Bispecific T-Cell Engagers Raise Questions on Target Selection and Drug Administration

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MORE THERAPEUTIC OPTIONS are becoming available for patients with relapsed/refractory multiple myeloma (RRMM), leading to a new paradigm of treatment for patients with multirefractory disease who are the first to be eligible for clinical trials. The sequencing and utilization of drugs in these heavily pretreated patients is an ongoing question for clinicians.

Two major changes to practice are now impacting treatment approaches for patients with RRMM: the wide adoption of chimeric antigen receptor (CAR) T-cell therapies, and bispecific T-cell engagers that have shown efficacy in later lines of therapy.

Challenging logistics lead to some eligible patients not receiving CAR T-cell therapy, and oncologists are increasingly seeing patients who progress following CAR T-cell therapy. In either situation, bispecific agents start to play a larger role. Teclistamab-cqyv (Tecvayli) was granted accelerated approval in October 2022, followed by elranatamab-bcmm (Elrexfio) and talquetamab-tgvs (Talvey) in 2023.^1-3

In 2 separate Case-Based Roundtable^TM events, oncologists discussed hypothetical cases of patients with multiple myeloma refractory to 4 or more lines of treatment and what role bispecific agents would play, particularly in relation to CAR T-cell therapy.

CHALLENGES OF PATIENTS WITH RELAPSED/REFRACTORY DISEASE

The National Comprehensive Cancer Network recommends CAR T-cell therapy or bispecific antibodies for patients who have received at least 4 prior therapies, including an anti- CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory imide drug.⁴

During the events, the physicians discussed the case of a man in his 60s who received 4 prior lines of prior therapy for multiple myeloma, including daratumumab (Darzalex), bortezomib (Velcade), lenalidomide (Revlimid), carfilzomib (Kyprolis), and dexamethasone, as well as autologous stem cell transplant. The patient then received ciltacabtagene autoleucel (cilta-cel; Carvykti) after 3 lines and showed signs of disease progression 17 months later. He was also in poor physical condition (ECOG performance status of 2).

Participants discussed next-line options including repeating prior therapies as well as using teclistamab and talquetamab. A key reason to distinguish between the bispecific options was that teclistamab targets the B-cell maturation antigen (BCMA), just as cilta-cel does, whereas talquetamab has a different target, GPRC5D.

The panels also discussed an alternate scenario where the patient temporarily postpones CAR T-cell therapy due to personal circumstances but receives a different treatment in the meantime. In either case, the issue of a patient receiving multiple BCMA-targeted therapies could be a concern, and regardless of target, T-cell redirection therapy could have lessened efficacy because of T-cell exhaustion.

GPRC5D VS BCMA TARGETING IN BISPECIFICS

Talquetamab was approved based on data from the phase 1 MonumenTAL-1 trial (NCT03399799).⁵ A weekly dose of 0.4 mg/kg was given to 143 patients, 0.8 mg/kg every other week was given to 145, and 51 who had received prior BCMA-targeted therapy received either dose. The median PFS was 7.5 months, 11.9 months, and 5.1 months, respectively, at 14.9 months’ median follow-up.⁵ In the BCMA-pretreated cohort, there was an overall response rate of 63%, including 53% with at least a very good partial response. These patients had received CAR T-cell therapy (71%), a bispecific antibody (35%), or both (6%).

The data from teclistamab’s initially reported cohorts in the MajesTEC-1 study (NCT04557098) that led to its approval did not include patients who had received prior BCMA-targeted therapy.⁶ However, results presented from cohort C included 38 patients who had had prior BCMA-targeted CAR T-cell therapy or an antibody-drug conjugate (ADC). In 25 patients evaluated for efficacy, 16 (64%) had received prior ADC, 11 (44%) had received prior CAR T-cell therapy, and 2 had received both.⁷ The overall response rate (ORR) was 40% including some rapid and deep responses, showing that serial use of BCMA-targeted therapies should not necessarily be avoided.

In the event moderated by Morie A. Gertz, MD, chair of general internal medicine at Mayo Clinic in Rochester, Minnesota, participants discussed how prior BCMA therapy affected their choice of treatment. Syed Ali Abutalib, MD, of City of Hope Chicago, chose to use talquetamab in this case, but said he was aware of data published in Blood in November 2022 on 15 patients who had favorable responses to bispecific antibodies after prior anti-BCMA CAR T-cell therapy or bispecific antibody.⁸ He asked if a certain duration of posttreatment interval could guide additional anti-BCMA therapy.

Gertz responded that the heterogeneity of the RRMM population makes it challenging to define when to do so, and said of these data, “It was at least meaningful that you wouldn’t exclude someone from a BCMA-directed bispecific if they had BCMA-directed CAR T-[cell therapy], but I don’t think I can define for you that it has to be greater than 6 months, or 12 months, or 24 months….” He said that personally, he would opt next for a different target using talquetamab or an investigational agent.

