Rakesh Popat, MBBS, MRCP, FRCPath, PhD, details the mechanism of action and the impetus for assessing JNJ-5322 in relapsed/refractory multiple myeloma.

Dr Popat on the Rationale for Assessing JNJ-5322 in Relapsed/Refractory Myeloma

“This is a novel antibody. It's been augmented such that the BCMA/GPRC5D binding is very tight. Of note, it binds to different epitopes than teclistamab and talquetemab.”

Rakesh Popat, MBBS, MRCP, FRCPath, PhD, a consultant hematologist at the University College Hospital at the University College London Hospitals (UCLH), lead of the Myeloma Clinical Trials Program, and the cancer program lead for the National Institute for Health Research UCLH Clinical Research Facility, detailed the impetus for evaluating the novel trispecific antibody JNJ-79635322 (JNJ-5322), and the mechanism of action of the agent, for the treatment of patients with relapsed/refractory multiple myeloma.

Several bispecific antibodies have been approved by the FDA for the treatment of patients with multiple myeloma, which include teclistimab-cqyv (Tecvayli) and elrantamab (Elrexfio), which target BCMA, Popat began. Talquetamab-tgvs (Talvey) is also an FDA-approved treatment that targets GPRC5D, he added. However, in patients with relapsed/refractory multiple myeloma, approximately 40% do no respond to these 3 respective treatments, he emphasized. Although talquetamab is an effective bispecific antibody, it’s known to be associated with on-target, off-tumor toxicities, which include skin, nail, and oral toxicities, such as dry mouth and problems with taste, he asserted. Therefore, the purpose of the phase 1 trial (NCT05652335) was to develop a trispecific antibody that could target BCMA-positive cells, along with GPRC5D-positive cells, according to Popat. With the specificity of the molecule, the hope is to reduce off-tumor toxicities, he stated. 

Regarding the mechanism of action of JNJ-5322, it’s a novel trispecific antibody, of which the BCMA and GPRC5D binding is very tight, Popat noted. It can bind to different epitopes compared with teclistamab and talquetamab, he continued. Furthermore, the CD3 portion of the agent is a low-affinity binder that can better lend itself for outpatient dosing, which also leads to a lower cytokine release syndrome profile, he contextualized. Additionally, the modulation of this component further improved pharmacokinetics, which allows for dosing every 2 to 4 weeks, he concluded.

Videos

Dr Popat on JNJ-5322 in Relapsed/Refractory Multiple Myeloma 

“All patients [in the BCMA/GRPC5D–naive cohort] treated at the recommended phase 2 dose responded. The very good partial response rate was over 90%. [These were] very strong efficacy data.”

Rakesh Popat, MBBS, MRCP, FRCPath, PhD, a consultant hematologist at University College London Hospitals as well as the leader of the Myeloma Clinical Trials Program and the cancer program lead at the National Institute for Health Research University College London Hospitals Clinical Research Facility, discussed efficacy findings with the trispecific antibody JNJ-5322 in patients with relapsed/refractory multiple myeloma.

, Popat presented data from a phase 1 study (NCT05652335) examining JNJ-5322 in patients with triple-class exposed relapsed/refractory multiple myeloma. The study included patients who were exposed to BCMA/GRPC5D–directed therapies and those who had not received a prior BCMA/GRPC5D agent; most patients included in the study were BCMA/GRPC5D naive, Popat began.

At a median follow-up of 12.2 months, results from the trial demonstrated that efficacy-evaluable patients in the BCMA/GRPC5D–naive cohort who received JNJ-5322 at the recommended phase 2 dose (RP2D) of 100 mg every 4 weeks (n = 27) achieved an overall response rate (ORR) of 100%, Popat explained. The very good partial response (VGPR) rate was 96.3%, he added. Moreover, the complete response (CR) or better rate was 70.4%.

Efficacy-evaluable patients who received JNJ-5322 at doses of 50 mg to 300 mg in the BCMA/GRPC5D–exposed subgroup (n = 20) experienced an ORR of 55.0%, Popat noted. The CR or better rate among these patients was 30% and the VGPR rate was 50%.

In terms of durability of response, no patients in the BCMA/GRPC5D–naive cohort treated at the RP2D experienced disease progression, although 1 patient died due to an infection, Popat said. The 12-month progression-free survival rate in this group was 95.0%, he concluded.

Rakesh Popat, MBBS, MRCP, FRCPath, PhD, discusses data with the trispecific antibody JNJ-5322 in relapsed/refractory multiple myeloma.

Rakesh Popat, BSc, MBBS, MRCP, FRCPath, PhD, consultant hematologist, University College Hospital, honorary associate professor, University College London, discusses investigational strategies to mitigate belantamab mafodotin-blmf (Blenrep)–related keratopathy in multiple myeloma.

Research is being generated regarding how to improve management strategies for belantamab mafodotin–related keratopathy in patients with relapsed/refractory multiple myeloma, Popat explains. Findings from the pharmacokinetic analysis of the phase 2 DREAMM-2 trial (NCT03525678) suggest that the severity of keratopathy correlates with trough levels of belantamab mafodotin. 

As such, clinical rationale exists to extend the infusion time of belantamab mafodotin to elicit a lower trough level. Moreover, some of the ongoing DREAMM trials and other investigator-initiated studies will be dosing belantamab mafodotin in 4-to-6-week cycles rather than 21-day cycles to minimize keratopathy among patients, Popat says.

Additionally, investigators are parsing out whether eye care specialists are needed to manage keratopathy in patients with multiple myeloma receiving belantamab mafodotin. Hematologists typically manage a wide range of treatment-related adverse effects (TRAEs), so once the field develops a better understanding of mitigating keratopathy, hematologists may be able to manage the TRAE without insight from ophthalmologists, Popat explains. In turn, patients could be spared an additional appointment to an eye care specialist, Popat concludes. 

