Utilizing Immunotherapy Treatments and Managing Toxicities in Multiple Myeloma

Christopher R. D’Angelo, MD

There are multiple types of immunotherapies used for the treatment of patients with multiple myeloma. These include antibody-drug conjugates, bispecific antibodies, and chimeric antigen receptor (CAR) T cells. Immunotherapy is currently one of the standards of care for those with multiple myeloma, with CAR T cells proving to be an effective option.

At the National Comprehensive Cancer Network (NCCN) 2022 Annual Meeting: Hematologic Malignancies, Christopher R. D’Angelo, MD, assistant professor in the Division of Hematology and Oncology at the University of Nebraska Medical Center in Omaha, Nebraska, led a panel of multidisciplinary experts on the effective use of immunotherapy in multiple myeloma treatment.

He was joined by Jason Bergsbaken, PharmD, MBA, BCOP, pharmacy coordinator of Regional Oncology Services at the University of Wisconsin Health and University of Wisconsin Carbone Cancer Center, and clinical assistant professor at the University of Wisconsin-Madison School of Pharmacy in Madison, Wisconsin; and Patricia A. Mangam RN, MSN, APRN-BC, nurse coordinator for the Multiple Myeloma/Lymphoma and Autologous Stem Cell Transplant Programs at the Abramson Cancer Center of the University of Pennsylvania in Philadelphia, Pennsylvania, to discuss treatment options, recently approved therapies, and how to best manage adverse effects (AEs).

Phase 2 DREAMM 2 Trial

The panel began by discussing the use of belantamab mafodotin-blmf (Blenrep), a B-cell maturation agent–targeted antibody-drug conjugate, which was granted accelerated approval by the FDA in August 2020, based on results from the phase 2 DREAMM-2 trial (NCT03525678).^1,2 This treatment is approved for use in patients with relapsed/refractory multiple myeloma who have had 4 prior lines of therapy including anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.

In the DREAMM-2 trial, 196 patients were randomly assigned 1:1 to either 2.5 mg/kg or 3.4 mg/kg of intravenous belantamab mafodotin once every 3 weeks. The primary end point was the overall response rate (ORR) with key secondary efficacy end points being clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), time to response (TTR), and time to progression (TTP), as well as safety.

Response rates that were observed between dose levels included the ORR of 31% in vs 34%, stringent complete response (CR) in 2% vs 3%, CR in 1% vs 0%, a very good partial response (PR) in 15% vs 17%, and a PR in 12% vs 14% in the 2.5 mg/kg group and the 3.4 mg/kg group, respectively. The CBR was 34% in the 2.5 mg/kg group and 39% in the 3.4 mg/kg group. The median PFS was 2.9 months vs 4.9 months, and the DOR lasted 4 months or more in 78 patients vs 87 patients in the lower and higher dose arms, respectively. Of note, at the time of reporting, the median OS was not reached in either arm.

In this trial, keratopathy and ocular toxicity were the most common AE, which improved with dose modifications. Thrombocytopenia was the most common hematologic AE, but was observed to be manageable, and there was 1 grade 5 AE in the 3.4 mg/kg arm.

The Use of Bridging Therapy

The panelists next began to discuss bridging therapy to help control disease, minimize toxicity, and maximize CAR T response. D’Angelo noted that the goal of bridging therapy was to try and get to CAR T therapy.

“We do feel bridging therapy is essential in our patients with an overwhelming amount of disease in their system. It is helpful for mitigating some of the toxicities that we know are common with the CAR T therapies,” Mangam said.

Some options for bridging therapy that was reviewed in the presentation included radiation, BCMA-directed therapy, steroids, and multi-agent drug combinations. “There’s no one-size-fits-all approach, it’s certainly a patient-by-patient situation. Rather than think about specific agents, I try to think about the goal, what we’re trying to achieve with bridging therapy,” said D’Angelo.

