BCMA-Targeting Drugs Take Center Stage in Myeloma

Sagar Lonial, MD

The treatment landscape for multiple myeloma (MM) is poised to enter a new era of innovation with the development of therapies that target B-cell maturation antigen (BCMA), which is highly expressed on plasma and MM cells,¹ according to Sagar Lonial, MD. The first new drug, belantamab mafodotin-blmf (Blenrep), gained FDA approval on August 5, 2020, and other novel therapies directed at BCMA are advancing in the pipeline.^2,3

Lonial, a 2020 Giants of Cancer Care^® award winner, will highlight BCMA-targeting drugs during a presentation today at 9:40 am titled “Novel Agents/Approaches in Myeloma.” The session is part of a robust lineup of presentations on hematologic malignancies.

Strategies directed at BCMA in MM are attractive because the antigen is expressed “much more exclusively on plasma cells,” resulting in fewer off-target effects and providing investigators with an opening to further attack the malignancy with a second or third antibody, Lonial said in an interview with OncLive® in advance of his presentation. BCMA, through its ligand, also promotes resistance, he said.

Lonial said he would focus on 3 major strategies currently under investigation for targeting BCMA in MM: antibody-drug conjugates such as belantamab mafodotin, bispecific and T-cell engager antibodies, and chimeric antigen receptor (CAR) T-cell therapies.

“Blocking BCMA through any of these approaches not only targets the tumor cell, but it also may help to overcome drug resistance,” Lonial said. “And those are really exciting opportunities.”

Belantamab Mafodotin

The FDA granted belantamab mafodotin accelerated approval as monotherapy for adults with relapsed/refractory (R/R) MM who have received at least 4 prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory drug.²

The decision was based on overall response rate (ORR) and duration of response (DOR) among 97 patients who received the monoclonal antibody at 2.5 mg/kg intravenously once every 3 weeks during the phase 2 DREAMM-2 trial (NCT03525678).⁴ Patients in the cohort had a median age of 65 years (range, 60-70) and a median 7 lines of prior therapy (range, 3-21), with 84% having received more than 4 prior lines (Figure⁶).^5,6

The ORR was 31% (95% CI, 21%-43%), including 1 (2%) patient with a stringent complete response (sCR), 1 (1%) with a complete response (CR), 15 (15%) with a very good partial response (VGPR), and 12 (12%) with a partial response (PR). After a median follow-up of 6.3 months, the median DOR was not reached.⁵ Seventy-three percent of responders had a DOR of at least 6 months.⁴ At the time of data cutoff, median progression-free survival (PFS) was 2.9 months (95% CI, 2.1-3.7) and overall survival data were immature.⁵

Lonial, the principal investigator for the study, said response rates and median PFS for belantamab mafodotin were comparable to study findings for other MM therapies in the R/R setting. However, he said that the DOR among responders in DREAMM-2 is noteworthy.

“For patients who do respond, the duration of response is 11 months, and I think that’s an important number to put in perspective,” he said. “It speaks to the tolerance of that treatment and the ability for responders to stay on it. That’s why I think it’s such an important step forward.”

In terms of adverse events, the label for belantamab mafodotin includes a boxed warning about the risk of changes in the corneal epithelium resulting in changes in vision, including severe vision loss and corneal ulcer, and symptoms such as blurred vision and dry eyes. Ophthalmic exams are recommended at baseline, prior to each dose, and for worsening symptoms. The FDA also is requiring that the drug be dispensed under a Risk Evaluation and Mitigation Strategy program due to the risk of ocular toxicity.⁴

“The ocular toxicity is somewhat unique for myeloma drugs,” Lonial said. “It is more of a finding on an exam by an ophthalmologist or an optometrist. It does not always result in significant symptoms. In fact, only 18% to 20% of the time, it actually results in change in visual acuity. And more importantly, partnering with an eye care professional is part of the process.”

Overall, Lonial said the drug represents “our go-to option for triple-class refractory myeloma.” Confirmatory data needed under the accelerated approval decision may be obtained from the phase 3 DREAMM-3 trial (NCT04162210), which is evaluating belantamab mafodotin monotherapy compared with pomalidomide (Pomalyst) and low-dose dexamethasone in patients with R/R MM who have undergone autologous stem cell transplant (ASCT) or are ineligible for ASCT and have disease progression after 2 or more prior lines of therapy.

