Navigating the Use of Bispecific Antibodies and CAR T-Cell Therapy in RRMM

Targeted Therapies in Oncology: How has the treatment landscape evolved for relapsed/ refractory multiple myeloma?

BINOD DHAKAL, MD: In the past 5 years, the treatment landscape has changed quite substantially. There were 2 major developments with immunotherapy: chimeric antigen receptor [CAR] T-cell therapy and bispecific antibody therapy. We have 2 CAR T-cell therapies targeting BCMA [B-cell maturation antigen] that are approved: ciltacabtagene autoleucel [Carvykti; cilta-cel] and idecabtagene vicleucel [Abecma; ide-cel].^1,2 There are 3 bispecific antibodies approved for the treatment of MM. Two of of the relapse. CAR T-cell therapy takes time, whereas bispecific antibody therapy can be given right away.

As mentioned, the available bispecific antibody therapies have 2 different targets: the BCMA and the non-BCMA target, GPRC5D. Patients who were exposed to BCMA- [directed therapy] can be given GPRC5D-[directed therapy]. This is important because now we have BCMA-targeted CAR T-cell therapy approved in the early line as early as second line with cilta-cel and third line and beyond with ide-cel. Thus, if the patient is already exposed to BCMA agents with CAR T-cell therapy, they can then receive GPRC5D-directed bispecific antibody therapy. This aspect of having a GPRC5D bispecific antibody therapy is important in the treatment landscape.

What are the unmet needs in treating patients with RRMM?

The main unmet need is how to expand access of these agents to the majority of patients. CAR T-cell therapy is available only in specific centers, and patients may not have that access locally and may have to travel. In addition, there are limited slots at each center for patients to receive CAR T-cell therapy.

In contrast, bispecific antibody therapies are given off the shelf and can be easily accessed. However, they are not available across all centers in the US and are limited to mainly academic centers with a few community sites offering this therapy.

It is going to take some time for community sites to broadly start administering bispecific antibody therapies, eliminating the need for patients to travel to an academic site. I believe this remains a major barrier.

Of note, these treatments are very effective, but they are not curative, and patients will need other therapies after relapse. There is a subset of patients [in whom] these agents still are not effective: for example, patients with poor prognostic features, extreme disease, high-risk cytogenetics, high-disease burden, and patients with high [levels of] bone marrow plasma cells. Future studies need to evaluate how these patients respond with combination therapy of these available agents.

In addition, patients with different comorbidities are excluded from clinical trials, and we do not have much data on how to use these newer agents, including the bispecific antibody therapies, for these patients. This includes patients who are either on dialysis or have heart failure, which can be present in an older patient population.

How do the updated long-term data from the MonumenTAL-1 trial influence treatment decisions for RRMM?

The phase 1/2 MonumenTAL-1 trial [NCT03399799] data led to the approval of talquetamab in patients with 4 or more prior lines of therapy.⁶ In the initial report, the response rate was 70%, which was impressive. The majority of patients had a good duration of response of almost a year, and given the type of patient population that was enrolled in that study, this response was impressive. There are 2 dose schedules that were approved: one scheduled weekly and the other every other week.

There are unique toxicities that are associated with this drug other than CRS and immune effector cell–associated neurotoxicity syndrome [ICANS]. These included the involvement of oral, nail, and skin toxicities.

In a recent update presented during the [21st] International Myeloma Society [Annual Meeting] conference [in Rio de Janeiro, Brazil], data from a longer follow-up were presented, showing continued benefit in terms of efficacy.⁷ In this longer follow-up, the overall response rate [ORR] was 74% for those receiving a dose every week.

In the prior T-cell redirection [TCR] therapy cohort, the response rate was 67%, with the majority of patients achieving very deep responses and more than 55% achieving very good partial response rates or better. What was also impressive is that in this longer follow-up, the ORR was consistent across all high-risk subgroups. In the prior TCR cohort, the ORR was 71% in those receiving prior CAR T-cell therapy and about 58% in those receiving prior BCMA-targeting bispecific antibody therapy.

