Encouraging Data From Novel Agents Will Expand the Multiple Myeloma Paradigm

Results shown from studies of bispecific antibodies, immunomodulatory drugs , and antibody-drug conjugates signal a bright future for relapsed or refractory myeloma treatment.

In the treatment armamentarium for relapsed or refractory multiple myeloma, drugs with novel mechanisms, including bispecific antibodies, immunomodulatory drugs (IMiDs), and antibody-drug conjugates (ADCs), are showing promise, according to a presentation by Ajay K. Nooka, MD, MPH, FACP, at the 19th International Myeloma Society Annual Meeting.1

“There are several novel upcoming therapies and combinations with high activity in the refractory space,” said Nooka, an associate professor in the Department of Hematology and Medical Oncology and the medical director of the Winship Data and Technology Applications Shared Resource at the Winship Cancer Institute, Emory University School of Medicine in Atlanta, Georgia. “There are newer targets under evaluation and personalized therapies, [such as] CAR T-cell agents, that may be a viable option for a large proportion of patients.”

Nooka first touched on iberdomide, an IMiD that has shown enhanced in vitro immune stimulatory activity compared with lenalidomide (Revlimid) and pomalidomide (Pomalyst). The agent is under investigation as both a monotherapy and in combination with other therapies for patients with relapsed or refractory multiple myeloma in the phase 1/2 multicohort CC-220-MM-001 study (NCT02773030).

Data from cohort B (n = 69) of CC-220-MM-001 showed that patients treated with iberdomide plus dexamethasone achieved an overall response rate (ORR) of 31.9%. Notably, ORR was also consistent among patients who were deemed to be IMiD-agent refractory (n = 66) and quad-class refractory (n = 37), at 33.3% and 32.4%, respectively.

In cohort E, iberdomide was combined with daratumumab (Darzalex) and dexamethasone and led to an ORR of 45.9% among 37 efficacy-evaluable patients. Cohort F (n = 25) of the trial evaluated iberdomide plus dexamethasone and bortezomib (Velcade) and in this group the ORR was 56.0%. Patients in cohort G (n = 8), who were treated with iberdomide plus dexamethasone and carfilzomib (Kyprolis), achieved an ORR of 50.0%. Investigators determined the maximum-tolerated dose of iberdomide to be 1.3 mg per day.

Mezigdomide (formerly CC-92480) is another IMiD that is being evaluated as a monotherapy and in combination with dexamethasone in patients with relapsed or refractory multiple myeloma in the phase 1/2 CC-92480-MM-001 trial (NCT03374085). Among all efficacy evaluable patients (n = 76), the ORR with mezigdomide monotherapy was 21.1%. Two dose-escaltion schedules were evaluated, and response rates varied. Patients who received mezigdomide on a continuous dosing schedule for 10 of 14 days at 1.0 mg daily of mezigdomide (n = 10) experienced an ORR of 40.0%. In prior reports, patients in this cohort required longer recovery time between cycles. Similarly, patients who received 1.0 mg of the agent daily for a 3-weeks-on-1-week off schedule (n = 11) achieved an ORR of 54.5%; this was determined to be the recommended phase 2 dose.

The phase 3 BELLINI study (NCT02755597) is examining venetoclax (Venclexta) in combination with bortezomib and dexamethasone vs bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received 1 to 3 lines of prior therapy. Venetoclax is being given at a dose of 800 mg daily. The primary end point is progression-free survival (PFS).

Nooka noted that the greatest improvements in PFS seen so far in the trial have been made by patients with t(11;14) or high BCL2 expression; patients with these characteristics who received venetoclax (n = 74) significantly outperformed those without (n = 40) in terms of PFS (HR, 0.32; 95% CI, 0.20-0.53; P < .0001). Additionally patients with only t(11;14) (HR, 0.12; 95% CI, 0.03-0.44; P = .0014) or only high BCL2 expression (HR, 0.37; 95% CI, 0.21-0.64; P = .0005) also experienced a significant PFS benefit when venetoclax was added to bortezomib and dexamethasone.

The ADC belantamab mafodotin-blmf (Blenrep) is being evaluated in combination with pomalidomide and dexamethasone in the phase 1/2 ALGONQUIN trial (NCT03715478). Nooka noted that patients in ALGONQUIN have experienced favorable results compared with data from other trials evaluating anti-CD38 monoclonal antibodies in combination with pomalidomide and dexamethasone for patients with multiple myeloma, such as the phase 3 APOLLO trial (NCT03180736) and the phase 3 ICARIA-MM trial (NCT02990338). All 3 of the patient populations in these trials shared similar median ages and median numbers of prior lines of therapy.

