Novel Therapies Move Through the Relapsed/Refractory Myeloma Pipeline

Ajai Chari, MD

Multiple investigational agents, including antibody-drug conjugates (ADCs), bispecific T-cell engagers (BiTEs), and cereblon E3 ligase modulators (CELMoDs), are gaining ground in the treatment of patients with relapsed/refractory multiple myeloma, according to Ajai Chari, MD.

"It is a very exciting time in relapsed/refractory multiple myeloma with many novel drugs being investigated," Chari said. "It seems like every day our table of approved drugs becomes obsolete because yet another drug has been approved."

One such approval was that of belantamab mafodotin-blmf (Blenrep), which received regulatory approval from the FDA on August 5, 2020, for use in patients with relapsed/refractory multiple myeloma who have received 4 prior therapies including an immunomodulatory drug (IMiD), a proteasome inhibitor, and an anti-CD38 antibody.¹

The regulatory decision was based on findings from the phase 2 DREAMM-2 trial in which the recommended 2.5 mg/kg dose of belantamab mafodotin induced an overall response rate (ORR) of 31%. Patients who received the ADC at a 3.4 mg/kg had an ORR of 34%.²

Beyond ADCs, BiTEs such as AMG 420, CC-93269, and teclistamab (JNJ-64007957), are also being explored. Results from a first-in-human study of AMG420 showed a response rate of 70%.³ Moreover, in phase 1 trials, CC-9329 elicited an overall response rate (ORR) of 43.3%,⁴ while teclistamab showed an ORR of 67%.⁵

CELMoDs have also emerged in the treatment landscape in recent years. Iberdomide (formerly CC-220) was found to have antitumor activity when combined with dexamethasone in heavily pretreated patients with relapsed/refractory disease, eliciting an ORR of 32.2%,⁶ while CC-92480 plus dexamethasone was found to result in an ORR of 21.1% in a comparable population.⁷

In an interview with OncLive^® during an Institutional Perspectives on Cancer webinar on Multiple Myeloma, Chari, a professor of medicine, hematologist, and oncologist at Mount Sinai Hospital, discussed the recent approval of belantamab mafodotin in relapsed/refractory multiple myeloma and other emerging agents under exploration in the space.

OncLive^®: What is the role of ADCs in multiple myeloma? What are some of the main agents being used?

ADCs are basically monoclonal antibodies with a toxin that is attached to the antibody, or payload, if you will. They allow for targeted, poisoned delivery to the cell of interest.

In August 2020, the FDA approved the ADC belantamab mafodotin for [patients with] relapsed/refractory multiple myeloma who received 4 prior lines of therapy. The target of this drug is BCMA and the poison or conjugate is MMAF, which is a highly potent monomethyl auristatin E or cell cycle inhibitor.

Could you speak to the data that led to the approval? Where will future research with the ADC be focused?

Belantamab mafodotin was approved on the basis of a study that was published in Lancet Oncology in 2020. In the trial, about [2]00 patients were treated with 2 different doses of the agent. The response rate was about 30% and the progression-free survival (PFS) ranged from 2.9 months to 4.9 months.

While these are encouraging data, we would like to do better. The point of those initial studies is to show that this drug does have single-agent activity, but the way we need to treat [patients with] advanced myeloma is with combination therapy.

Ongoing studies are evaluating belantamab mafodotin in combination with lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone, as well as novel compounds, such as checkpoint inhibitors. Another randomized study is [examining this agent with] pomalidomide (Pomalyst) and dexamethasone. Those are just some of the efforts being made to continue to advance this agent and move it into the combination setting.

BiTEs are also showing promise in this space. What are some of the key agents under investigation?

BiTEs are very exciting. In multiple myeloma, several compounds that have been presented at national meetings already. [The] AMG 420 [data] have been published in the Journal of Clinical Oncology. Additionally, we have CC-93269 and teclistamab. Sample sizes range from 30 to 80 [patients] with a median of 3 to 6 prior lines of therapy.

What has been very impressive is that we are seeing response rates ranging from approximately 70% to [over] 80% in this very heavily pretreated population. Just to put that into historic context, when patients were refractory to all available drugs, papers showed that [if an agent elicited] response rates of around 20% to 30% with a PFS of around 3.5 months, [those data] were adequate for regulatory approval. We are seeing very exciting response rates in this setting.

The main toxicities [associated with these agents] included cytokine release syndrome (CRS). Approximately [60]% to almost 80% of patients experienced CRS, although most cases were grade 1 or 2 in severity. Infections have also been observed with these compounds, ranging from 30% to 60% of patients, approximately 30% of which are grade 3 or higher. Additionally, grade neutropenia has been seen in approximately 40% of patients treated.

