New BiTE Agents Provide Effective Options for Treatment of Relapsed/Refractory Multiple Myeloma

Since October 2022, 7 new agents have been approved by the FDA based on the treatment paradigm of bispecific T-cell engagement. This significant number of approvals demonstrates the attractiveness of this approach for treatment and highlights a new direction for drug development of bispecific T-cell engagers (BiTEs) that appears primed to take hold in the approach to cancer therapy. As such, it is important to become familiar with the current landscape of bispecific T cell–engaging therapies and the individual agents available.

Of the 7 new approvals in the past year, 3 of the agents have been approved for relapsed/refractory (R/R) multiple myeloma (MM). These agents are teclistamab-cqyv (Tecvayli; Janssen Biotech), which was approved on October 25, 2022; talquetamab-tgvs (Talvey; Janssen Biotech), which was approved August 9, 2023; and elranatamab-bcmm (Elrexfio; Pfizer), which was approved August 14, 2023. Each of these agents was granted accelerated approval for treatment of adults with R/R MM who have received at least 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.^1-3

Mechanism of Action

Bispecific antibodies can, in some ways, be thought of as next-generation monoclonal antibodies.⁴ Whereas the traditional monoclonal antibodies target a single epitope, bispecific antibodies have 2 binding domains, each of which can be directed at a different epitope/antigen. This added level of variability allows for pairing of these targets in a variety of ways, including the ability to engage T cells directly with tumors or malignant cells. In BiTE antibodies, 1 of the 2 epitopes is T cell specific. In the case of the 3 MM agents above, as well as all currently approved bispecific T cell–engaging agents, this target is CD3.

The second domain binds a tumor cell–specific antigen. For teclistamab-cqyv and elranatamab-bcmm, the second binding domain is directed at B-cell maturation antigen (BCMA), whereas talquetamab-tgvs binds to GPRC5D. By binding CD3 on the T cell and its respective second antigen, these antibodies can bring the T cell and the malignant cell into proximity, allowing the formation of an immune synapse. Subsequently, the T cell is activated and releases perforins and granzymes. This results in T cell–dependent killing of the tumor cell.⁵

In both cases, the secondary binding target, be it BCMA or GPRC5D, is highly selective for plasma cells. BCMA has been a notable and validated target for MM therapies. Belantamab mafodotin, an antibody-drug conjugate targeting BCMA, was approved in 2020 based on results demonstrating an overall response rate (ORR) of 31% in a heavily pretreated patient populatio with R/R disease.⁶

In addition, 2 chimeric antigen receptor (CAR) T-cell therapies targeting BCMA have also been approved. Idecabtagene vicleucel (Abecma; Bristol Myers Squibb) was approved in 2021 based on results demonstrating an ORR of 73% in a heavily pretreated, R/R patient population, and ciltacabtagene autoleucel (Carvykti; Janssen Biotech, Inc) was approved in 2022 based on results demonstrating an ORR of 97% in a similarly previously heavily pretreated population.^7,8

Dosing and Administration

A class effect related to BiTE antibodies is the propensity to cause cytokine release syndrome (CRS). To help minimize the occurrence, each of these agents is given in a step-up dosing schema. Although the specifics vary for each agent, the general approach is similar: Administer 2 or 3 lower doses, each approximately 3 days apart, culminating in the treatment dose that is used going forward.^9-13 Each step-up dose is dependent on the previous administration occurring without incident. Additionally, for each agent, there are recommendations on how to address missed doses during the step-up period as well as during the treatment period, requiring a restart using a prior dose in the step-up process if the time since prior dose exceeds a maximum.^9-13

Tables 1 and 2

Both teclistamab-cqyv and talquetamab-tgvs have weight-based dosing (see Table 1⁹ and Table 2¹¹ above), whereas elranatamab-bcmm uses a flat dosing scheme (see Table 3¹³ below). For the weight-based dosing, it can result in the need to round the dose based on volume for administration. To this end, the package inserts for these agents both include tables with recommended dose, volume for injection, and number of vials required for the dose, all based on the weight range of the patient.

Table 3

Talquetamab-tgvs is unique among these 3 agents in that it has the ability to be dosed weekly or every 2 weeks starting at the first treatment dose (Table 211); this is a result of there being 2 recommended phase 2 dosing schemes, both of which were examined in the MonumenTAL-1 trial (NCT04634552). No specific criteria are given for utilization of one schema over the other, and this is left to the discretion of the treating physician. Safety and efficacy will be discussed below.¹²

Elranatamab-bcmm also has every-2-week dosing; however, in this case it is as part of the continuation of treatment rather than an alternative dosing schedule. If patients reach week 25 and have responded to therapy, which is defined as having achieved an International Myeloma Working Group (IMWG) partial response or better with responses persisting for at least 2 months.¹³

To further mitigate and prevent CRS, patients are required to be premedicated prior to each step-up dose and the first treatment dose. For all agents, the recommended pretreatment medications include dexamethasone; a histamine-1 receptor antagonist (diphenhydramine or equivalent); and an antipyretic, such as acetaminophen. Dosing depends on which antibody treatment is then used.^9,11,13

As each of these agents carries a black box warning for CRS and immune effector cell–associated neurotoxicity syndrome (ICANS), it is recommended that patients be hospitalized for 48 hours following each step-up dose and the initial treatment dose for observation. For elranatamab-bcmm, however, the recommendation is only for 24 hours of observation following the second step-up dose, and there is no recommendation for observation following the first treatment dose.