OUTPATIENT TREATMENT WITH BISPECIFICS

Unlike current CAR T-cell therapies, bispecific antibodies are available off the shelf, but there are still challenges to using them in the outpatient setting, particularly in dealing with cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). Both bispecifics must be given with a step-up dosing on days 1, 4, and 7, and patients should be hospitalized for 48 hours after administration of these doses.^9,10

Stan Nabrinsky, MD, of Illinois Cancer Specialists in Elgin, told Gertz, “When there is no reliable treatment we can give in a community setting, it becomes for us the question of referring the patient out and following what an [academic] center like yours, or the transplant team, will tell us to do.”

Gertz agreed that obstacles exist in the nonacademic setting; in addition to discomfort with managing CRS, hospital administration or the pharmacy department may stand in the way for financial reasons such as maintaining sufficient doses of tocilizumab (Actemra) to manage CRS.

He said that in his experience, “after we’ve done the first 4 doses and we’ve eliminated the risk of CRS and eliminated the risk of ICANS, and they’re stabilized and showing the response, we return them to the community.” Gertz argued this was a more logistically practical approach for patients. “Most patients don’t want to hang around [the Mayo Clinic in] Rochester, Minnesota, having to get treatment that’s once a week. They can’t live their lives; they want to get back home.”

During the other roundtable event, Harpaul Gill, MD, of Atlanta Cancer Care, asked if it will continue to be necessary to give the first doses in a specialized center.

“If you don’t have the ability to give tocilizumab in your emergency [department], you don’t have the ability to give tocilizumab at 10 o’clock at night, then I think the answer to that question is yes,” answered the moderator, Sagar Lonial, MD, FACP, chief medical officer of Winship Cancer Institute of Emory University in Atlanta, Georgia. “We’ve done that for many patients, where we’ve given the first cycle or 2 of therapy and then sent them back to their [oncologist].”

However, Lonial was optimistic about the potential to give bispecifics in the community setting in the future. He discussed his institution’s study of a group of 48 real-world patients with RRMM. After the first 15 patients were treated with teclistamab, the next 33 received prophylactic tocilizumab with the treatment.

“I suspect as [oncologists] get more and more comfortable with this…the ability to do this and have the support system set up to help you manage it will be easier and easier for outpatient administration,” Lonial said.

Findings from the study, which were presented at the 2023 American Society of Hematology Annual Meeting and Exposition, showed that 10 of the 33 patients (30.3%) who received prophylactic tocilizumab had CRS compared with 11 of 15 (73.3%) who did not receive it prophylactically, and the rate of concurrent ICANS decreased from 20% to 6.1%.¹¹

“Because [of] the kinetics of [a bispecific], you give it at 10 in the morning, but it’s 1 am when they run into the [emergency department] short of breath with CRS. If there isn’t some sort of protocol in place, that’s what I worry about,” Dean M. Kirkel, MD, of Northwest Georgia Oncology Centers, commented to Lonial’s group. “It’s not that it couldn’t be managed, but [I worry about] not having a system in place. That sounds like this really takes a village to do well. I’m not sure we are there yet.”

TOXICITY AND DOSING FOR TALQUETAMAB

In clinical trials, there was a rate of any-grade CRS of 76% and ICANS of 9% with talquetamab, and any-grade CRS of 72% and ICANS of 6% with teclistamab, although these toxicities tended to be more tolerable than those experienced with CAR T-cell therapy.^9,10

With teclistamab, cytopenias and infections were also frequent adverse events of concern.⁹ With talquetamab, skin and nail toxicity, dysgeusia, and infections occurred at high rates.¹⁰ Lonial said dose modifications and use of oral steroids can address the specific toxicities of talquetamab such as dysgeusia and nail or skin changes.

“It seems to be a time-limited effect, meaning as you get further away from the first few doses of therapy, even if you keep the same dose and schedule, you do see reductions in that,” he explained. “There are some very nice schemas for how to adjust the doses or hold doses based on the severity of what I think are unusual toxicities for us.”

He also examined the different dose cohorts of MonumenTAL-1. “It brings up an important dose and schedule question about bispecifics. In general, should we be giving them every week, or should we try to go to less frequent dosing? From a patient perspective, less frequent dosing is certainly preferable. The advantage may also be that you don’t have the same pool of exhausted T cells by giving it every week as you would…if you give it every other week.”

When asked which dosing approach he uses, Lonial said he currently gives once-a-week talquetamab for the first few months, then switches to every other week to try to reduce T-cell exhaustion over time.

