There has been a surge in treatment advancements for multiple myeloma that have improved outcomes for patients in the front- and later-line disease settings, creating an eager need to keep abreast of these latest systemic therapy innovations. In an interview with Targeted Therapies in Oncology, Sagar Lonial, MD, program cochair for the upcoming 24th Annual International Congress on Hematologic Malignancies. hosted by Physicians Education Resource., LLC (PER.), detailed breakthroughs in the care of patients with multiple myeloma as well as other hematologic cancers, and offered a preview of what attendees might expect to hear at the meeting.
Particularly in the era of COVID-19 [coronavirus disease 2019] where so much information is continuing to come out but the live meeting opportunities are limited, [this meeting] provides an opportunity to hear from leading experts in their fields [giving] you the moment to moment changes that are occurring, said Lonial, who is also a professor and the chair of the Department of Hematology and Medical Oncology at Emory University School of Medicine, as well as chief medical officer at Winship Cancer Institute of Emory University in Atlanta, Georgia. These changes are occurring so fast, its hard for the [community oncologist] to keep up.
Anti-BCMA Agents and Other Advances in Multiple Myeloma
Lonial detailed the FDAs August 2020 approval of the B-cell maturation antigen (BCMA) antibody-drug conjugate belantamab mafodotin-blmf (Blenrep; Bela-maf) for the treatment of patients with relapsed/refractory disease following at least 4 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.1 This marks the first time a systemic therapy agent aimed at inhibiting BCMA received approval in the United States.
We have periods of time where a lot happens. Were seeing BCMA-targeted therapies really come to the forefront, Lonial said. Right now, [there are] 3 different ways to target BCMA. You can use the antibody-drug conjugate bela-maf, you can use a bispecific T-cell engager, or you can use a CAR [chimeric antigen receptor] T-cell therapy.
One of the advantages of targeting BCMA is that it is expressed exclusively on plasma cells, leading to fewer off-target affects, Lonial said. Additionally, BCMA activation has been shown to promote drug resistance,2 so inhibiting it may provide the dual benefit of suppressing tumor growth as well as overcoming drug resistance.
Regarding bispecific T-cell engager (BiTE) therapies, Lonial said clinicians may be familiar with this approach by looking at an established agent for the treatment of acute lymphoblastic leukemia (ALL), blinatumomab (Blincyto). Here, the bispecific CD19-directed T-cell engager binds to CD19 expressed on tumor cells and CD3 expressed on T cells,3 bringing them in close proximity with one another. I was skeptical that this approach would work in myeloma because I thought that T cells would be exhausted, and I wasnt sure youd be able to get them to work. But certainly, at higher doses, it appears that youre getting response [rates above] 65% to 70%.
Two notable BiTEs in clinical development that are aiming at BCMA for the treatment of multiple myeloma include teclistamab (JNJ-7957) and AMG 420, which have both been explored in phase 1 clinical trials (NCT03145181 and NCT02514239, respectively) with results presented at recent medical meetings.
In CAR T-cell therapy, a modality that Lonial said clinicians are familiar with due to recent successes in ALL and large B-cell lymphoma, there are multiple agents in development that target BCMA for the treatment of multiple myeloma. One of the advantages that has come to light over the CD19-directed agents is the lower rates of cytokine release syndrome and neurologic toxicity which account for the most troublesome adverse events of CAR T-cell therapy administration that lead to hospitalization. We dont know if thats a function of BCMA or of myeloma, Lonial said.
Of all BCMA-targeted CAR T-cell therapies, the most advanced in terms of FDA clearance is idecabtagene vicleucel (ide-cel; BB2121), which just earned priority review in September 2020. The Prescription Drug User Fee Act action date has been set as March 27, 2021.4
Other advances in multiple myeloma that Lonial mentioned included the development of the novel cereblon E3 ligase modulator (CELMoD) iberdomide, which has demonstrated response rates of up to 30% in patients with heavily pretreated multiple myeloma when used in conjunction with dexamethasone.5 Additionally, Lonial noted that the use of minimal residual disease (MRD) status as a patient selection tool will become more prominent as more agents are approved across settings.
