Dr Dholaria on the Use of Liso-Cel in Relapsed/Refractory CLL

Bhagirathbhai Dholaria, MBBS, associate professor, medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, discusses 

the benefits and limitations of lisocabtagene maraleucel

 (liso-cel; Breyanzi) for patients with relapsed/refractory chronic lymphocytic leukemia (CLL).

In the phase 1/2 TRANSCEND CLL 004 trial (NCT03331198), patients with relapsed/refractory CLL received cyclophosphamide and fludarabine–based lymphodepletion followed by a single infusion of liso-cel. Patients in this trial were heavily pretreated; all patients had received prior BTK inhibitors, and several patients with a BTK domain mutation had prior exposure to venetoclax (Venclexta), Dholaria says.

Among patients who achieved a complete response with liso-cel, the median progression-free survival (PFS) was not yet reached at a median follow-up of approximately 24 months. The median PFS was approximately 26.9 months among patients who achieved a partial response. The median PFS was approximately 18.0 months in the overall population. The PFS outcomes were similar between patients who had received prior BCL-2 and BTK inhibitors and the overall trial population, Dholaria explains. 

Liso-cel is effective in patients with relapsed/refractory CLL, and may address some traditional factors associated with high-risk disease, including prior exposure to BTK inhibitors or BCL-2 inhibitors, Dholaria notes. However, one drawback to CAR T-cell therapy is the short-term and long-term toxicity profile associated with this agent, Dholaria emphasizes. Since lymphodepletion is necessary for in vivo CAR T cell expansion, CAR T-cell therapy may not be optimal for patients who are older and/or have several comorbidities, according to Dholaria. Furthermore, the risk of developing cytokine release syndrome and neurotoxicity is high during the first few weeks after liso-cel infusion, Dholaria says. Patients may also experience disease relapse after receiving liso-cel, indicating that this agent is not a curative therapy, Dholaria explains. Relapse-prevention strategies need to be further developed for patients who experience initial responses with liso-cel, Dholaria emphasizes.

Another limitation of CAR T-cell therapy is its cost and lack of accessibility, Dholaria notes. CAR T-cell therapy administration is limited to large academic cancer centers, which may prevent patients from receiving this treatment, Dholaria concludes.

Videos

Bhagirathbhai Dholaria, MBBS, discusses the benefits and limitations of liso-cel for patients with relapsed/refractory chronic lymphocytic leukemia.

Dr Dholaria on the Investigation of Noncovalent BTK Inhibitors in CLL

Bhagirathbhai Dholaria, MBBS, assistant professor, medicine (hematology/oncology), Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, discusses the ongoing examination of noncovalent BTK inhibitors in patients with chronic lymphocytic leukemia (CLL).

Multiple noncovalent BTK inhibitors are under investigation in patients with CLL, including pirtobrutinib (Jaypirca), Dholaria says. This agent was initially approved by the FDA in 2023 

for the treatment of patients with relapsed/refractory mantle cell lymphoma

. Pirtobrutinib was also evaluated in patients with CLL or small lymphocytic lymphoma (SLL) in the CLL/SLL cohort of the single-arm, multicohort, phase 1/2 BRUIN trial (NCT03740529), in which the agent yielded an overall response rate (ORR) of 72% (95% CI, 63%-80%), all of which were partial responses. Furthermore, the median time to response with pirtobrutinib in this cohort was 3.7 months (range, 1.7-27.9), and the median duration of response was 12.2 months (95% CI, 9.3-14.7). Notably, in patients with CLL/SLL who had received a prior BTK inhibitor, the ORR was 73.3% (95% CI, 67.3%-78.7%). The BRUIN trial findings supported the 2023 

 for adult patients with CLL/SLL who have received 2 or more prior lines of therapy, including a BCL-2 inhibitor and a BTK inhibitor.

Another noncovalent BTK inhibitor on the horizon for patients with CLL is nemtabrutinib (ARQ-53), Dholaria explains. Initial findings from the single-arm, phase 1/2 MK-1026-001/BELLWAVE-001 trial (NCT03162536) showed that whennemtabrutinib was given at a daily dose of 65 mg, it elicited an ORR of 75% in patients with CLL/SLL that was relapsed or refractory to at least 2 prior therapies. Updated data from this trial showed that at a median follow-up of 4.8 months (range, 0.1-38.8), the ORR in the CLL/SLL cohort was 56% (95% CI, 42%-69%).

Other noncovalent BTK inhibitors are in the pipeline as well and long-term clinical data from larger patient subsets may be available in the future, Dholaria concludes.

Bhagirathbhai Dholaria, MBBS, discusses the ongoing evaluation of noncovalent BTK inhibitors in patients with chronic lymphocytic leukemia.