Given the unique mechanism of action, which is half binding to T cells and half binding to BCMA, this is a very exciting approach that we will quickly move up to earlier lines of therapy.

Could you speak to the advantages of BiTEs compared with some of the other modalities, such as CAR T-cell therapies?

We have different ways to target BCMA. We have CAR T-cell therapies, which have to be genetically manufactured. However, ADCs and BiTEs are ready to go off the shelf. These agents don't have to be manufactured for each patient, which is nice because if someone is progressing with advanced multiple myeloma, you don't need to wait 3 to 6 weeks to get CAR T cells manufactured; that is great for patients.

Could you expand upon novel CELMoDs and how they differ from other investigational agents?

CELMoDs are very important. Iberdomide was [evaluated in] a 66-patient study presented at the 2019 ASCO Annual Meeting and showed response rates of approximately 32%. That response rate was found to be comparable in IMiD-, pomalidomide-, and daratumumab (Darzalex)-refractory patients.

Also, what was kind of intriguing was that for this disease setting, the rates of grade 3 or 4 neutropenia, were quite modest. Given the heavily pretreated nature [of this patient population] and the way we see these drugs typically work, that was very exciting.

Another CELMOD is the CC-92480 compound, which was examined in combination with dexamethasone. [These data were] presented during the 2020 ASCO Virtual Scientific Program by Paul G. Richardson, MD, of Dana-Farber Cancer Institute, in a phase 1 study. Results showed a response rate of approximately 20% for all evaluable patients, but at the recommended phase 2 dosing, the response rate was approximately 55%. Admittedly, these data were observed in small number of patients, just 11, but they are very encouraging.

Grade 3 or 4 neutropenia was a bit higher than what we saw with Iberdomide, at about 64%. However, again, to be see activity like this in a heavily pretreated patients is very exciting. As such, not only do we have thalidomide, lenalidomide, and pomalidomide, we have next-generation compounds such as CELMoDs that are very promising.

Finally, could you shed light on melflufen and its potential role in this disease?

The last compound that I want to cover is called melflufen, which is a peptidase enhanced therapy with an alkylating payload. Basically, it is melphalan, but it is very lipophilic, so it gets into the cells and then is hydrolyzed to release the amino peptidase. Then, the melphalan can stay within the myeloma cell.

The agent is being examined in the HORIZON study, which enrolled approximately 157 patients; 119 were triple-class refractory and 55 had extramedullary disease. This drug, which is given intravenously through a central line once a month, showed an ORR of 29%. Responses in the triple-class refractory and extramedullary disease populations were comparable, at 26% and 24%, respectively. The main toxicities were hematologic [in nature]; they included grade 3 or 4 neutropenia, which occurred in about 80% of patients, and thrombocytopenia, which occurred in about 76% of patients. This is yet another option for patients with heavily pretreated disease.

References

1. FDA approves GSK’s BLENREP (belantamab mafodotin-blmf) for the treatment of patients with relapsed or refractory multiple myeloma. News release. Published August 5, 2020. Accessed August 5, 2020. https://bit.ly/3gxEXB1
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 [published online December 16, 2019]. Lancet Oncol. https://doi.org/10.1016/S1470-2045(19)30788-0.
3. Topp MS, Duell J, Zugmaier G, et al. Evaluation of AMG 420, an anti-BCMA bispecific T-cell engager (BiTE) immunotherapy, in R/R multiple myeloma (MM) patients: updated results of a first-in-human (FIH) phase I dose escalation study. J Clin Oncol. 2019;37(suppl 15):8007. doi:10.1200/JCO.2019.37.15_suppl.8007

Costa L, Wong SW, Bermúdez A, et al. First clinical study of the B-cell antigen 2+1 T cell engager CC-93269 in patients with relapsed/refractory multiple myeloma: interim results of a phase I multicenter trial. Presented at: the 2020 European Hematology Congress: Virtual. June 11-21, 2020. Abstract #S205.

1. 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

Lonial S, Van de Donk N, Popat R, et al. A phase 1b/2a study of the CELMoD iberdomide (CC-220) in combination with dexamethasone in patients with relapsed/refractory multiple myeloma. Presented at: The 17th International Myeloma Workshop; September 12-15, 2019; Boston, MA. Abstract 198.

• Richardson PG, Vangsted AJ, Ramasamy K, et al. First-in-human phase I study of the novel CELMoD agent CC-92480 combined with dexamethasone (DEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2020;38(suppl 15):8500. doi:10.1200/JCO.2020.38.15_suppl.8500