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Joseph Mikhael, MD, Discusses Emerging Therapies in MM

At the virtual 2021 Great Debates & Updates in Hematologic Malignancies, Joseph Mikhael, MD, MEd, FRCPC; chief medical officer, International Myeloma Foundation; professor, Translational Genomics Research Institute (TGen), City of Hope Cancer Center; director of myeloma research and consultant hematologist, HonorHealth Research Institute; presented on emerging therapies in multiple myeloma (MM).

Here, we focus on what’s coming down the pipeline in MM.

“I don't know if we've ever had a time in myeloma where we've had as many emerging therapies as we do now …What we’re talking about today is not only disrupting the myeloma cells interaction with its environment, but literally turning the environment on the cell itself. And that’s the kind of things that we’re seeing in emerging therapy,” Dr Mikhael said.

In CAR-T therapy, there are 2 major therapy updates: idecabtagene vicleucel and ciltacabtagene autoleucel.

Idecabtagene vicleucel could very well be the first approved agent in MM for CAR T, as it has demonstrated tolerability and promising efficacy in early results from the first in-human, phase 1, CRB-401 study, Dr Mikhael said.

“Being able to leverage that T cell engagement in such a way by taking a patients T cells, manufacturing them, multiplying them … and being able to return to the patient with receptors specifically for their disease is quite attractive,” Dr Mikhael said.

An updated from the CRB-401 study had dose escalation (n = 21) and expansion (n = 41) in about 62 relapsed or refractory multiple myeloma (RRMM) patients. The total response rate was approximately 75% and the higher doses saw a response rate over 80%.

“Putting this in context, this is nearly triple what we've expected to see with single agent studies,” Dr Mikhael told listeners.

Median progression free survival (PFS) was 8.8 months (95% CI, 5.9-11.9 months) across all treated patients, and the median overall survival (OS) was 34.2 months (95% CI, 19.2-NE months).

According to Dr Mikhael, ciltacabtagene autoleucel is a bit behind in development, but impressive in both safety and efficacy. Cytokine release syndrome (CRS) was of particular importance, he added.

“Cytokine release syndrome is one of the Achilles heels of CAR T cell therapy, but thankfully we’re getting better at both preventing it and intervening in treating it when it actually occurs,” Dr Mikhael said.

The recently updated phase 1B/2 CARTITUDE-1 study looked into the safety of ciltacabtagene autoleucel. Out of 92 patients with CRS, the majority (94.6%) were Grades 1 and 2. Incidents occurring in Grades 3 and above shrank. The overall response rate (ORR) was 97%, with 67% of patients achieving a stringent complete remission (sCR). There’s also a significant portion of patients (93%) that achieved MRD negativity. At median duration of follow-up of 12.4 months (range, 1.5-24.9), median PFS was not met. The overall 12-month PFS rate was 76.6% (95% CI, 66.0-84.3) and the 12-month OS rate was 88.5% (95% CI, 80.2-93.5).

Dr Mikhael concluded that idecabtagene vicleucel will likely be the first CAR T approved therapy for MM. At minimum, the response rate has been 70%, if not higher, with a minimum PFS of 8 months (and OS over 18 months).

However, ciltacabtagene autoleucel demonstrates even greater efficacy.

“This is impressive … especially in patients expecting an overall survival of 8 months,” Dr Mikhael said.

When describing the mechanisms of bispecific antibody therapies that adhere to both BCMA-expressing myeloma cells and local T cells, there are 3 drugs Dr Mikhael said are emerging as “really exciting drugs in multiple myeloma”. They include teclistamab, talquetamab and cevostamab.

Teclistamab is a humanized BCMA x CD3 bispecific IgG-4 antibody that redirects CD3*T cells to BCMA. Prognosis is poor for patients who progress on available classes of therapy, with ORR ~30%, mPFS of ~3 months, and mOS between 6 and 11 months, according to updated results from an ongoing phase 1 study of teclistamab administered IV or SC in patients with RRMM.

“We’re at least seeing a doubling with this approach with bispecific therapy with teclistamab … of over 70% (ORR for SC cohorts) ultimately in that final cohort of 1,500,” Dr Mikhael said.

BCMA, however, is not the only target, Dr Mikhael said, referring to G-protein—coupled Receptor Class 5 member D(GPRC5D) Expression, a type-C 7-pass transmembrane receptor protein heavily expressed in myeloma cells. Results from a phase 1 study of GPRC5D with 137 patients found most were triple-class refractory (79%), penta-exposed (73%), and penta-drug refractory (31%). ORR for IV doses was 78% and ORR for SC doses was 67%. About half of patients (47%) experienced CRS and 5% experienced neurotoxicity.

The other target was Fc Receptor Homolog 5 (Fcrh5) expression, which again is heavily expressed (100%) on myeloma cells. A study on the first FCRH5 bispecific antibody, cevostamab, had 51 patients with an ORR of 52%, including 3 sCR, 3CR and 4 VGPR, and a CRS of 75%.

“I think bispecific therapies are very attractive. Being able to gauge T cells without having to bring patients in, and collect their T cells, and wait for the manufacturing—that can be difficult. Remember, myoma is still a disease where the majority of people being treated are being treated in community practices. I think we're seeing less toxicity and improving efficacy as we go,” Dr Mikhael said.—Emily Bader

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