The rates of duration of response, progression-free survival [PFS], and overall survival [OS] were also impressive. The median PFS was 12.3 months. The PFS was similar for those who received prior CAR T-cell therapy, which was 4.1 months, and those who received prior BCMA-targeting bispecific antibody therapy.

Safety data were consistent with previous reports, and there were no new safety signals observed. Weight loss occurred in 39% of patients receiving the weekly dose, about 34% in those receiving the dose every other week, and 39% in the prior TCR cohort.

Overall, rates of dose reduction due to adverse events [AEs] were around 15% with the weekly dose, 10% in the dose every other week, and 12% in the prior TCR cohort. Complete discontinuation of the drug due to AEs was about 5% in the weekly dose, 10% in patients receiving a dose every other week, and 5% in the prior TCR cohort. There were no treatment-related deaths.

[Findings from] this longer follow-up of the MonumenTAL-1 study showed a high ORR across all cohorts, including those in the prior TCR cohort, with the duration of response and PFS lasting almost up to a year. Patients also achieved deeper responses, and the safety profile was consistent with previous reports as were the efficacy data. This highlights the overall clinical benefit of GPRC5D-directed talquetamab with the approved doses.

Please discuss step-up dosing and initial challenges when using talquetamab for this patient.

For this patient who is a 72-year-old man and who received 5 prior lines of therapy, including the BCMA-directed CAR T-cell therapy, [he] is now treated with talquetamab every other week for a full dose schedule. Following the second step-up dose, the patient experienced grade 1 CRS and reported altered taste and dry mouth.

For talquetamab, there are 2 different dosing schedules approved. One is 0.4 mg every week, and the other is 0.8 mg every other week; thus, either dose can be given to a patient depending on their preferences and other factors.

The step-up dosing is done to mitigate the risk of CRS, and with this step-up dosing approach, the rates of CRS and ICANS, especially grade 3, are decreased to less than 1% across all dose levels, which is quite encouraging. When you look at the CRS rates with the step-up dosing approach in real-world data, the rates of CRS and ICANS are consistent with what is observed in [findings from] the clinical trials.⁸

CRS typically occurs in the step-up doses before the first full dose is given. For example, in [findings from] a real-world study, for the first step-up dose, the CRS rate was 30% and mainly grade 1 and then 31% in dose 2 of the step-up dosing approach. In dose 3, especially when given every other week [0.8-mg dose], the CRS rate was 14%. Similarly, during the step-up doses, ICANS also occurred, most of it grade 1 and grade 2. It is encouraging that in these real-world data, the CRS profile is consistent with what is shown in [findings from] the clinical trial.

There was an evaluation that was done in the MonumenTAL-1 study to decrease the frequency of the step-up dosing, and what it showed is that if you decrease the frequency of the step-up dosing given every other week to reach 0.8 mg/kg of talquetamab, the rates of CRS seem to be higher.⁶ For example, grade 2 CRS in the step-up dose given weekly was 16%. But if you decrease the frequency of the step-up doses to the alternative schedule, grade 2 CRS can increase to 50%. Thus, it is preferable to continue the same step-up dosing per the recommendation as it seems to give the best chance of low rates for CRS.

What mitigation strategies would you initiate for this patient?

This patient [mentioned in the case], after the first month of treatment, achieved stringent complete response [CR] but is experiencing oral, skin, and nail toxicities. The unique AEs associated with targeting GPRC5D are one of the major issues for the patients receiving this drug and can impact their quality of life, especially for patients who lose sense of taste. Unfortunately, there are no specific preventive measures that will be effective for all patients.

However, there are some measures that can be done to minimize these AEs. For example, I always educate the patient extensively so that they are aware of these AEs that can occur during the treatment. There are a few supportive strategies that we recommend [for] minimizing AEs, and this is specific to each AE. For example, with oral AEs and the loss of taste, I always recommend a dietitian consultant to explore what the patient can taste. Having sour candies before a meal may be effective against loss of taste.

For dry mouth and stomatitis, I encourage the patient to have steroid mouthwashes. For skin AEs, if they are minor, I recommend moisturizers or steroid creams as needed. For the nail changes, using emollients and nail protectors may be helpful. For weight loss, which may or may not occur with loss of taste or taste change, patients may consult a dietitian to help ensure they receive appropriate nutrition by consulting on the appropriate diet intake. These strategies may or may not work for all patients, but it has helped the majority of my patients.