Bhagirathbhai R. Dholaria, MBBS, assistant professor of medicine, Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, discusses next steps for investigating subcutaneous talquetamab and daratumumab (Darzalex) in relapsed/refractory multiple myeloma based on data from the phase 1 TRIMM-2 trial (NCT04108195).

The multicohort study evaluated whether the addition of daratumumab to the bispecific T-cell engager talquetamab could improve immune responses in patients with multiple myeloma.

Updated findings from the multicohort study were presented at the 2023 ASCO Annual Meeting, showing that both the 0.4 mg/kg and 0.8 mg/kg weekly doses of subcutaneous talquetamab plus daratumumab produced overall response rates (ORRs) of above 70% and no overlapping toxicities. Moreover, patients in the 0.8 mg/kg group who had been previously exposed or were refractory to anti–CD38-directed therapy experienced ORRs of over 80%, and those who had previously received T-cell redirection therapies had an ORR of 78.9% with an additional 10 months of follow-up.

These findings support the continued investigation of the talquetamab and daratumumab in multiple myeloma. Investigators plan to continue following patients and collecting data within this study, Dholaria says. If the regimen demonstrates efficacy and safety outcomes consistent with the data from TRIMM-2, the regimen's further investigation will gain more support, he adds. 

talquetamab was granted accelerated approval by the FDA for adults with relapsed/refractory multiple myeloma

 who have received at least 4 prior lines of therapy, on August 9, 2023. The regulatory decision was based on data from the phase 1/2MonumenTAL-1 trial (NCT03399799, NCT4634552).

In addition to TRIMM-2, there are several ongoing studies evaluating the regimen in combination with established agents, as well as novel myeloma-directed therapies, Dholaria continues. The phase 3 MonumenTAL-3 study (NCT05455320) is evaluating talquetamab and daratumumab with or without pomalidomide, he introdues. Meanwhile, the phase 1/2 RedirecTT-1 trial (NCT04586426) is combining both talquetamab and the T-cell–redirecting bispecific antibody teclistamab (Tecvayli) in patients with relapsed/refractory multiple myeloma or extramedullary disease, Dholaria notes. In the future, studies of talquetamab may attempt to utilize the agent in combination with other immunotherapies, such as immune checkpoint inhibitors, Dholaria concludes.

Dr Dholaria reports serving as a consultant or in an advisory role for Arivan research, Beam Therapeutics, Gamida Cell, Jazz Pharmaceuticals, and Pluristem Therapeutics; he received honoraria from Adaptive Biotechnologies, Curio Science, MJH Healthcare Holdings LLC, and Wiley; he received institutional research funding from Angiocrine Bioscience, Janssen Oncology, MEI Pharma, Orca Bio, Pfizer, Poseida therapeutic, Takeda, WUGEN, Inc; he has stock and other ownership interests with Iovance Biotherapeutics and Syndax.

Bhagirathbhai Dholaria, MBBS, discusses next steps for investigating subcutaneous talquetamab and daratumumab in relapsed/refractory multiple myeloma based on data from the phase 1 TRIMM-2 trial.
 


Dr Dholaria on Ongoing Investigations of Talquetamab and Daratumumab in R/R Multiple Myeloma

Bhagirathbhai R. Dholaria, MBBS, assistant professor of medicine, Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, discusses additional 10-month follow-up data from the phase 1 TRIMM-2 trial (NCT04108195) of subcutaneous talquetamab and daratumumab (Darzalex) in relapsed/refractory multiple myeloma.

In this multicohort study, adding the monoclonal antibody daratumumab to the bispecific T-cell engager talquetamab was hypothesized to enhance clinical responses for patients with multiple myeloma. Initial data from the phase 1b portion of the study showed that the combination had preliminary efficacy and bolstered immune responses in this patient population.

Updated results from the trial demonstrated that patients who received talquetamab at a weekly dose of 0.4 mg/kg had an overall response rate (ORR) of 71.4%, Dholaria states. The ORR was 84.0% in those who received the 0.8 mg/kg twice-weekly dose. Patients received 1800 mg of subcutaneous daratumumab in both cohorts. Moreover, with an additional 10 months of follow-up, in the 0.8 mg/kg group, patients who were either previously exposed or refractory to anti–CD38-directed therapy experienced ORRs of over 80% with the regimen, Dholaria reports. Moreover, patients who had previously received T-cell redirection therapies had an ORR of 78.9%, he adds.

No new or additive toxicities were seen with the regimen during this period of additional follow-up, Dholaria continues. As expected, most adverse effects (AEs) were hematologic (60%), Dholaria states. The percentage of patients who experienced grade 3 or 4 neutropenia was 28.6% in the 0.4 mg/kg group, and 27.5% in the 0.8 mg/kg group. Infections were predominantly low grade, although the rates of clinically significant grade 3/4 infection risk were 21.4% and 25.5% in the low and high dose talquetamab groups, respectively. However, most severe infections occurred in the first 6 to 8 months of treatment, Dholaria notes.