Rakesh Popat, BSc, MBBS, MRCP, FRCPath, PhD, discusses investigational strategies to mitigate belantamab mafodotin-blmf–related keratopathy in multiple myeloma.  



Dr. Popat on Investigational Strategies for Belantamab Mafodotin–Related Keratopathy in Multiple Myeloma 

Rakesh Popat, BSc, MBBS, MRCP, FRCPath, PhD, consultant hematologist, University College Hospital, honorary associate professor, University College London, discusses mitigating belantamab mafodotin-blmf (Blenrep)–related keratopathy in relapsed/refractory multiple myeloma.

Keratopathy is a common adverse effect observed in approximately 70% of patients with relapsed/refractory multiple myeloma treated with belantamab mafodotin, Popat explains. Although not all patients develop symptoms, signs of keratopathy may be noted by an eye care specialist. Patients who develop symptomatic keratopathy may experience blurred vision, dry eye, gritty eyes, and photophobia, Popat says.

Preservative-free eye drops should be given to all patients before and during treatment with belantamab mafodotin to mitigate the risk of keratopathy. Moreover, dosing of these eye drops should be increased to every 2 to 3 waking hours for symptomatic patients to provide relief, Popat concludes.

Rakesh Popat, BSc, MBBS, MRCP, FRCPath, PhD, discusses mitigating belantamab mafodotin-blmf–related keratopathy in relapsed/refractory multiple myeloma.  



Dr. Popat on Mitigating Belantamab Mafodotin–Related Keratopathy in Multiple Myeloma 

Rakesh Popat, BSc, MBBS, MRCP, FRCPath, PhD, consultant hematologist, University College Hospital, honorary associate professor, University College London, discusses the toxicities associated with belantamab mafodotin-blmf (Blenrep) in relapsed/refractory multiple myeloma. 

Weighing the risks and benefits of all therapies in oncology is an important step of the treatment-decision process, Popat says. Moreover, all treatment recommendations should be personalized to the individual patient.

Findings from the phase 2 DREAMM-2 trial (NCT03525678), which led to the August 2020 FDA approval of belantamab mafodotin, demonstrated clinical activity and a tolerable safety profile with the antibody-drug conjugate in patients with heavily pretreated relapsed/refractory multiple myeloma. Notably, most patients who required treatment discontinuations stopped treatment because of disease progression rather than adverse effects (AEs), Popat says. 

Regardless, making a patient aware of the potential toxicities associated with belantamab mafodotin, including thrombocytopenia and keratopathy, is critical, Popat explains. Moreover, explaining how these AEs could affect a patient’s quality of life, as well as the how the efficacy of the agent compares with that of standard of care therapies, is important, Popat concludes.

Rakesh Popat, BSc, MBBS, MRCP, FRCPath, PhD, discusses the toxicities associated with belantamab mafodotin-blmf in relapsed/refractory multiple myeloma.  



Dr. Popat on Weighing Belantamab Mafodotin–Related Toxicities in Multiple Myeloma 

Rakesh Popat, BSc, MBBS, MRCP, FRCPath, PhD, consultant hematologist, University College Hospital, honorary clinical senior lecturer, University College London Cancer Institute, North Thames Clinical Research Network Specialty Lead for Hematology, Cancer Division, discusses unmet needs in triple-class refractory multiple myeloma.

Despite significant advancements that have been made over the past decade, multiple myeloma remains an incurable hematologic malignancy, Popat says. Currently, a major challenge in myeloma involves developing novel treatments for patients with triple-class refractory disease, Popat explains. 

These heavily pretreated patients have progressed on or become intolerant of proteasome inhibitors, immunomodulatory agents, and CD38-directed monoclonal antibodies, says Popat. 

These 3 drug classes have been brought into earlier lines of treatment in combination regimens for patients with multiple myeloma. Therefore, limited treatment options are available for patients with heavily pretreated progressive disease, concludes Popat. 

Rakesh Popat, BSc, MBBS, MRCP, FRCPath, PhD, discusses unmet needs in triple-class refractory multiple myeloma.  



Dr. Popat on Unmet Needs in Triple-Class Refractory Multiple Myeloma 

Rakesh Popat, BSc, MBBS, MRCP, FRCPath, PhD, consultant hematologist, University College Hospital, honorary clinical senior lecturer, University College London Cancer Institute, North Thames Clinical Research Network Specialty Lead for Hematology, Cancer Division, discusses results from the phase I, dose-expansion DREAMM-1 trial in relapsed/refractory multiple myeloma.

DREAMM-1 investigated the BCMA antibody-drug conjugate GSK2857916 for the first time in humans, explains Popat. Patients enrolled had progressive multiple myeloma after autologous stem cell transplant, or treatment with alkylators, proteasome inhibitors, and immunomodulatory agents.

In part 2 of the trial, heavily pretreated patients who were refractory to both an immunomodulatory agent and proteasome inhibitor had a nearly 60% overall response rate and median progression-free survival of 7.9 months was noted with the 3.4 mg/kg recommended dose of GSK2857916, which was identified in part 1 of the trial.

Thrombocytopenia and corneal adverse events including blurred vision, dry eye, and photophobia were commonly reported; however, the treatment was generally well-tolerated, concludes Popat. 

Rakesh Popat, BSc, MBBS, MRCP, FRCPath, PhD, discusses results from the phase I, dose-expansion DREAMM-1 trial in relapsed/refractory multiple myeloma.
 

Rakesh Popat, BSc, MBBS, MRCP, FRCPath, PhD

Articles