Dr Dhakal on Notable Multiple Myeloma Trials Presented in 2024

Binod Dhakal, MD, associate professor, Division of Hematology and Oncology, Medical College of Wisconsin, discusses key trials presented at the 

21st International Myeloma Society Annual Meeting

The conference showcased several exciting developments in multiple myeloma management, with many promising data presentations, Dhakal begins. Notably

 which investigated treatment with daratumumab (Darzalex) and hyaluronidase-fihj (subcutaneous daratumumab; Darzalex Faspro) plus bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) in patients with newly diagnosed, transplant-ineligible multiple myeloma, provided encouraging results with this combination therapy in this population, he reports. Notably, investigators reported that results were statistically significant in favor of the investigational arm, with a rate of complete response or better at 81.2% vs 61.6% with VRd (OR, 2.73; 95% CI, 1.71-4.34; 

 which focuses on patients with minimal residual disease (MRD)–positive, newly diagnosed multiple myeloma in the post-transplant setting, Dhakal continues. This trial examines daratumumab combined with lenalidomide, evaluating its efficacy compared with alternative therapies. The CEPHEUS and AURIGA trials are vital, as their findings will help refine treatment strategies based on MRD responses, potentially leading to more personalized treatment approaches for patients, he emphasizes.

Other significant updates from the conference included overall survival data with ciltacabtagene autoleucel (Carvykti), as well as improvements in the safety and efficacy profiles of other CAR T-cell therapies, Dhakal elucidates. Bispecific antibodies, such as teclistamab-cqyv (Tecvayli), were also highlighted, with 1-year follow-up data providing insights into this agent’s long-term efficacy and safety, he notes. This collection of CAR T-cell therapy and bispecific antibody data demonstrates several myeloma treatment advances, he states.

These studies represent a robust expansion of therapeutic options for patients, with continued developments in targeted and personalized treatment approaches showing promise for improved outcomes and tolerability, Dhakal says. Overall, the new data discussed at the 21st International Myeloma Society Annual Meeting reflect exciting progress in optimizing myeloma care, offering meaningful benefits for various patient subgroups, he concludes.

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Binod Dhakal, MD, discusses key trials presented at the 21st International Myeloma Society Annual Meeting in patients with multiple myeloma.

Dr Dhakal on the Design of the CARTITUDE-4 Study in R/R Myeloma

Binod Dhakal, MD, associate professor, Division of Hematology and Oncology, Medical College of Wisconsin, discusses the design of the phase 3 CARTITUDE-4 study (NCT04181827) of ciltacabtagene autoleucel (Carvykti; cilta-cel) in patients with relapsed/refractory multiple myeloma and highlights next steps for researching this agent.

International Myeloma SocietyAnnual Meeting

. At a median follow-up of 33.6 months (range, 0.1-45.0), the 30-month overall survival (OS) rate for patients treated with cilta-cel was 76.4% compared with 63.8% for patients receiving standard-of-care (SOC) treatment (HR, 0.55; 95% CI, 0.39-0.79; 

 = .0009). This corresponds to a 45% reduction in the risk of death.

The phase 3 randomized trial compares cilta-cel with SOC in patients who had received 1 to 3 prior lines of therapy, including those refractory to lenalidomide (Revlimid), Dhakal begins. Patients were randomly assigned 1:1 to either the cilta-cel arm or the SOC arm. The SOC consisted of 1 of 2 regimens: pomalidomide (Pomalyst), bortezomib (Velcade), and dexamethasone (PVd), or daratumumab (Darzalex) plus pomalidomide and dexamethasone (DPd); both were considered effective standard regimens at the time of the investigation, he reports. Patients who received cilta-cel underwent bridging therapy with either PVd or DPd based on physician choice, followed by a single infusion of cilta-cel, and then entered a follow-up phase.

The primary end point of the study is progression-free survival (PFS), and secondary end points include OS, response rates, minimal residual disease negativity, quality of life, and safety assessments, he expands. Dhakal says investigators continue to monitor patients for long-term safety and to identify emerging safety signals. Notably, the median PFS has not yet been reached, which remains a key focus as the trial progresses, he notes.

The phase 3 CARTITUDE-5 (NCT04923893) and CARTITUDE-6 (NCT05257083) trials are underway to evaluate the use of cilta-cel in newly diagnosed multiple myeloma, Dhakal continues. CARTITUDE-5 is enrolling patients who are not eligible for or have deferred transplant, and CARTITUDE-6 is enrolling transplant-eligible patients, comparing CAR T-cell therapy with stem cell transplant, he states. These trials will provide valuable insights into the role of CAR T-cell therapy in the frontline treatment of multiple myeloma, Dhakal concludes.

Binod Dhakal, MD, discusses the design of the CARTITUDE-4 study investigating cilta-cel in relapsed/refractory multiple myeloma.

Binod Dhakal, MD, discusses survival data with ciltacabtagene autoleucel in lenalidomide-refractory relapsed/refractory multiple myeloma.

Dr Dhakal on Survival and Safety Outcomes With Cilta-Cel in R/R Myeloma Multiple Myeloma

Binod Dhakal, MD, associate professor, Division of Hematology and Oncology, Medical College of Wisconsin, discusses survival and safety data from the phase 3 CARTITUDE-4 study (NCT04181827) evaluating ciltacabtagene autoleucel (Carvykti; cilta-cel) in patients with relapsed/refractory multiple myeloma.

CARTITUDE-4 is a randomized trial evaluating the efficacy of cilta-cel vs standard of care (SOC) treatment in patients with multiple myeloma who have received 1 to 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or are refractory to lenalidomide (Revlimid). SOC regimens included either daratumumab, pomalidomide, and dexamethasone (DPd) or pomalidomide, bortezomib, and dexamethasone (PVd). Previously reported data from the initial analysis demonstrated a significant progression-free survival (PFS) benefit for cilta-cel, with a hazard ratio (HR) of 0.26 at a median follow-up of 15.9 months. On April 5, 2024, the FDA approved cilta-cel for this population based on data from CARTITUDE-4.

. At a median follow-up of 33.6 months, (range, 0.1-45.0), the 30-month overall survival (OS) rate with cilta-cel was 76.4% vs 63.8% with SOC (HR, 0.55; 95% CI, 0.39-0.79; 

 = .0009), Dhakal reports. This translated to a 45% reduction in the risk of death. The 30-month OS rates were 76% with cilta-cel and 64% with the SOC.

In terms of progression-free survival (PFS), the 30-month PFS rate was 59.4% and 25.7% with cilta-cel vs the SOC, respectively. This translated to a 71% reduction in the risk of disease progression or death (HR, 0.29; 95% CI, 0.22-0.39; 

 <.0001). Although the median PFS and OS were not reached in either treatment arm, OS and PFS benefit with cilta-cel vs SOC was observed across all prespecified patient subgroups, Dhakal notes.

The regimen's safety profile was consistent with previous interim analyses, he continues. There were 50 deaths in the cilta-cel arm and 82 in the SOC arm, with 21 and 51 deaths attributed to progressive disease in these respective arms, Dhakal reports. Overall, this study marks a significant milestone in multiple myeloma treatment, demonstrating a survival benefit with cilta-cel for patients experiencing their first relapse, Dhakal concludes.

Binod Dhakal, MD, discusses survival data with ciltacabtagene autoleucel in lenalidomide-refractory relapsed/refractory multiple myeloma.
 

Dr Dhakal on Survival and Safety Outcomes With Cilta-Cel in R/R Myeloma

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.

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

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