Adam D. Cohen, MD, director, Myeloma Immunotherapy, associate professor in medicine, hematology/oncology, Abramson Cancer Center, University of Pennsylvania, discusses unmet needs and areas for future investigation within the relapsed/refractory multiple myeloma treatment landscape.

The armamentarium for this population has greatly expanded in recent years with the addition of several BCMA-directed CAR T-cell therapies and bispecific antibodies. In 2021, the CAR T-cell therapies 

ciltacabtagene autoleucel (cilta-cel;Carvykti)

 both gained FDA approval for patients with relapsed or refractory disease who have progressed on 4 or more previous lines of therapy. The regulatory decisions were based on findings from the phase 2 KarMMa trial (NCT03361748) and the phase 1b/2 CARTITUDE-1 trial (NCT03548207), respectively. The bispecific antibody 

 also gained approval for this population in 2022 based on data from the phase 1/2 MajesTEC-1 trial (NCT03145181; NCT04557098).

BCMA-targeted agents are highly potent and produce deep and durable responses in triple- or penta-refractory patients, Cohen begins. Although their use has significantly improved treatment outcomes, these agents are not curative for the majority of patients, Cohen states. Therefore, it is important to better understand the optimal role and sequencing of BCMA-targeted immunotherapies in this field, he says.

Additionally, there are still patient subsets that do not respond well to current CAR T-cell therapies or bispecific antibodies, Cohen adds. This can include patients with extramedullary disease or those who have high-risk cytogenetics, he adds. Clinical trials that are done in multiple myeloma often exclude patients with higher-risk features such as renal failure, plasma cell leukemia, amyloidosis, or central nervous system involvement, Cohen notes.

It is important to understand the efficacy and safety of these agents in these difficult-to-treat populations, as patients with these conditions commonly seek treatment for their disease in the real-world setting, Cohen states. To this end, research efforts should focus on collecting more data on the use of BCMA-targeted therapies in these underrepresented groups, Cohen concludes.

Dr. Cohen reports serving as a consultant or in an advisory role for Celgene, BMS, Takeda, Janssen, Seattle Genetics, AstraZeneca, Genentech/Roche, Oncopeptides, GlaxoSmithKline, Arcellx, Ichnos; he received research funding from Novartis, GlaxoSmithKline; he has intellectual property licensed by institution to Novarti.

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Adam D. Cohen, MD, discusses unmet needs and areas for future investigation within the relapsed/refractory multiple myeloma treatment landscape.
 
 

Dr Cohen on Efforts Needed to Unmet Needs in R/R Multiple Myeloma

Adam D. Cohen, MD, director, Myeloma Immunotherapy, associate professor in medicine, hematology/oncology, Abramson Cancer Center, University of Pennsylvania, discusses a presentation given at the Baptist Health South Florida Miami Cancer Institute Global Summit on Immunotherapies for Hematologic Malignancies on the current landscape of treatment options in multiple myeloma, and elaborates on attempts to utilize these options in earlier lines of therapy. 

Two CAR T-cell therapies are currently FDA approved for the treatment of patients with multiple myeloma, including idecabtagene vicleucel (ide-cel; Abecma) for patients with relapsed/refractory disease who have progressed on 4 or more previous lines of therapy, Cohen begins. This includes a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. This approval was based on findings from the phase 2 KarMMa trial (NCT03361748).

Following the FDA approval of ide-cel for this patient population, the FDA then approved treatment withciltacabtagene autoleucel (cilta-cel; Carvykti) for patients with relapsed or refractory disease after 4 or more prior lines of therapy. This approval was based on data from the phase 1b/2 CARTITUDE-1 trial (NCT03548207), which showed that patients receiving cilta-cel achieved an objective response rate (ORR) of 98% and a stringent complete response rate of 78%. 

These studies show that patients who have previously undergone BCMA-directed therapy can still respond to subsequent CAR T-cell therapies, Cohen says. However, the durability of responses may be decreased in later-line settings, he notes. Moreover,, the use of CAR T-cell therapies in earlier lines of treatment is of great interest in the field, Cohen explains. 

For example, the phase 3 KarMMa-3 trial (NCT03651128) attempted to investigate the use of ide-cel vs standard-of-care regimens in patients with triple-class exposed relapsed/refractory multiple myeloma, Cohen details, adding that this patient population recieved fewer prior lines of therapy than patients in previous studies. On this study, ide-cel is being compared with investigator's choice of therapy, which includes daratumumab (Darzalex), pomalidomide (Pomalyst), dexamethasone, bortezomib (Velcade) and ixazomib (Revlimid). The trial's primary end point was progression-free survival (PFS).

