Ongoing Analyses and Recent Data for Talvey in Multiple Myeloma

Multiple myeloma (MM) is a plasma cell disorder that accounts for approximately 2% of all cancer diagnoses and deaths in both the United States and worldwide.^1,2 It is estimated that there are 35,780 new cases and 12,540 deaths per year in the United States.²

Although the incidence in the United States may be low, the number of cases from year to year has steadily increased, with the 2021 incidence rate at approximately 7.0 per 100,000 citizens compared with an age-standardized incidence of 2.1 per 100,000 in 2016.^1,3 The overall 5-year survival rate for patients with MM is 61.1%. However, that rate does differ based on the stage of the disease; patients with localized disease show an 80.3% 5-year survival rate, whereas those with distant disease show 60.4%.²

The risk of developing MM is associated with many factors. Patients aged >65 years are at higher risk; it is much rarer to see MM in those aged <40 years.⁴ MM is more common in men than women; in the United Kingdom, the age-standardized incidence rate is 11.6 versus 7.3 per 100,000 per year for men and women, respectively.⁵ Race can also be a risk factor for MM. For example, Black Americans have approximately a 2-fold higher incidence of MM compared with non-Hispanic White individuals (14.4 vs 6.4 cases per 100,000).⁶ This can extend further geographically; MM is more common in the Middle East, North Africa, and the Mediterranean than elsewhere.⁴

Although race, gender, and age do play a role in the risk of MM, genetics and plasma abnormalities are also critical to understanding a patient’s risk of MM. Patients with a family history of MM have an increased risk, with those patients having a first-degree relative with MM having a significantly greater risk of developing MM (odds ratio, 1.90; 95% confidence interval, 1.26-2.87).⁷ Those that have a singular plasmacytoma or have plasma cells that make an excess of a specific protein (M protein) may also have increased risk for MM.⁴

Treatment of MM can depend on the patient’s individual risk stratification for MM, the patient’s eligibility for hematopoietic stem-cell transplant, and the individual comorbidities that a patient may have.¹ In general, those that are candidates for transplant may receive a combination of bortezomib, lenalidomide, and dexamethasone (VRd) followed by transplant.¹ Patients at a higher risk, yet still candidates for transplant, may receive carfilzomib, lenalidomide, and dexamethasone or another similar regimen.¹ Those that are not transplant candidates will often receive VRd as an initial therapy followed by lenalidomide and dexamethasone maintenance therapy.¹ Patients with relapsed and refractory (R/R) disease may also be treated with a CAR-T cell therapy such as ciltacabtagene autoleucel or idecabtagene vicleucel.⁸

While there are options for MM treatment, an unmet need still exists. Often, patients with MM do not do well in the upfront setting and are labeled as high risk.⁹ However, there is a lack in both optimal biomarkers to identify these high-risk patients, but also novel drugs that utilize these markers as targets.⁹ Furthermore, particularly in the R/R setting, an understanding of the optimal sequencing of many novel mechanisms of action is lacking.¹⁰ Finally, although there are many new and powerful drugs with robust and durable efficacy, patients will ultimately progress, highlighting the need for continued development of novel mechanisms of action.¹⁰

Talquetamab Accelerated Approval

On August 9, 2023, the FDA granted accelerated approval to talquetamab-tgvs (Talvey; Janssen Biotech, Inc) for the 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.¹¹ This approval is based on the response rate demonstrated in the MonumenTAL-1 trial.¹²

Mechanism of Action

Talquetamab-tgvs is a bispecific T-cell engaging antibody that binds to CD3 receptors expressed on the surface of T cells and G protein-coupled receptor class C group 5 member D expressed on the surfaces of MM and nonmalignant plasma cells.¹² The activation of T cells by talquetamab-tgvs causes the release of proinflammatory cytokines leading to MM cell lysis.¹²

Ongoing Clinical Trials and Analyses

Although talquetamab-tgvs is an option for heavily pretreated patients with MM, the clinical development process of the molecule does not plan to stop there. Janssen Biotech is currently conducting multiple trials evaluating talquetamab-tgvs in both its current indication and additional lines of therapy.

