Binod Dhakal, MD, an associate professor of medicine in the Division of Hematology at the Medical College of Wisconsin, discusses the mechanism of action of orvacabtagene autoleucel (orva-cel; JCARH125) in multiple myeloma.

Orva-cel is an investigational CAR T-cell therapy product that demonstrated an overall response rate of 91% in heavily pretreated patients with relapsed/refractory multiple myeloma, according to data from the phase 1/2 EVOLVE study (NCT03430011).

The product targets BCMA, which is currently the leading target antigen for CAR T-cell therapies in multiple myeloma, says Dhakal. Compared with idecabtagene vicleucel, orva-cel is a fully humanized product, Dhakal explains. Additionally, although data have not demonstrated that soluble BCMA affects responses to CAR T-cell therapy, orva-cel has a very low affinity for soluble BCMA, concludes Dhakal.

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Binod Dhakal, MD, discusses the mechanism of action of orvacabtagene autoleucel in multiple myeloma.  



Dr. Dhakal on the Mechanism of Action of Orva-Cel in Multiple Myeloma 

Binod Dhakal, MD, an associate professor of medicine in the Division of Hematology at the Medical College of Wisconsin, discusses responses achieved with orvacabtagene autoleucel (orva-cel; JCARH125) in patients with multiple myeloma.

Sixty-two patients with relapsed/refractory multiple myeloma were enrolled to the phase 1/2 EVOLVE study (NCT03430011), which evaluated the CAR T-cell therapy. Participants received 3 different doses of orva-cel: 300 × 106 , 450 × 106 , and 600 × 10

 CAR+ T cells after lymphodepletion with fludarabine/cyclophosphamide, Dhakal says. Notably, patients were considered to be heavily pretreated, having received a median of 6 prior lines of therapy. Ninety-two percent of patients were penta-exposed.

Results from the trial were presented during the 2020 ASCO Virtual Scientific Program and showed that orva-cel resulted in an overall response rate of 91%, says Dhakal. Moreover, patients who received the product at 600 × 106 CAR+ T cells experienced a favorable minimal residual disease negativity rate, Dhakal notes.

Although the median follow-up time for the trial is shorter than other studies that have been done, mature data are highly anticipated, Dhakal concludes.

Binod Dhakal, MD, discusses responses achieved with orvacabtagene autoleucel in patients with multiple myeloma.


Dr. Dhakal on Responses Achieved With Orva-Cel in Multiple Myeloma

Binod Dhakal, MD, associate professor of medicine, Division of Hematology, Medical College of Wisconsin, discusses the differences in onset of cytokine release syndrome (CRS) with CAR T-cell therapies in multiple myeloma.

CRS and neurotoxicity remain the main adverse effects of concern with CAR T-cell therapy across the hematologic cancer space, says Dhakal. In relapsed/refractory multiple myeloma, 3 CAR T-cell products are moving through the pipeline toward FDA approval: idecabtagene vicleucel (ide-cel; bb2121), orvacabtagene autoleucel (orva-cel; JCARH125), and ciltacabtagene autoleucel (cilta-cel; JNJ-68284528). 

Although cross-trial comparisons are discouraged, the median onset of CRS appears to differ between the approved products. CRS onset typically occurs 1 to 2 days after infusion with ide-cel and orva-cel, respectively. However, the median onset of CRS was 7 days with cilta-cel. Currently, the field is unclear about why the onset of CRS is delayed with cilta-cel, but experts hypothesize that it could be due to the dose of the infused T cells. Ide-cel and orva-cel are dosed much higher compared with cilta-cel, suggesting that CAR T-cell expansion occurs later with cilta-cel, concludes Dhakal. 

Binod Dhakal, MD, discusses the differences in onset of cytokine release syndrome with CAR T-cell therapies in multiple myeloma.  



Dr. Dhakal on the Onset of CAR T-Cell Therapy–Induced CRS in Multiple Myeloma 

Binod Dhakal, MD, assistant professor, Medical College of Wisconsin, discusses early data with bispecific T-cell engager (BiTE) antibody constructs in multiple myeloma.

There are 2 BiTEs candidates under investigation: AMG 420 and AMG 330. Phase I data on both constructs were presented at the 2018 ASH Annual Meeting, indicating preliminary efficacy, says Dhakal. Regarding AMG 420, 3 patients who received the maximum tolerated dose of 400 µg/day achieved a complete response. Another ongoing trial is examining a long-acting BiTE. This BiTE, as opposed to other earlier constructs, is given weekly as opposed to an every 2-week cycle.

BiTE constructs, as opposed to CAR T cell therapy, are exciting because they offer the ability to receive more timely therapy, explains Dhakal. These products do not take as long to cultivate, and as such are often termed to be “off-the-shelf,” he says. Investigators are hopeful that these products may be able to be brought into earlier lines of treatment as well as used in combination with other therapies.

Binod Dhakal, MD

Articles

Dr. Dhakal on the Mechanism of Action of Orva-Cel in Multiple Myeloma

Dr. Dhakal on Responses Achieved With Orva-Cel in Multiple Myeloma

Dr. Dhakal on the Onset of CAR T-Cell Therapy–Induced CRS in Multiple Myeloma

Dr. Dhakal on Early Data With BiTEs in Multiple Myeloma