Another consideration regarding prescribing for each of these agents is that each has an associated Risk Evaluation and Mitigation Strategy program. As such, prior to ordering these therapies, prescribers must meet several criteria. First, prescribers must be certified with the program by enrolling and completing training. The health care facility and/or dispensing pharmacy must also be certified with the program and must verify prescribers are certified prior to dispensing. Prior to starting therapy, the prescribing physician must also counsel patients regarding the risk of CRS and neurologic toxicity, including ICANS, and provide patients with a wallet card.

Clinical Efficacy

The accelerated approval for each of these agents is based on key pivotal trials, each of which enrolled patients with R/R MM who had previously received at least 3 prior therapies, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.^10,12,14 In the case of elranatamab-bcmm, patients were also stratified based on being naive to or receiving prior BCMA-directed monoclonal antibody therapy or CAR T cell–directed therapy.1⁴

The efficacy of teclistamab-cqyv was assessed in the open-label phase 1/2 single-arm MajesTEC-1 study (NCT03145181 [phase 1] and NCT04557098 [phase 2]). The primary end point was ORR, defined as partial response or better per IMWG criteria, assessed by independent review, the results of which are listed below in Table 4.^9-14 Additional key findings include a median time to first response of 1.2 months (range, 0.2-5.5 months). With a median follow-up of 7.4 months among responders, the estimated duration of response (DOR) rate was 90.6% (95% CI, 80.3%, 95.7%) at 6 months and 66.5% (95% CI, 38.8%, 83.9%) at 9 months.9,10 A total of 44 patients (26.7%) were found to have no minimal residual disease (MRD), with a rate of 46% among patients with a complete response or better.⁹

Table 4: B-cell maturation antigen (BMCA); complete response (CR); duration of response (DOR); not available (NA); not estimable (NE); overall response rate (ORR); partial response (PR); stringent complete response (sCR); very good partial response (VGPR).

The single-arm, open-label, multicenter MMY1001 study (MonumenTAL-1; NCT03399799 [phase 1], NCT04634552 [phase 2]) assessed the efficacy of talquetamab-tgvs in patients with R/R MM. The primary efficacy outcome measures were ORR and DOR as assessed by an independent review committee using IMWG criteria. Results were stratified for the weekly and every-2-week dosing regimens (Table 4).9-14 In the weekly cohort, the median duration of follow-up from first response among responders was 13.8 months (range, 0.8-15.4 months), whereas in the biweekly schedule it was 5.9 months (range, 0-9.5 months), with an estimated 85% of responders maintaining response for at least 9 months. Median time to first response for the weekly and biweekly groups was 1.2 months (range, 0.2-10.9 months) and 1.3 months (range, 0.2-9.2 months), respectively.^11,12 MRD was assessed in 16 patients with samples available who obtained a CR or better response. Among these patients, 11 (69%) were MRD negative.¹²

Elranatamab-bcmm was evaluated in patients with R/R MM in the open-label, single-arm, multicenter MagnetisMM-3 study (NCT04649359). As previously mentioned, this study further delineated patients based on prior exposure to BCMA-targeted therapies. Efficacy was based on response rate and DOR, as assessed by independent review based on IMWG criteria. Efficacy results from patients who were naive to BCMA-directed therapy naive are shown in Table 4.^9-14 Among the patients enrolled to the prior BCMA-treated cohort (cohort B), the confirmed ORR was 33.3% (95% CI 22.0, 46.3), with a median DOR not reached.^13,14 Among patients obtaining a CR or better, 60.5% were MR negative.

Adverse Effects

Among all 3 agents, CRS and neurologic toxicities were common. Additionally, various gastrointestinal and skin-related toxicities were noted. The most common adverse effects (AEs; > 20%) noted for teclistamab-cqyv were pyrexia, CRS, musculoskeletal pain, injection site reaction, fatigue, upper respiratory tract infection, nausea, headache, pneumonia, and diarrhea.^9,10

For talquetamab-tgvs, the most common AEs (> 20%) were CRS, dysgeusia, nail disorder, musculoskeletal pain, skin disorder, rash, fatigue, decreased weight, dry mouth, pyrexia, xerosis, dysphagia, upper respiratory tract infection, and diarrhea.^11,12 For elranatamab-bcmm, the most common AEs noted (> 20%) included CRS, fatigue, injection site reaction, diarrhea, upper respiratory tract infection, musculoskeletal pain, pneumonia, decreased appetite, rash, cough, nausea, and pyrexia.1^3,14

By far the most notable safety consideration for these agents is CRS. As previously discussed, multiple steps are taken to mitigate the risk of CRS developing, using various step-up dosing schemes and premedications given to the patients prior to the first several administrations. Despite these efforts, however, CRS is still relatively common, occurring in 50% to 75% of patients (Table 5^9,11,13). Awareness of signs and symptoms of CRS and ICANS, as well as proper grading and management, is a key educational aspect that a pharmacy can take the lead on for its respective institution. For institutes with prior experience with CAR T-cell therapies, CRS management and treatment will follow those same recommendations.