Please explain the data regarding GPRC5D-related toxicity.

The GPRC5D-directed and BCMA- directed bispecific antibody therapies share common AEs, specifically CRS and ICANS. The data for CRS and ICANS are comparable, showing grade 3 and 4 CRS in less than 1% to 2% across GPRC5D- and BCMA- targeted bispecific antibodies.⁹ For ICANS, it was less than 1% for BCMA- directed bispecific antibodies and less than 2% for GPRC5D- directed bispecific antibodies.

The risk of infections is present with any bispecific antibody therapy, but with GPRC5D, the risk of grade 3 or 4 infections is much lower than [with] BCMA-directed bispecific antibodies. For example, for BCMA-targeted bispecific antibodies across the board, the risk of grade 3 or 4 infections is about 30% to 40%, whereas for GPRC5D, the risk is about 17%. When using more aggressive preventive strategies, the risk is even lower in clinical practice vs clinical trials.

The MajesTEC-1 trial [NCT04557098] is the first pivotal study that led to the approval of teclistamab in patients with RRMM.¹⁰ In the primary report, the [findings from the] study showed that in patients who had been heavily treated with a median of 5 prior lines of therapy, the ORR was about 60% and the PFS was approximately 11.8 months, which was quite impressive.

In the recent update, with a longer follow-up of 22.8 months, the agent continued to show impressive efficacy, with an ORR of 63% and complete response or better rate of 45.5%.¹¹ The median duration of response was 21.6 months, the PFS was 11.3 months, and the OS [was] almost 22 months. These were impressive data.

In terms of the safety regarding CRS and ICANS, as mentioned, there was no change in the long-term follow-up. Infection occurred in 78.8% of the patients, and grade 3 and 4 infection occurred in 56.2%. Investigators also reported that grade 3 or 4 infections generally decreased over time, especially for patients who transitioned to dosing every other week using intravenous immunoglobulin therapy as well as other preventive measures.

In the MagnetisMM-3 trial [NCT04649359], which is the first pivotal study that led to the approval of talquetamab in RRMM, the patient population was comparable with the MajesTEC-1 trial [population]. Patients had 5 median prior lines of therapy, and the majority [had] triple-refractory [disease].¹² The ORR was about 60%, with the median PFS not reached; however, longer follow-up data show an impressive safety and efficacy profile.¹² For example, at the median follow-up of 70.6 months, the ORR was 73% and the majority of patients achieved CR. The duration of response was not reached, the median PFS was 17.2 months, and the OS was 22 months.

The CRS and ICANS rates [of] grade 3 and higher were less than 1% in the primary presentation, and this remained unchanged in the follow-up. The infection risk continues to remain, occurring in 30% to 40%, yet there were no new infections that were reported in the follow-up and the risk of infections was shown to decrease with the decrease in the frequency, similar to [findings from] the MajesTEC-1 trial.

Which patients are best suited for these agents?

Both bispecific antibody therapies are quite a significant development. Considering patients who [have] triple-class exposed or refractory [disease], having a drug that elicits an ORR of 60% to 70% and a PFS of at least a year or more is remarkable.

Both bispecific antibody therapies are suitable for eligible patients with RRMM. However, there are currently no data that suggest one bispecific antibody therapy is superior to the other. That said, certain patient characteristics may guide the choice between them. The BCMA-[directed] bispecific antibody carries a higher risk of severe infections, particularly grade 3 and higher. Therefore, for patients with a history of recurrent infections, it may be preferable to avoid this as the initial treatment. If a patient has already been treated with BCMA-targeted agents, it may be better to opt for a non-BCMA bispecific antibody to target a different pathway.

REFERENCES

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2. FDA approves idecabtagene vicleucel for multiple myeloma. FDA. March 29, 2021. Accessed January 8, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-idecabtagene-vicleucel-multiple-myeloma

3. FDA approves teclistamab-cqyv for relapsed or refractory multiple myeloma. FDA. October 25, 2022. Accessed January 8, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-teclistamab-cqyv-relapsed-or-refractory-multiple-myeloma

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