Based on data from KarMMa-3 that were published in the 

, patientsreceiving ide-cel were shown to have a significantly improved PFS vs its comparator arms, Cohen says. This trial demonstrated the efficacy and utility of ide-cel and may support future attempts to expand ide-cel's approval to less heavily pretreated populations, Cohen concludes.

Editor’s Note: Dr. Cohen reports serving as a consultant or in an advisory role for Celgene, BMS, Takeda, Janssen, Seattle Genetics, AstraZeneca, Genentech/Roche, Oncopeptides, GlaxoSmithKline, Arcellx, Ichnos; he received research funding from Novartis, GlaxoSmithKline; he has intellectual property licensed by institution to Novarti.

Adam D. Cohen, MD, discusses the current landscape of treatment options in multiple myeloma, and elaborates on attempts to utilize these options in earlier lines of therapy. 

Dr. Cohen on the Use of CAR T-cell Therapy in Earlier Lines of Multiple Myeloma Treatment 

Adam D. Cohen, MD, assistant professor of medicine, director, Myeloma Immunotherapy, University of Pennsylvania, discusses the efficacy of ciltacabtagene autoleucel (cilta-cel; Carvykti) in patients with lenalidomide-refractory multiple myeloma.

Cohort A of the phase 2 CARTITUDE-2 trial (NCT04133636) evaluated cilta-cel to determine the minimal residual disease (MRD)–negativity rate in patients with relapsed/refractory multiple myeloma who received 1-3 prior lines of therapy, including a proteasome inhibitor and immunomodulatory therapy. Patients were required to be lenalidomide (Revlimid) refractory.

 International Myeloma Society Meeting showed that 20 of the 25 patients enrolled in cohort A received treatment with cilta-cel, Cohen says. The median number of prior lines of therapy was 2, all patients were lenalidomide refractory, 40% were triple-class refractory, 60% were refractory to daratumumab (Darzalex), and 85% received prior stem cell transplant, Cohen adds.

Treated patients achieved an overall response rate of 95%, including a complete response rate of 90%, Cohen continues. The primary end point of the trial is MRD negativity, and in Cohort A, all 16 evaluable patients were MRD negative, Cohen adds. 

At the data cutoff of 17 months, the median duration of response has not been reached, and approximately 90% of the responders were still in response at 12 months or more, Cohen explains. Additionally, the estimated 15-month progression-free survival rate was approximately 70%. The efficacy data have been positive, though longer follow-up is needed, Cohen concludes.

Adam D. Cohen, MD, discusses the efficacy of ciltacabtagene autoleucel in patients with lenalidomide-refractory multiple myeloma.


Dr. Cohen on the Efficacy of Cilta-Cel in Lenalidomide-Refractory Multiple Myeloma

Adam D. Cohen, MD, assistant professor of medicine, director, Myeloma Immunotherapy, University of Pennsylvania, discusses the safety profile of ciltacabtagene autoleucel (cilta-cel) in patients with multiple myeloma, based on data from the phase 2 CARTITUDE-2 study (NCT04133636). 

The main hematologic toxicities observed with cilta-cel on the study were similar to those reported in the phase 1/2 CARTITUDE-1 trial (NCT03548207); they included neutropenia, anemia, and thrombocytopenia, according to Cohen. These toxicities are most often associated with lymphodepletion conditioning therapy, as well as the CAR T-cell therapy itself, Cohen explains.

The rates of grade 3/4 thrombocytopenia and anemia appeared to be less than what was reported on CARTITUDE-1, and prolonged grade 3/4 cytopenias also occurred less frequently; this may be because the CARTITUDE-2 study enrolled a less heavily pretreated population, Cohen concludes.

Adam D. Cohen, MD, discusses the safety profile of ciltacabtagene autoleucel in patients with multiple myeloma, based on data from the phase 2 CARTITUDE-2 study.

Dr. Cohen on the Safety Profile of Cilta-Cel in Multiple Myeloma 

Adam D. Cohen, MD, assistant professor of medicine, director, Myeloma Immunotherapy, University of Pennsylvania, discusses outcomes with ciltacabtagene autoleucel (cilta-cel), as demonstrated in the phase 2 CARTITUDE-2 study (NCT04133636) in patients with multiple myeloma.