Table 5: CRS among BiTE antibodies (bispecific T-cell engager [BiTE]; cytokine release syndrome [CRS]).

Across all agents, common warnings and precautions include CRS, neurologic toxicity (including ICANS), infections, neutropenia, and hepatotoxicity. Talquetamab-tgvs also includes warnings for oral toxicity, weight loss, and skin toxicity, whereas teclistamab-cqyv includes a warning for hypersensitivity reactions.

Final Thoughts

The R/R MM space is replete with multiple treatment options depending on prior therapeutic agents received, decision to proceed to or previously having had a stem cell transplant, and persistent AEs or other comorbidities. Most recently, BCMA has become a promising therapeutic target, with 3 agents all utilizing it as a target. Prior to the bispecific antibodies discussed here, these 3 approaches represented the most recent additions to the treatment landscape. With the withdrawal of belantamab mafodotin-blmf from the market in November 2022 due to not meeting the follow-up requirements for the accelerated approval, the heavy-pretreatment MM space is more focused on CAR T-cell therapies. With that focus, as well as a similar mechanism of action, it is common to see CAR T-cell therapies and the bispecific antibody therapies talked about together and compared. This will likely continue to be a point of consideration in this space, given the high ORR seen among all these therapies as well as continued research into the place in therapy and sequential treatment for all these agents. Efficacy comparison, though, is only part of the equation.

When looking at comparative safety and AEs, one cannot ignore the risk for CRS and ICANS among all these agents. Compared with those among the CAR T-cell therapies, the reported rates of CRS among the BiTE antibodies are quantitatively lower, particularly when looking at grade 3 or greater.^{7,8,10,12,14,15} Further, another common comparison between these agents and CAR T-cell therapy is the complexity of the treatment process. CAR T-cell therapy does represent a highly efficacious treatment option for patients; however, it is a complex process, and many patients may not be fit to undergo the conditioning and preparation needed for CAR T-cell treatment. These agents provide an alternative that might be more appropriate in those instances as well as another option for treating the ominous disease state that is MM.

References

1. FDA approves teclistamab-cqyv for relapsed or refractory multiple myeloma. FDA. October 25, 2022. Accessed October 19, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-teclistamab-cqyv-relapsed-or-refractory-multiple-myeloma

2. FDA grants accelerated approval to talquetamab-tgvs for relapsed or refractory multiple myeloma. FDA. August 9, 2023. Accessed October 1, 2023. https://www.fda.gov/drugs/resources-information-approved drugs/fda-grants-accelerated-approval-talquetamab-tgvs-relapsed-or-refractory-multiple-myeloma

3. FDA grants accelerated approval to elranatamab-bcmm for multiple myeloma. FDA. August 14, 2023. Accessed October 19, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-elranatamab-bcmm-multiple-myeloma

4. Bispecific antibodies: an area of research and clinical applications. FDA. August 2, 2023. Accessed October 19, 2023. https://www.fda.gov/drugs/news-events-human-drugs/bispecific-antibodies-area-research-and-clinical-applications

5. van de Donk NWCJ, Zweegman S. T-cell-engaging bispecific antibodies in cancer. Lancet. 2023;402(10396):142-158. doi:10.1016/S0140-6736(23)00521-4

6. Lonial S, Lee HC, Badros A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol. 2020;21(2):207-221. doi:10.1016/S1470-2045(19)30788-0

7. Munshi N, Anderson L Jr, Shah N, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Eng J Med. 2021;384(8):705-716. doi:10.1056/NEJMoa2024850

8. Berdeja JG, Madduri D, Usmani SZ, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet. 2021;398(10297):314-324. doi:10.1016/S0140-6736(21)00933-8

9. Tecvayli. Prescribing information. Janssen Biotech; 2022. Accessed October 19, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761291s000lbl.pdf

10. 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

11. Talvey. Prescribing information. Janssen Biotech; 2023. Accessed October 19, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761342s000lbl.pdf

12. Chari A, Minnema MC, Berdeja JG, et al. Talquetamab, a T-cell-redirecting GPRC5D bispecific antibody for multiple myeloma. N Engl J Med. 2022;387(24):2232-2244. doi:10.1056/NEJMoa2204591

13. Elrexfio. Prescribing information. Pfizer; 2023. Accessed October 19, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761345s000lbl.pdf

14. Lesokhin AM, Tomasson MH, Arnulf B, et al. Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results. Nat Med. 2023;29(9):2259-2267. doi:10.1038/s41591-023-02528-9

15. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 1.2024. Accessed October 19, 2023. https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf

About the Author

Glenn Roma, PharmD, PhD, BCOP, is an investigational drug service pharmacist and the oncology PGY2 residency program director at Baptist Cancer Center/Baptist Clinical Research Institute in Memphis, Tennessee.