FDA-Approved Treatments

Currently, there are 2 FDA-approved CAR T-cell agents: idecabtagene vicleucel (ide-cel; Abcema) and ciltacabtagene autoleucel (cilta-cel; Carvykti).^3,4 Ide-cel was approved by the FDA in March 2021, for patients with relapsed/refractory multiple myeloma after 4 or more prior lines of therapy, with results from the phase 2 KarMMa trial (NCT03361748) leading to the approval.⁵ Cilta-cel was approved in February 2022, for patients with relapsed/refractory multiple myeloma after 4 or more prior lines of therapy. The approval was based on results from the phase 1/2 CARTITUDE-1 trial (NCT03548207).⁶

Between the 2 trials, 26% vs 42% of patients were penta-refractory, 36% vs 24% had high-risk cytogenetics, 94% vs 90% had autologous stem cell transplant, and an ECOG performance status of 1 in 56% vs 60% in the KarMMa vs CARTITUDE-1 trials, respectively.

Efficacy was evaluated independently in an adjusted analysis.⁷ There was no head-to-head comparison, however, the analysis was used to demonstrate the PFS data in each trial including cilta-cel observed response vs ide-cel (HR, 0.33; 95% CI, 0.21-0.52; P < .0001) and cilta-cel adjusted response vs ide-cel (HR, 0.50; 95% CI, 0.29-0.87; P < .0137).

Management of Toxicities from CAR T-Cell Therapy

The panel then discussed how toxicities could be managed during treatment. The NCCN has created guidelines to best incorporate some unique toxicities observed in patients receiving CAR T-cell therapy.⁸ Patients may observe cytokine release syndrome (CRS), neurological toxicity, or hemophagocytic lymphohistiocytosis/macrophage-activation syndrome.

Management of CRS is important, with D’Angelo noting that he often used anti–IL-6 therapy for patients experiencing any-grade toxicity. The NCCN also discusses the use of corticosteroids as an option for CRS treatment.

Immune-effector cell-associated neurotoxicity syndrome is also something to be aware of when treating patients with CAR T-cell therapy. Delayed toxicities were also observed, specifically in the CARTITUDE-1 trial. Patients experienced parkinsonism (6%), cranial nerve palsies (3%), and there was a single-event of Guillain-Barré Syndrome. Additionally, later in the trial, there were reduced AEs observed.

References

1. FDA granted accelerated approval to belantamab mafodotin-blmf for multiple myeloma. FDA. August 5, 2020. Accessed October 14, 2022. https://bit.ly/3CZa9a1

2. Lonial S, Lee HC, Badros A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol. 2020;21(2):207-221. doi:10.1016/S1470-2045(19)30788-0

3. FDA approves idecabtagene vicleucel for multiple myeloma. FDA. March 26, 2021. Accessed October 14, 2022. https://bit.ly/3CC0Mf2

4. FDA approves ciltacabtagene autoleucel for relapsed or refractory multiple myeloma. FDA. February 28, 2022. Accessed October 14, 2022. https://bit.ly/3T7agWA

5. Munshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med. 2021;384(8):705-716. doi:10.1056/NEJMoa2024850

6. Berdeja JG, Madduri D, Usmani SZ, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet. 2021;398(10297):314-324. doi:10.1016/S0140-6736(21)00933-8. Published Correction appears in Lancet. 2021 Oct 2;398(10307):1216.

7. Martin T, Usmani SZ, Schecter JM, et al. Matching-adjusted indirect comparison of efficacy outcomes for ciltacabtagene autoleucel in CARTITUDE-1 versus idecabtagene vicleucel in KarMMa for the treatment of patients with relapsed or refractory multiple myeloma. Curr Med Res Opin. 2021;37(10):1779-1788. doi:10.1080/03007995.2021.1953456. Published Correction appears in Curr Med Res Opin. 2021 Oct 6;1-12.

8. Thompson JA, Schneider BJ, Brahmer J, et al. Management of immunotherapy-related toxicities, version 1.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2022;20(4):387-405. doi:10.6004/jnccn.2022.0020