SEQUENCING QUESTIONS WITH NEW AGENTS

Promising novel therapies could be even more beneficial to patient outcomes when used earlier in sequence, and in RRMM, exhaustion of other drug classes can happen rapidly because of combination therapies.

“The FDA got it wrong by requiring [prior] lines of therapy as opposed to drug class refractoriness, because you can [become] penta-refractory after 2 lines of therapy nowadays,” Gertz commented.

The physicians discussed when talquetamab should be used in the treatment sequence, considering it was introduced after the approval of CAR T-cell therapy. “I would think [of using it] after CAR T cells, because I think you will get…longer progression-free survival with the CAR T cells and maybe use [talquetamab] afterward,” suggested Satvir Singh, MD, of Suburban Hematology Oncology Associates in Duluth, Georgia, in Lonial’s group. “Or it could be patient dependent, like [the scenario of ] the patient who wanted to wait for CAR T cells, [thus using] it as a bridging therapy. I’m thinking that CAR T cells give you a longer duration of response.”

Gill agreed with Singh about CAR T-cell therapy’s greater ORR and duration of response, and asked Lonial which patients, if any, would be best suited to receive bispecifics rather than CAR T-cell therapy. Lonial responded that those with cardiac and pulmonary dysfunction could be at risk of more serious CRS from CAR T-cell therapy, and those who want to avoid being hospitalized could also be candidates for bispecifics.

Abutalib brought up that if CAR T-cell therapy and bispecifics are used up front, oncologists will then have to determine how other agents that currently work well in the front line should be used, which would be challenging.

Gertz said that researchers don’t know yet whether the ideal approach will be to use the strongest combinations of agents up front or reserve some for later in the sequence, and that even with a frontline combination that leads to high rates of minimal residual disease negativity, maintenance therapy would likely still be used.

“I don’t know whether the final answer is going to be everything we’ve got, every different class, all at once, or [if ] we’re not going to exhaust ourselves because [otherwise] patients are going to relapse, [and then] I will have nothing [to use],” Gertz concluded.

_REFERENCES

_{1 .FDA approves teclistamab-cqyv for relapsed or refractory multiple myeloma. FDA. October 25, 2022. Accessed November 15, 2023. https://tinyurl.com/bdeekz4z}

_{2. FDA grants accelerated approval to elranatamab-bcmm for multiple myeloma. FDA. August 14, 2023. Accessed November 15, 2023. https://tinyurl.com/38t58tx3}

_{3. FDA grants accelerated approval to talquetamab-tgvs for relapsed or refractory multiple myeloma. FDA. Updated August 10, 2023. Accessed November 15, 2023. https://tinyurl.com/58vmnx8f}

_{4. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 2.2024. Accessed November 15, 2023. https://tinyurl.com/34v8675z}

_{5. Touzeau C, Schinke C, Minnema M, et al. Pivotal phase 2 MonumenTAL-1 results of talquetamab (TAL), a GPRC5DXCD3 bispecific antibody (BSAB), for relapsed/refractory multiple myeloma (RRMM). HemaSphere. 2023;7(S3):e5955094. doi:10.1097/01.HS9.0000967676.59550.94}

_{6. Moreau P, Garfall AL, van de Donk NWCJ, et al. Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 2022;387(6):495-505. doi:10.1056/NEJMoa2203478}

_{7. Touzeau C, Krishnan AY, Moreau P, et al. Efficacy and safety of teclistamab (tec), a B-cell maturation antigen (BCMA) x CD3 bispecific antibody, in patients (pts) with relapsed/refractory multiple myeloma (RRMM) after exposure to other BCMA-targeted agents. J Clin Oncol. 2022;40(suppl 16):8013. doi:10.1200/JCO.2022.40.16_suppl.8013}

_{8. Aleman A, Kogan Zadjman A, Ghodke-Puranik Y, et al. Salvage with sequential T cell redirection for myeloma patients who have previously progressed on T cell directed therapy is associated with significant cellular activation of the immune microenvironment. Blood. 2022; 140(suppl 1): 4193-4195. doi:10.1182/blood-2022-169538}

_{9. Tecvayli. Prescribing information. Janssen Pharmaceutical Companies; 2022. Accessed November 15, 2023. https://tinyurl.com/46axb2c4}

_{10. Talvey. Prescribing information. Janssen Pharmaceutical Companies; 2023. Accessed November 15, 2023. https://tinyurl.com/4tczj285}

_{11. Marin E, Scott S, Maples K, et al. Prophylactic tocilizumab to prevent cytokine release syndrome (CRS) with teclistamab administration. Abstract presented at: 2023 American Society of Hematology Annual Meeting and Exposition; December 9-12, 2023; San Diego, CA. Accessed November 15, 2023. https://tinyurl.com/bdzyrdmm}