In ALGONQUIN, patients (n = 56) experienced an ORR of 88.9% compared with 69% in for efficacy-evaluable patients in APOLLO (n = 151) and 63% in ICARIA-MM (n = 154). Additionally, the median PFS was 17 months (95% CI, 14.5-not reached [NR]), 12.4 months (95% CI, 8.3-19.3), and 11.5 months (95% CI, 8.9-13.9), respectively.

Finally, Nooka turned his attention to rapidly expanding class of bispecific antibodies. Specifically, he highlighted top-line data from trials evaluating the BCMA x CD3 agents teclistamab, elranatamab, ABV-383, and REGN5458, as well as the GPRC5D x CD3 bispecific antibody talquetamab.

In the phase 1/2 MajesTEC-1 trial (NCT04557098) teclistamab (Tecvayli) monotherapy displayed clinical efficacy in patients with highly refractory multiple myeloma. Among 165 patients, many of whom were triple-class refractory (77.6%), the ORR was 63.0% including a 6.7% complete response rate. Common adverse effects (AEs) of any grade included infections (76.4%), cytokine release syndrome (CRS; 72.1%), and neutropenia (70.9%). Results of MajestTEC-1 were recently published in the New England Journal of Medicine2 and a biologics license application was submitted to the FDA in December 2021.3 Teclistamab was granted conditional marketing authorization for use as a single agent in adult patients with relapsed and refractory multiple myeloma who have received at least 3 prior therapies, including an IMiD, a proteasome inhibitor, and an anti-CD38 antibody by the European Commission in August 2022.4

Similarly, in the phase 1/2 MagnetisMM-3 trial (NCT04649359),elranatamab was examined in a 94-patient population that was overwhelmingly triple-class refractory (95.7%). The ORR was 60.6% and the median PFS, median duration of response (DOR), and median overall survival (OS) were all NR. The most common any-grade AEs included CRS (60.6%), infections (52.1%), and anemia (43.6%).

Efficacy evaluable patients (n = 60) treated with ABV-383 in a phase 1/2 trial (NCT03933735) achieved an ORR of 81%. The median DOR was NR, and the 6-month and 12-month OS rates were 81.7% (95% CI, 66.2%-90.6%) and 72.1% (95% CI, 52.1%-84.8%), respectively. In the safety population (n = 114), the most common AEs of any grade were CRS (54%), infections (32%), and neutropenia (27%).

REGN5458 is under evaluation in a phase 1/2 trial (NCT03761108). Among 75 efficacy-evaluable patients, the ORR was 75%. The median DOR and median OS have not yet been reached. Any-grade AEs have consisted of CRS (38%), anemia (32%), and CRS (28%).

Talquetamab displayed activity in a mostly triple-refractory (77%) population in the phase 1/2 MonumenTAL-1 trial (NCT04634552). Patients who received the agent at a dose of 405 μg/kg (n = 30) experienced an ORR of 70% and those treated with 800 μg/kg (n = 25) had an ORR of 66.7%. The primary safety concerns were like the other agents and included infections, anemia, and CRS. Based on these data, the agent was granted a breakthrough designation by the FDA in June 2022.5

“The next step should be moving these highly potent agents into earlier combinations that can result in much deeper responses to MRD [minimal residual disease] negativity,” Nooka said. “[This] could lead to long remissions and possibly may offer a cure for a proportion of the patients.”

References

1. Nooka AK. Novel upcoming therapies. Presented at: 19th International Myeloma Society Annual Meeting. August 25-27, 2022. Los Angeles, CA.

2. Moreau P, Garfall AL, van de Donk NW, et al. Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 2022;387(6):495-505. doi:10.1056/NEJMoa2203478

3. Janssen submits biologics license application to US FDA seeking approval of teclistamab for the treatment of patients with relapsed or refractory multiple myeloma. News release. The Janssen Pharmaceutical Companies of Johnson & Johnson. December 29, 2021. Accessed August 27, 2022. bit.ly/3FFmcYY

4. Janssen marks first approval worldwide for Tecvayli (teclistamab) with EC authorisation of first-in-class bispecific antibody for the treatment of patients with multiple myeloma. News release. The Janssen Pharmaceutical Companies of Johnson & Johnson. August 24, 2022. Accessed August 27, 2022. bwnews.pr/3TgQzfi

5. Janssen announces US FDA breakthrough therapy designation granted for talquetamab for the treatment of relapsed or refractory multiple myeloma. News release. The Janssen Pharmaceutical Companies of Johnson & Johnson. June 29, 2022. Accessed August 27, 2022. bit.ly/3AqKjZR