CARTITUDE-2 is evaluating the safety and efficacy of cilta-cel in patients with progressive disease following 1 to 3 prior lines of therapy, as well as in those who are lenalidomide (Revlimid) refractory and who have not received prior BCMA-targeting agents.

Data from cohort A showed that the CAR T-cell therapy induced an overall response rate of 95% in the 20 patients enrolled, according to Cohen. Additionally, 75% of patients achieved a complete response (CR) or better with cilta-cel, making the efficacy similar to what had been reported in the phase 1/2 CARTITUDE 1 trial (NCT03548207), Cohen adds.

In cohort A, the median time to response was approximately 1.0 month, and the median time to CR was 1.9 months. The median follow-up was 5.8 months at the time of data cutoff, and no patients had progressed at that time, Cohen explains. All patients are in ongoing remission, although more follow-up is needed to determine the durability of responses and how these data compare with what has been observed in more heavily pretreated patients, Cohen concludes. 

Adam D. Cohen, MD, discusses outcomes with ciltacabtagene autoleucel, as demonstrated in the phase 2 CARTITUDE-2 study in patients with multiple myeloma.

Dr. Cohen on CARTITUDE-2 Data With Cilta-Cel in Multiple Myeloma 

Adam D. Cohen, MD, assistant professor of medicine, director, Myeloma Immunotherapy, University of Pennsylvania, discusses mitigation strategies that can be used for patients with relapsed/refractory multiple myeloma who are receiving the CAR T-cell therapy ciltacabtagene autoleucel (cilta-cel).

The phase 1/2 CARTITUDE-1 study (NCT03548207) examined cilta-cel in patients who had received 3 or more prior lines of therapy or were double refractory to a proteasome inhibitor and an immunomodulatory drug (IMiD) and had received a proteasome inhibitor, IMiD, and an anti-CD38 antibodty.

Results from an analysis of the trial showed that these patients had a least 2 of the following features: high tumor burden, grade 2 or higher cytokine release syndrome (CRS), prior immune effector cell–associated neurotoxicity syndrome (ICANS), as well as very high CAR T-cell expansion and persistence, according to Cohen. These findings inspired mitigation strategies that were incorporated in the studies that followed CARTITUDE-1, Cohen explains. 

One strategy was to allow investigators to give their choice of bridging therapy to reduce the risk of rapid progression during manufacturing, Cohen notes. In CARTITUDE-1, patients were restricted to receive the same therapies they had previously received. As such, many patients were highly refractory and progressed through manufacturing and bridging therapy, according to Cohen.

Additional efforts include more aggressive management of CRS and ICANS, a handwriting analysis for all patients because micrographia was an early sign of movement and neurocognitive-like disorders, and prolonged neurologic monitoring beyond the first 100 days of treatment, Cohen explains. The incidence of neurocognitive and movement disorders has decreased dramatically since these efforts were implemented, Cohen concludes. 

Adam D. Cohen, MD, discusses mitigation strategies that can be used for patients with relapsed/refractory multiple myeloma who are receiving the CAR T-cell therapy ciltacabtagene autoleucel. 

Dr. Cohen on Mitigation Strategies for CAR T-Cell Therapy in Multiple Myeloma

Adam D. Cohen, MD, assistant professor of medicine, director, Myeloma Immunotherapy, University of Pennsylvania, discusses the ongoing phase II DREAMM-2 study in multiple myeloma. 

Prior to the trial, the phase I DREAMM-1 study demonstrated an overall response rate (ORR) of 60% with the investigational antibody-drug conjugate (ADC) belantamab mafodotin (GSK2857916). 

DREAMM-2 is a registration study that is evaluating the ADC in a heavily pretreated and refractory population, explains Cohen. To be eligible for enrollment, patients had to have been exposed to a proteasome inhibitor, an immunomodulatory drug, and a CD38-targeted antibody.  

In the trial, patients will be randomized to receive 3.4 mg/kg or 2.5 mg/kg of intravenous belantamab mafodotin. According to topline findings reported in a press release, belantamab mafodotin resulted in a clinically meaningful ORR in patients with relapsed myeloma, meeting the primary endpoint of the trial.

Adam D. Cohen, MD, discusses the ongoing phase II DREAMM-2 study in multiple myeloma. 
 

Adam D. Cohen, MD

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