occurred. The analysis comprised patients who achieved a partial response (PR) or better by C17 and maintained a response through C17.
Patients received cevostamab dosages ranging from 40 to 160 mg and a median of 17 treatment cycles (range: 16–17). The best overall response (BOR) among the 16 patients evaluated was: severe complete response (sCR) in 7 patients, complete response (CR) in 3 patients, very good partial response (VGPR) in 5 patients, and partial response (PR) in 1 patient. 13 of the 16 patients remained in remission at the end of the study, with 8 patients (BOR: 5 sCR, 1 CR, 2 VGPR) sustaining a response 6 months after therapy completion and 3 patients (BOR: 2 sCR, 1 CR) maintaining a response 12 months after therapy completion. Eight patients were followed for 6 months. None (0/10) of the patients who finished C17 and achieved a sCR or CR relapsed. Only 3 of the 16 patients (BOR: 2 VGPR, 1 PR) had PD after C17 of cevostamab was completed.
Initial findings from this Phase I study suggest that patients can maintain lasting responses (6 months) after 17 cycles of cevostamab therapy, suggesting the potential for an extended treatment-free time following fixed-duration therapy. To establish the duration of response and associated correlates post therapy completion, additional data are required. Additional data will be reported on responding patients who prematurely discontinued therapy (i.e., before to completion of C17) and patients who were retreated with cevostamab.
Joshua Richter, MD - About The Author, Credentials, and Affiliations
Dr. Joshua Richter is an Associate Professor of Medicine in the Division of Hematology and Medical Oncology at the Tisch Cancer Institute. He is the multiple myeloma director at the Mount Sinai Blavatnik Family-Chelsea Medical Center. Dr. Richter treats patients suffering from plasma cell dyscrasias, such as multiple myeloma and associated disorders like AL amyloidosis, plasma cell leukemia, and Waldenstrom's Macroglobulinemia. Dr. Richter has a lot of experience with clinical trials in precision medicine that look at new treatments like antibody therapy and immunotherapy. He has written a lot about these topics and has been asked to speak about them in his own country, in other countries, and around the world. Journals such as the New England Journal of Medicine, Blood, and the Journal of Clinical Oncology have published his work.
NIH - anti-CD38 monoclonal antibody. NIH, 2023
ASH - 1924 Enduring Responses after 1-Year, Fixed-Duration Cevostamab Therapy in Patients with Relapsed/Refractory Multiple Myeloma: Early Experience from a Phase I Study. ASH, December 10, 2022