Moving forward, Lonial believes belantamab mafodotin has the potential to be used earlier in the treatment timeline for MM and in combination with other therapies. The agent is being tested in combination with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone in the phase 1 DREAMM-9 trial (NCT04091126) in patients with newly diagnosed MM who are not eligible for ASCT.Ongoing combination studies include the phase 2 DREAMM-4 trial (NCT03848845) pairing belantamab mafodotin with the PD-1 inhibitor pembrolizumab (Keytruda) in R/R MM.

Antibodies With Dual Targets

Lonial said the concept of a bispecific T-cell engager was established in hematologic malignancies with blinatumomab (Blincyto), a CD19-directed CD3 T-cell engager. The agent is approved for treating patients with B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission and for R/R B-cell precursor ALL. Blinatumomab binds to CD19 on the surface of B cells and to CD3 on the surface of T cells, mediating the formation of a synapse between the T cell and the tumor cell that promotes anticancer processes.⁷

Recent phase 1 study findings have demonstrated high response rates for 2 novel agents in this category, CC-93269 and teclistamab (JNJ- 64007957), Lonial noted.

CC-93269 is a T-cell engager that binds to BCMA and CD3, inducing crosslinking between the T cells and the BCMA-expressing cells that leads to T-cell activation and MM cell death.⁸ Interim results from a dose-finding study (NCT03486067) demonstrated an 89% ORR among 9 patients treated at the highest of 3 dose levels (10 mg), according to findings presented at the virtual 25th European Hematology Association Congress in June. This included an sCR/CR in 4 patients (44%), a VGPR in 1 (33%), and a PR in 1 (11%). In the total patient population (n = 30), the ORR was 43% with an sCR/CR of 17%.⁸

Teclistamab is a bispecific antibody that redirects CD3-positive T cells to BCMA-expressing myeloma cells to induce cytotoxicity, said Saad Z. Usmani, MD, of the Levine Cancer Institute in Charlotte, North Carolina, while presenting phase 1 study (NCT03145181) findings at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program. Among 78 patients with R/R MM treated across multiple dose levels, the best response was observed in patients who received teclistamab intravenously at 270 μg/kg. The ORR was 67% among 12 patients, including 50% with a VGPR or better.⁹

“What we need to see is the durability of those responses and what the mechanisms of failure are for this,” said Lonial, referring to the class of therapies. “Is it inducing ultimately T-cell exhaustion? Or are there new mechanisms of resistance that we just don’t know? But this is another way to go after BCMA.”

CAR T Cells

In terms of CAR T-cell therapies that target BCMA, Lonial said the incidence of significant cytokine release syndrome or neurologic toxicity is “much lower than we’ve seen with CD19” as a CAR target. “We don’t know if that’s a function of BCMA or of myeloma, all those kinds of [questions] are in development,” he said. “But it seems like it’s somewhat better tolerated overall.”

The agent furthest along in development is idecabtagene vicleucel (ide-cel; bb2121). The FDA is scheduled to decide by March 27, 2021, on a biologics license application for ide-cel as a treatment for patients with MM who have received at least 3 prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody.¹⁰

The application is supported by data from the phase 2 KarMMA trial (NCT03361748) in heavily pretreated patients (N = 128) with refractory MM.¹⁰ Treatment with ide-cel resulted in an ORR of 73% (95% CI, 65.8%-81.1%; P < .0001), meeting the trial’s primary end point, according to findings presented at the 2020 ASCO Virtual Scientific Program. After a median follow-up of 13.3 months across target dose levels, the CR rate was 33% (95% CI, 24.7%-40.9%; P < .0001), the median DOR was 10.7 months (95% CI, 9.0-11.3), and the median PFS was 8.8 months (95% CI, 5.6-11.6).¹¹

Investigators also reported results for orvacabtagene autoleucel (orva-cel), a BCMA-directed CAR T-cell therapy, from the phase 1/2 EVOLVE study (NCT03430011) in patients with R/R MM who had undergone at least 3 prior therapies. Among 62 patients treated across 3 dosing levels, the ORR was 92% at a median follow-up of 6.9 months, with a VGPR or better of 68%. Enrollment at the recommended phase 2 dose (600 x 106) is ongoing, and a cohort was recently added for patients who experienced progression following prior BCMA-directed therapy.¹²

