Research Developments Provide Clarity and Raise Further Questions in Myeloma, Myelofibrosis, DLBCL, and MDS

Increased data on novel chimeric antigen receptor (CAR) T-cell targets, approved bispecific antibodies, and standard JAK inhibitors are broadening and complicating the decision-making process for the treatment of patients with hematologic malignancies, according to Sikander Ailawadhi, MD.

“The field is advancing quickly and there are rapidly changing treatment options—these new treatment options are exactly the reason why patient survival is improving tremendously,” Ailawadhi said in an interview following an OncLive^® Institutional Perspectives in Cancer (IPC) webinar on myeloma and hematology, which he chaired.

One recent advancement in the myelodysplastic syndrome (MDS) paradigm was the October 2023 FDA approval of ivosidenib (Tibsovo) for adult patients with relapsed/refractory IDH1-mutant MDS. In the pivotal, single-arm, phase 1 AG120-C-001 trial (NCT02074839), ivosidenib elicited a complete response rate of 38.9% (95% CI, 17.3%-64.3%) in patients (n = 18), with a median time to response of 1.9 months (range, 1.0-5.6).¹

Furthermore, the September 2023 FDA approval of momelotinib (Ojjara) for patients with myelofibrosis and anemia has added another JAK inhibitor to the available treatment options for patients with splenic involvement. This regulatory decision was based on findings from the phase 3 MOMENTUM trial (NCT04173494), in which a greater proportion of patients who received momelotinib (n = 130) achieved a total symptom score reduction of 50% or higher than those who received danazol (n = 65), at 25% vs 9%, respectively (proportion difference, 16%; 95% CI, 6%-26%; P= .0095).²

In the interview, Ailawadhi, an oncologist in the Department of Hematology at Mayo Clinic in Jacksonville, Florida, highlighted key points that were presented at the meeting, including CAR T-cell therapy targets beyond BCMA, characteristics of myelofibrosis that influence decisions between JAK inhibitors, differences between bispecific antibodies to consider when managing diffuse large B-cell lymphoma (DLBCL), and the benefits of ivosidenib for patients with IDH1-mutated MDS who are ineligible for intensive therapy.

OncLive: Based on the presentation by Ricardo D. Parrondo, MD, of Mayo Clinic in Jacksonville, Florida, on future directions in multiple myeloma, what non-BCMA CAR T-cell agents are currently under investigation?

Ailawadhi: [Although we have BCMA-directed CAR T-cell therapies], we look for treatment options that are non-BCMA as well. There are CAR T-cell therapies against the GPRC5D target, for example. There’s a [GPRC5D-targeted] bispecific antibody currently available, talquetamab-tgvs [Talvey], but there are also CAR T-cell therapies in development against that target. CAR T-cell therapies have been tested and are in development against CD38. That is the marker against which we have daratumumab [Darzalex] and isatuximab [Sarclisa] as 2 immunotherapies. There are also CARs using non–T-cell cellular options, for example, CAR natural killer [NK] cells and CAR macrophages.

Within CAR T-cell therapies, there is also the development of allogeneic CAR T-cell therapies, which use donor T cells rather than the patient’s own T cells. The biggest advantage [with allogeneic CAR T-cell therapies] is that they’re off the shelf, so patients don’t have to go through the manufacturing process. [Another target is] SLAMF7, against which we have an immunotherapy called elotuzumab [Empliciti]. We have different targets, different techniques, such as allogeneic [CAR T-cell therapy], and different cellular components, such as CAR NK cells.

Regarding the presentation by Naseema Gangat, MBBS, of Mayo Clinic in Rochester, Minnesota, on new approvals and data in myelofibrosis, how do you select between JAK inhibitors for JAK inhibitor-naive patients?

That’s an important question, but unfortunately, it does not have a straightforward answer. It depends a little on the treatment choice and it depends a little on the patient’s situation or condition. For example, if a patient has anemia with spleen enlargement and some symptoms, momelotinib has shown benefit in that area, so that might be the preferred agent.

If a patient has splenic enlargement and some symptoms, but not necessarily anemia, then ruxolitinib [Jakafi] might be the better choice. Similarly, if there are only symptoms, no spleen enlargement or anemia, then ruxolitinib might be a good choice. If there is only spleen enlargement, again, ruxolitinib is a good choice. If the patient has spleen enlargement with or without any symptoms and has a low platelet count, then pacritinib [Vonjo] might be beneficial. [We need to consider the] combination of symptoms the patient has and the manifestation of their disease, and based on that, the choice is between momelotinib, ruxolitinib, or pacritinib.

Based on the presentation by Muhamad Alhaj Moustafa, MD, MS, of Mayo Clinic in Jacksonville, Florida, on bispecific antibodies in DLBCL, what factors influence your choice between glofitamab-gxbm (Columvi) and epcoritamab-bysp (Epkinly) in patients with relapsed/refractory disease?

A few differences between these 2 drugs should be discussed with patients and we depend heavily on informed decision making with patients. For example, [we discuss] the administration of these drugs. Glofitamab is given as an intravenous infusion over 4 hours, and epcoritamab is [administered through] a subcutaneous injection. There lies a difference that patients will sometimes base their choices on.

Additionally, glofitamab is approved as a time-limited treatment for 12 cycles. [Conversely], epcoritamab is approved as a treatment until progression, so the patients get the advantage of a shot in the skin, but they have to continue it for as long as it works. Also, glofitamab should be preceded by a dose of obinutuzumab [Gazyva]. In rare cases where the patient has a history of a significant reaction to obinutuzumab, we will not be able to use glofitamab either. Otherwise, overall, the efficacy and the rest of the adverse effect profiles for the 2 drugs seem close to each other.

Regarding the presentation by Talha Badar, MBBS, MD, of Mayo Clinic in Jacksonville, Florida, on recent advances in MDS, what is the significance of the FDA approval of ivosidenib in patients with IDH1-mutated MDS?

FDA approvals will help our patients and IDH1 inhibitors in clinical trials showed benefit among patients with MDS who progressed on hypomethylating agents [HMAs]. These patients traditionally have dismal outcomes. IDH1 mutations occur in approximately 3% of patients [with MDS], and targeted therapy is a welcome addition to the treatment [armamentarium], especially for patients who are ineligible for intensive therapy. If HMAs are initially given, for patients in whom HMAs do not provide benefits or have stopped working and who are not candidates for intensive chemotherapy—and in this age group, a lot of patients are not candidates—then although IDH1 mutations are relatively infrequent at least for that small percentage of patients, we have a treatment option.

What is your main message for academic and community colleagues regarding advances in the treatment of patients with hematologic malignancies?

Our focus now is that although on the one hand, we keep developing these new classes of drugs and newer drugs within the same classes, we are also spending a lot of time trying to understand how to sequence these agents and where to use what, so the right patient gets the right treatment at the right time. By doing that, we are improving outcomes.

One important factor to keep in mind as we conduct these [IPC] programs [is that] they are targeted at both academic and community physicians. With these complex, novel treatment options there is an ever-increasing need for collaboration between community physicians and academic centers, so the patients who are appropriate candidates for some of these complex treatments can be referred in a timely manner and derive the maximal benefit from them.

References

1. FDA approves ivosidenib for myelodysplastic syndromes. FDA. October 24, 2023. Accessed January 3, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ivosidenib-myelodysplastic-syndromes
2. Verstovsek S, Gerds AT, Vannuchi AM, et al. Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study. Lancet. 2023;401(10373):269-280. doi:10.1016/S0140-6736(22)02036-0