New CAR T Therapy Shows 100% Overall Response Rate in Relapsed and Refractory Multiple Myeloma

It is hard to keep up with the recent developments of CAR-T products used in relapsed/refractory multiple myeloma (RRMM) patients, but an exciting new CAR-T ddBCMA treatment stands out, showing an impressive 100% objective response rate at the recent ASCO meeting.

Earlier in the year we saw the first product come to market (Bristol-Myers’ Abecma, or idecabtagene vicleucel, or ide-cel for short). Then came the recent news that Johnson & Johnson has filed a regulatory dossier for FDA approval of its product ciltacabtagene autoleucel (or cilta-cel for short). US approval for cilta-cell is expected around late November 2021.

There is plenty of ongoing debate in the financial press as to whether cilta-cel’s outcomes are more compelling than those for ide-cel though with a camp of “experts” claiming that the patient cohort for ide-cel was more heavily pre-treated (or more “sick”) than the cohort for cilta-cel. I fully expect that in the months to come Bristol-Myers and Johnson & Johnson will start a heated competition, though I doubt that this competition will move the price needle in favor of us, patients (but that is just my personal opinion). One thing is for sure – before the end of this year, we, myeloma patients MAY have multiple CAR-T options available. Both of the products mentioned above are autologous CAR-T products, or treatments derived from a patient’s own T-cells. 

Quite a slew of  articles both for ide-cel and cilta-cel have been using “superlatives” when describing patient outcomes, but neither can beat the “100% objective response rate (ORR) in patients with relapsed/refractory multiple myeloma, with deep and durable responses noted in those with poor prognostic factors” with the entry of CAR-T ddBCMA presented at the most recent ASCO meeting. This autologous CAR-T product/construct also targets the protein BCMA, present on the surface of myeloma cells, but those are the major similarities with ide-cel and cilta-cel. The novelty with CAR-T ddBCMA is that it does not use a binding domain that is derived from antibodies (viral vectors) or single chains but is a synthetic protein that is “small, stable and engineered to reduce immunogenicity” (to lower side effects), and that can be modified to bind to not just BCMA but also to other targets. 

So far, only Phase I human studies have been published on a cohort of 12 patients. Please remember that Phase I studies are dose ranging studies to help researchers decide which dose is both safe and effective. In this study, 6 patients were dosed with 100 million cells and 6 patients were dosed with 300 million cells.

Study Results

The reported outcomes are stellar:

• “Of the 12 patients who were included in the analysis, all 12 responded to treatment; this included 6 complete responses (CRs)/stringent CRs, 3 very good partial responses (VGPRs), and 3 partial responses.”
• “We had an impressive 100% Overall Response Rate (ORR) with responses seen beyond 1 year with ongoing minimal residual disease (MRD) negativity. All but 3 patients were able to achieve a VGPR or better, and responses continued to deepen over time.”

Study Patient Population

The patient population had the following characteristics:

• Lower dose : median age of 73 with median 5 lines of prior therapy
• Higher dose : median age of 60 with median 4 lines of prior therapy
• More than half of the patients had a prior auto-stem cell transplant
• Several patients had prior treatment with the recently approved product Blenrep (a BCMA targeted antibody drug conjugate. It is noted in the posted article that these specific patients achieved “impressive” responses following treatment with CAR-T ddBCMA.

“One patient in particular had bulky extramedullary disease, bone marrow disease of 50% at baseline with high-risk cytogenetics, penta-refractory disease, and previously received treatment with a BCMA-targeted ADC. By 1 month, the patient was PET-CT negative, bone marrow negative, and was MRD negative 10-4. [or less than one out of 10,000 cells tested was cancerous]”.

Safety and Side Effects

The following was reported with respect to safety/side effects: 

• One serious adverse event related to the drug product occurred which required prolonged hospitalization
• Most patients ended up with grade 3/4 adverse hematologic events such as neutropenia, thrombocytopenia, lymphocytopenia and decreased hemoglobin. These side effects seem to be standard in most CAR-T studies.
• Cytokine release syndrome (CRS) was reported in 6/6 patients dosed at 100 million cells, but only with grade 1/2 severity. Five out of 6 patients dosed at 300 million cells also experienced 1/2 CRS and 1 out of 6 experienced grade 3 CRS.

As patients, we look forward to future news about this product as it seems to be another entry that may give us additional hope at time of relapse. The development company Arcellx is currently designing Phase II studies. As such, it will be several years before we may see this product come to market (assuming that the Phase II program will support a regulatory submission and approval). Those interested in learning more about the product can visit the website of Arcellx, Inc. and/or check out additional details about the Phase I clinical study NCT04155749.