Another emerging CAR T-cell therapy in this space is JNJ-4528, which is being developed under breakthrough therapy designations in the United States and China.¹³ Patients with R/R MM who had received at least 3 prior therapies were treated with JNJ-4528 (called ciltacabtagene autoleucel in China) in the phase 1b/2 CARTITUDE-1 study (NCT03548207). All 29 (100%) patients dosed during the study demonstrated a response, defined as a PR or better, including a VGPR of 97%, according to updated results presented at the 2020 ASCO Virtual Scientific Program. After a median follow-up of 11.5 months, responses continued in 22 patients.¹⁴

References

1. Cho S-F, Anderson KC, Tai Y-T. Targeting B cell maturation antigen (BCMA) in multiple myeloma: potential uses of BCMA-based immunotherapy. Front Immunol. 2018;9:1821. doi:10.3389/fimmu.2018.01821
2. FDA granted accelerated approval to belantamab mafodotin-blmf for multiple myeloma. FDA. August 5, 2020. Accessed October 25, 2020. https://bit.ly/2J4MdIO​
3. FDA approves GSK’s Blenrep (belantamab mafodotin-blmf) for the treatment of patients with relapsed or refractory multiple myeloma. News release. GlaxoSmithKline plc. August 6, 2020. Accessed October 25, 2020. https://bit.ly/3jnvTPK​
4. Blenrep. Prescribing information. GlaxoSmithKline; 2020. Accessed October 25, 2020. https://bit.ly/34tjtSo 
5. 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):201-221. doi.10.1016/S1470-2045(19)30788-0
6. Multi-discipline review. FDA. September 1, 2020. Accessed October 26, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/761158Orig1s000TOC.cfm 
7. Blincyto. Prescribing information. Amgen Inc; 2020. Accessed October 25, 2020. https://bit.ly/31CxuLB​
8. Costa LJ, Wong SW, Bermúdez A, et al. Interim results from the first clinical study of the B-cell antigen 2+1 T cell engager CC-93269 in patients with relapsed/refractory multiple myeloma. Presented at: 2020 European Hematology Association Congress; June 11-21, 2020; virtual. Abstract S205. https://bit.ly/31GbiQJ​
9. Usmani SZ, Mateos M-V, Nahi H, et. al. Phase I study of teclistamab, a humanized B-cell maturation antigen (BCMA) x CD3 bispecific antibody, in relapsed/refractory multiple myeloma (R/R MM). J Clin Oncol. 2020;38(suppl 15):100. doi:10.1200/JCO.2020.38.15_suppl.100
10. U.S. Food and Drug Administration (FDA) accepts for priority review Bristol Myers Squibb and bluebird bio application for anti-BCMA CAR T cell therapy idecabtagene vicleucel (ide-cel, bb2121). News release. Bristol Myers Squibb and bluebird bio Inc. September 22, 2020. Accessed October 18, 2020. https://bit.ly/3kaMXd1​
11. Munshi NC, Anderson LD, Shah N, et al; KarMMa Study Investigators. Idecabtagene vicleucel (ide-cel; bb2121), a BCMA-targeted CAR T-cell therapy, in patients with relapsed and refractory multiple myeloma (RRMM): initial KarMMa results. J Clin Oncol. 2020;38(suppl 15):8503. doi:10.1200/JCO.2020.38.15_suppl.8503
12. Mailankody S, Jakubowiak AJ, Htut M, et al. Orvacabtagene autoleucel (orva-cel), a B-cell maturation antigen (BCMA)-directed CAR T cell therapy for patients (pts) with relapsed/refractory multiple myeloma (RRMM): update of the phase 1/2 EVOLVE study (NCT03430011). J Clin Oncol. 2020;38(suppl 15):8504. doi:10.1200/JCO.2020.38.15_suppl.8504
13. The China Center for Drug Evaluation, National Medical Products Administration has recommended breakthrough therapy designation for ciltacabtagene autoleucel (cilta-cel, LCAR-B38M CAR-T cells), an investigational BCMA CAR-T cell therapy. News release. Legend Biotech Corporation. August 5, 2020. Accessed October 18, 2020. https://bwnews.pr/3jji1pT 
14. Berdeja JG, Madduri D, Usmani SZ, et al. Update of CARTITUDE-1: a phase Ib/II study of JNJ-4528, a B-cell maturation antigen (BCMA)-directed CAR-T-cell therapy, in relapsed/refractory multiple myeloma. J Clin Oncol. 2020;38(suppl 15):8505. doi:10.1200/JCO.2020.38.15_suppl.8505