New Options Abound in Relapsed or Refractory Multiple Myeloma

Ajay Nooka, MD

There are several agents with promising efficacy in the relapsed or refractory multiple myeloma (RRMM) space, according to Ajay Nooka, MD. The area of high unmet need is triple-refractory disease, and there are agents in development that may soon offer a solution for these patients.¹

“There are additional clearly fill the need, and these are very effective in highly-refractory myeloma patients. What we need to understand is that triple-class refractory disease is an unmet need and there are limited options for BCMA-refractory disease,” said Nooka during his presentation. “There are limited data as well to make the right determination of what treatment to give.”

During the Meet the Professor Session 8: Multiple Myeloma at the 10th Annual Meeting of the Society of Hematologic Oncology, Nooka, a professor and the director of the Myeloma Program, Department of Hematology and Medical Oncology at Emory University School of Medicine, Atlanta, Georgia, discussed the new regimens with positive clinical trials in RRMM.

Novel Treatments for RRMM

Among the novel agents being evaluated for the treatment of RRMM, there are immunomodulatory drugs (IMIDs), monoclonal antibodies (mAb), antibody-drug conjugates, and bispecific antibodies, explained Nooka.

“There are newer targeted under evaluation, which are high activity. And there is potential to use these as salvage therapy for these patients, explained Nooka.

The first novel drug discussed was iberdomide (CC-220; Bristol Myers Squibb), an IMID that is currently under investigation in a phase 1/2 study.

IMIDs

Preclinically, iberdomide was shown to enhance the immune stimulatory activity in comparison with lenalidomide (Revlimid®; Bristol Myers Squibb) and pomalidomide (Pomalyst®; Bristol Myers Squibb). The ongoing phase 1/2 CC-220-MM-001 study (NCT02773030) is evaluating iberdomide in combination with other agents in approximately 449 patients who are relapsed or refractory to ≥ 2 prior regimens including lenalidomide, pomalidomide, and a proteosome inhibitor. Five drug combination cohorts will be explored in the study.²

In the phase 1 portion of the study, the goal was to determine the maximum-tolerated dose of iberdomide and determine the recommended phase2 dose (RP2D). In phase 2, the study aims to determine the safety and preliminary efficacy of the agent.

Nooka’s presentation highlighted results from cohort B of phase 1 of the CC-220-MM-001 study, which included 172 patients. In all evaluable patients (n = 69), the objective response rate (ORR) observed with iberdomide/dexamethasone was 31.9%. Responses in the all-evaluable population included very good partial responses (VGPRs) in 4.3%, partial response (PRs) in 27.5%, molecular response (MRs) in 14.5%, stable disease (SD) in 37.7%, and progressive disease (PD) in 15.9%.

In patients who were refractory to an IMID, the ORR was 33.3%. VGPRs were observed in 4.5% of patients, PRs were achieved in 28.8%, and there were MRs in 10.8%, SD in 40.5%, and OD in 16.3%. Among patients who were quad-class refractory, the ORR observed with iberdomide plus dexamethasone was 32.4%, which included VGPRs in 5.4%, PRs in 27.0%, MRs in 10.8%, SD in 40.5%, and PD in 16.2%.

In phase 2 at the recommended phase 2 dose (RP2D) of 1.0 mg once daily iberdomide, there was 1 complete response (CR), 1 VGPR, 2 PRs, and 1 MR. Notably, 7 out 11 patients treated with the RP2D were triple class refractory.

mAbs

Early data around modakafusp alfa (TAK-573; Takeda, Teva Pharmaceutical Industries)

shows that the agent can activate innate and adaptive immune cells, and direct antiproliferative, and apoptotic signals to tumor cells.³

Data Nooka displayed from the first 59 patients in a first-in-human phase 1 study of modakafusp alfa (NCT03215030) showed that the agent was administered at dose levels from 0.001 to 6 mg/kg following a 3+3 dose-escalation design.

Results showed that the ORR in all comers was 38%, with a 28% VGPR rate. In the anti-CD38 mAb refractory group, the ORR was also 38%. In patients who were exposed to anti-BCMA therapy, the ORR was 20%.

Bispecific Antibodies

Teclistamaband elranatamab are 2 bispecific antibodies discussed during the presentation.

Teclistamab was evaluated in the phase 1/2 MajesTEC-1 study (NCT04557098), which included 165 patients with RRMM. The ORR observed in the study was 63.0%, which included stringent CRs in 32.7% of patients, CRs in 6.7%, VGPRs in 19.4%, and PRs in 4.2%.⁴ For elranatamab as evaluated in the phase 1/2 MagnetisMM-3 study (NCT04649359), the treatment appears well-tolerated.⁵

In 94 patients, treatment-emergent adverse events were observed in 100% of patients with 75% being grade 3 or 4 events. The majority of the events were hematologic TEAEs including neutropenia (36.7%) anemia (36.7%), and thrombocytopenia (30.0).

Novel Mechanisms

Venetoclax was highlighted as an agent with a mechanism of action that is still novel in myeloma. The BCL-2 inhibitor has been evaluated in combination with bortezomib (Velcade; Takeda Oncology) and dexamethasone in the phase 3 BELLINI clinical trial (NCT02755597).

In the study, 291 patients with RRMM were included and treated with either the experimental combination or placebo with bortezomib and dexamethasone until disease progression. The study met its primary end point of progression-free survival improvement. According to Nooka, both the PFS and overall survival rates were also satisfactory in subgroups of patients who were BCL2 high or had a 11;14 translocation.6

Concluding his presentation, Nooka explained that how to sequence therapies in myeloma remains a challenge but predicts that the highly-active drugs will be moved up in treatment.

_REFERENCES:

_{1. Nooka A. Addtional Agents for RRMM - How Do/Will They Fit. Presented at: 10th Annual Meeting of the Society of Hematologic Oncology (SOHO 2022); September 28-October 1, 2022; Houston TX.}

_{2. Lonial S,van de Donk N, Popat R, et al. First clinical (phase 1b/2a) study of iberdomide (CC-220; IBER), a CELMoD, in combination with dexamethasone (DEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2019; 37(15:8006-8006. doi: 10.1200/JCO.2019.37.15_suppl.8006}

_{3. Vogl DT, Kaufman JT, Holstein SA, et al Modakafusp Alfa (TAK-573), an immunocytokine, shows clinical activity in patients with relapsed/refractory multiple myeloma; updated results from a first-in-human phase 1 study. Blood. 202;138 (suppl 1): 898. doi: 10.1182/blood-2021-148463}

_{4. Moreau P. Garfall AL, von de Donk N, et al. Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 2022; 387:495-505. doi: 10.1056/NEJMoa2203478}

_{5. Lesokhin AM, Arnulf B, Niesvizky R, et al. Initial safety results for MagnetisMM-3: A phase 2 trial of elranatamab, a B-cell maturation antigen (BCMA)-CD3 bispecific antibody, in patients (pts) with relapsed/refractory (R/R) multiple myeloma (MM). J Clin Oncol. 2022; 40(16). doi: 10.1200/JCO.2022.40.16_suppl.8006}

_{6. Kumar SK, Harrison SJ, Cavo M, et al. Venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (BELLINI): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. Published October 29, 2020. doi: 10.1016/S1470-2045(20)30525-8}