If somebodys MRD positive, is that where you treat with a BCMA-directed therapy early to try and eliminate that? Those, I think, are really exciting questions were going to be able to answer.
Trends in Cellular Therapy and Other Topics
Lonial said that cellular therapy for the treatment of hematologic diseases by way of allogeneic stem cell transplants, in his view, represented the first time immunotherapy was used for the treatment of any malignancy. Moving into the modern treatment era, investigators are striving to refine these approaches and incorporate new modalities, such as CAR T-cell therapy, for the treatment of patients with hematologic cancers.
Another focus of the meeting will include looking at precision medicine techniques of the solid tumor world and applying those principles to cancers of the blood.
Using genetics and genomics to identify lymphoma subsets is getting us into both an immune era and a precision medicine era, Lonial said. The challenge for us in hematologic malignancies is marrying the 2 concepts together. How do you take both precision medicine and immune therapy and make it one treatment approach for a patient?
Lonial said the CAR T-cell therapy workshop which will be moderated by fellow meeting cochair Andre H. Goy, MD, who is physician in chief of Hackensack Meridian Health Oncology Care Transformation Service, chairman & chief Physician Officer of the John Theurer Cancer Center, Lydia Pfund Chair for lymphoma Academic Academic Chairman Oncology of Hackensack Meridian School of Medicine at Seton Hall University, and professor of medicine at Georgetown Universitymay be especially helpful for all clinicians hoping to learn more about this treatment modality, regardless of whether or not their centers are approved to administer it.
Knowing when to refer from the community [setting to an academic institution] for a CAR T-cell [administration] and what that can offer patients is critically important, he said. The advantage of CAR [T-cell therapy] from my perspective is it is a one-and-done therapy. And if that one-and-done really is done, then its a true victory. We dont want to limit [this only] to people who are seen in academic centers.
Finally, meeting cochair Jorge E. Cortes, MD, the director of Georgia Cancer Center and an Eminent Scholar of the Georgia Research Alliance at Augusta University in Georgia, will moderate sessions addressing the treatment of indolent non-Hodgkin lymphoma and myelodysplastic syndromes, among others.
Lonial concluded by describing what he hopes will be a broad overview for attendees who treat patients in the community and academic settings alike. You get experts in [the treatment of hematologic cancers]which I think is prone for rapid change, expansion, and discoveryto hear in one setting whats newest in lymphoma, whats newest in leukemia, whats newest in myeloma, and whats newest in CAR T-cell therapy. That opportunity is very important, and it provides people with a case-based learning approach.
1. FDA granted accelerated approval to belantamab mafodotin-blmf for multiple myeloma. FDA. Updated August 6, 2020. Accessed October 27, 2020. https://bit.ly/37M2UDd
2. Tai YT, Acharya C, An G, et al. APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment. Blood. 2016;127(25):3225-3236. doi:10.1182/ blood-2016-01-691162
3. Blincyto. Prescribing information. Amgen; 2020. Accessed October 27, 2020. https://bit.ly/2TsOL5d
4. US Food and Drug Administration (FDA) accepts for priority review Bristol Bristol Myers Squibb and bluebird bio application for anti-BCMA CAR T cell therapy idecabtagene vicleucel (ide-cel, bb2121). News release. Bristol Myers Squibb. September 22, 2020. Accessed October 27, 2020. https://bit.ly/3kDhakH
5. Lonial S, Van de Donk N, Popat R, et al. A phase 1b/2a study of the CELMoD iberdomide (CC-220) in combination with dexamethasone in patients with relapsed/refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2019;19(suppl 10):E52-E53. doi:10.1016/j.clml.2019.09.080
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