MonumenTAL-1 (NCT03399799/NCT04634552) was a phase 1/2 study that had shown a 73% overall response rate (ORR) in 100 patients receiving a 0.4-mg/kg weekly dose and 73.6% ORR in those receiving an 0.8-mg/kg biweekly dose of talquetamab-tgvs with a median follow-up of 13.8 months and 5.9 months, respectively.¹² More recently, long-term follow-up data were presented at the 2024 European Hematology Association (EHA) Congress.¹³ Patients receiving talquetamab-tgvs with a median of 20 to 30 months of follow-up at either dose had an ORR of 74.1% (0.4-mg/kg weekly dose) and 69.5% (0.8-mg/kg biweekly dose), maintaining their high ORR levels with a similar safety profile as in the original analysis.¹³

MonumeTAL-2 (NCT05050097) is a currently ongoing phase 1 study exploring talquetamab-tgvz in combination with carfilzomib, daratumumab, lenalidomide, or pomalidomide in the treatment of patients with MM.¹⁴ The primary objective of this study is to identify adverse events and characterize the safety of the various treatment regimens that are being explored.¹⁴ Secondary objectives include ORR, duration of response, and time to treatment response.¹⁴ The most recent readout at the 2024 EHA Congress had demonstrated that 35 patients treated with talquetamab + pomalidomide in both a weekly and biweekly dosing schedule exhibited an ORR of 93.8% and 84.2% with a median follow-up of 15 months and 11.1 months, repectively.¹⁵ A total of 91.4% of patients in this analysis experienced a grade 3/4 adverse event, with the most common being neutropenia (54.3%), anemia (25.7%), and infections (22.9%). Rates of discontinuation due to adverse events were 11.4%.¹⁵

MonumenTAL-3 (NCT05455320) is a currently ongoing multicenter, open-label, randomized, phase 3 study evaluating the efficacy of talquetamab + daratumumab + hyaluronidase (Tal-D) or talquetamab + daratumumab + hyaluronidase + pomalidomide (Tal-DP) versus daratumumab + hyaluronidase + pomalidomide + dexamethasone in patients with MM, that have received at least 1 prior line of therapy.¹⁶ Patients in this trial may be exposed to a proteasome inhibitor, lenalidomide, and anti-CD38 therapies, but must at least be lenalidomide-refractory.¹⁶ The primary endpoint for MonumenTAL-3 is progression-free survival as defined by International Myeloma Working Group criteria or death, whichever occurs first.¹¹ Secondary endpoints include ORR, overall survival (OS), safety, patient-reported outcomes, and pharmacokinetic/pharmacodynamic parameters.¹⁶ Finalized results for this trial are not published at this time.¹⁶

MonumenTAL-6 (NCT06208150) is an ongoing phase 3 randomized study that compares talquetamab + pomalidomide, talquetamab + teclistamab, and an investigator’s choice of elotuzumab, pomalidomide, and dexamethasone or pomalidomide, bortezomib, and dexamethasone in R/R patients who have received 1 to 4 lines of therapy including an anti-CD38 antibody and lenalidomide.¹⁷ The primary outcome of this study is progression-free survival defined as the duration from the date of randomization to progressive disease or death, whichever comes first.¹⁷ Secondary objectives include ORR, OS, time to next treatment, and health-related quality of life. There are no public data available for this study as of this date.¹⁷

Finally, MonumenTAL-8 (NCT06550895) is an upcoming phase 2 clinical trial focused on evaluating the safety of ciltacabtagene-autoleucel and talquetamab in patients with high-risk MM.¹⁸ This study will have 3 different cohorts. One cohort will include newly diagnosed MM patients considered ineligible for high-dose chemotherapy with autologous stem cell transplant.¹⁸ The other 2 cohorts will include patients who have had at least 3 prior lines of antimyeloma therapy and have received at least 1 complete cycle of therapy.¹⁸ Key exclusion criteria for this study depend on cohorts but may include receipt of a strong CYP450 inducer within 5 half-lives prior to daratumumab + lenalidomide + dexamethasone induction therapy for the former cohort and prior treatment with a CAR-T or GPRC5D therapy for the latter.¹⁸