Dysgeusia and weight loss were generally manageable with dose modifications or other mitigation strategies, Dholaria adds. Dose reduction of talquetamab due to AEsoccurred in 16.9% of patients, and discontinuation occurred in 1.5% of patients. Other AEs seen with the regimen included skin rash, nail toxicity, gastrointestinal toxicities, and facial hair loss, Dholaria concludes.

Dr Dholaria reports serving as a consultant or in an advisory role for Arivan research, Beam Therapeutics, Gamida Cell, Jazz Pharmaceuticals, and

Pluristem Therapeutics; he received honoraria from Adaptive Biotechnologies, Curio Science, MJH Healthcare Holdings LLC, and Wiley; he received institutional research funding from Angiocrine Bioscience, Janssen Oncology, MEI Pharma, Orca Bio, Pfizer, Poseida therapeutic, Takeda, WUGEN, Inc; he has stock and other ownership interests with Iovance Biotherapeutics and Syndax.

Bhagirathbhai Dholaria, MBBS, discusses additional 10-month follow-up data from the phase 1 TRIMM-2 trial of subcutaneous talquetamab and daratumumab in relapsed/refractory multiple myeloma.


Dr Dholaria on Updated Efficacy Data From the TRIMM-2 Trial of Talquetamab and Daratumumab in R/R Multiple Myeloma

Bhagirathbhai Dholaria, MBBS, assistant professor of medicine, Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, discusses patient characteristics in the phase 1 MagnetisMM-1 trial (NCT03269136) in relapsed/refractory multiple myeloma.

A majority of phase 1 studies evaluating bispecific T-cell engagers are evaluating similar groups of heavily pretreated patients with multiple myeloma, Dholaria says. The MagnetisMM-1 study ​evaluated the bispecific antibody elranatamab (PF-06863135) alone and in combination with immunomodulatory agents, such as lenalidomide (Revlimid) and pomalidomide (Pomalyst), in patients with relapsed/refractory multiple myeloma.


In the study, nearly all patients were exposed to prior monoclonal antibodies, including CD38-directed monoclonal antibodies, such as daratumumab (Darzalex) and isatuximab-irfc (Sarclisa), Dholaria adds.

Moreover, a proportion of patients had received prior antibody-drug conjugates, such as belantamab mafodotin-blmf (Blenrep), or prior CAR T-cell therapy, Dholaria continues. Patients had received prior BCMA-directed therapies, but were intolerant of or progressed onthem, Dholaria concludes.

Bhagirathbhai Dholaria, MBBS, discusses patient characteristics in the phase 1 MagnetisMM-1 trial in relapsed/refractory multiple myeloma. 


Dr. Dholaria on Patient Characteristics in the MagnetisMM-1 Trial in Multiple Myeloma 

Bhagirathbhai Dholaria, MBBS, assistant professor of medicine, Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, discusses the rationale for the phase 1 MagnetisMM-1 trial (NCT03269136) in relapsed/refractory multiple myeloma.

Novel therapies are needed to improve outcomes for patients with relapsed/refractory multiple myeloma, Dholaria explains. The MagnetisMM-1 study evaluated the safety and efficacy of the novel bispecific antibody elranatamab (PF-06863135) alone and in combination with immunomodulatory agents, such as lenalidomide (Revlimid) and pomalidomide (Pomalyst), in patients with relapsed/refractory multiple myeloma.

Currently, the data are not mature enough to draw conclusions as to whether elranatamab stands out among other BCMA-directed bispecific antibodies being evaluated in similar ongoing clinical trials, Dholaria explains. Many of these agents have demonstrated efficacy, as well as tolerability, among patients with relapsed/refractory multiple myeloma. 

Elranatamab is being evaluated as a single agent in the ongoing phase 2 MagnetisMM-3 trial (NCT04649359).

Bhagirathbhai Dholaria, MBBS, discusses the rationale for the phase 1 MagnetisMM-1 trial in relapsed/refractory multiple myeloma.   



Bhagirathbhai Dholaria, MBBS

Articles

Dr Dholaria on the Use of Liso-Cel in Relapsed/Refractory CLL

Dr Dholaria on the Investigation of Noncovalent BTK Inhibitors in CLL

Dr Dholaria on Ongoing Investigations of Talquetamab and Daratumumab in R/R Multiple Myeloma

Dr Dholaria on Updated Efficacy Data From the TRIMM-2 Trial of Talquetamab and Daratumumab in R/R Multiple Myeloma

Dr. Dholaria on Patient Characteristics in the MagnetisMM-1 Trial in Multiple Myeloma

Dr. Dholaria on the Rationale for the MagnetisMM-1 Trial in Multiple Myeloma