Withdrawn Trials

MonumenTAL-5 (NCT05461209) was a phase 3 study comparing talquetamab with belantamab mafodotin in patients with R/R MM who had received at least 4 prior lines of therapy, including a proteasome inhibitor, immunomodulatory drug, and an anti-CD38 antibody.¹⁹ Aside from the ClinicalTrials.gov page stating the trial was withdrawn for business reasons, there is no other available information on why the MonumenTAL-5 study was not continued.¹⁹ However, there is speculation that the study was stopped due to the US market withdrawal of belantamab mafodotin.²⁰

Conclusion

Although currently affecting fewer patients than more common cancers, MM is slowly rising in incidence. Prior treatment of this disease relied on the use of proteasome inhibitors, immunomodulatory drugs, and some monoclonal antibodies.¹ However, as patients will ultimately progress, there is a great need for continued development of novel mechanisms of action and molecular targets to take advantage of in MM treatment. Talquetamab-tgvs currently represents a novel mechanism of action that is a robust, viable, and safe treatment option in heavily pretreated patients with R/R MM.¹³ However, as trials evaluating talquetamab-tgvs progress, this agent may be able to be utilized to great effect in earlier lines of therapy, providing MM patients another way to fight their disease.

References

1. Padala SA, Barsouk A, Barsouk A, et al. Epidemiology, staging, and management of multiple myeloma. Med Sci (Basel). 2021;9:3.
2. National Cancer Institute. Cancer Stat Facts: Myeloma. Accessed July 22, 2024. https://seer.cancer.gov/statfacts/html/mulmy.html
3. Cowan AJ, Allen C, Barac A, et al. Global burden of multiple myeloma. JAMA Oncol. 2018;4:1221.
4. University of Rochester Medical Center. Multiple Myeloma: Risk Factors. Accessed July 22, 2024. https://www.urmc.rochester.edu/encyclopedia/content.aspx?contenttypeid=34&contentid=17932-1
5. Bird S, Cairns D, Menzies T, et al. Sex differences in multiple myeloma biology but not clinical outcomes: results from 3894 patients in the Myeloma XI Trial. Clin Lymphoma Myeloma Leuk. 2021;21:667-675.
6. Bertrand KA, Szalat R. Deciphering racial disparities in multiple myeloma outcomes. Blood Adv. 2024;8:234-235.
7. Schinasi LH, Brown EE, Camp NJ, et al. Multiple myeloma and family history of lymphohaematopoietic cancers: results from the International Multiple Myeloma Consortium. Br J Haematol. 2016;175:87-101.
8. NCCN. Multiple Myeloma (Version 1.2025). Accessed October 10, 2024. https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf
9. CancerNetwork. Treatment options and unmet needs evaluated in multiple myeloma. Accessed October 10, 2024. https://www.cancernetwork.com/view/treatment-options-and-unmet-needs-evaluated-in-multiple-myeloma
10. Dingli D. Navigating unmet needs and challenges in multiple myeloma treatment. Targeted Oncology. Accessed October 10, 2024. https://www.targetedonc.com/view/navigating-unmet-needs-and-challenges-in-multiple-myeloma-treatment
11. FDA. FDA grants accelerated approval to talquetamab-tgvs for relapsed or refractory multiple myeloma. Published August 9, 2024. Accessed July 22, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-talquetamab-tgvs-relapsed-or-refractory-multiple-myeloma
12. FDA. Talvey (talquetamab-tgvs) [package insert]. Accessed July 23, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761342s000lbl.pdf
13. European Hematology Association. Long-term efficacy and safety results from the phase 1/2 MonumenTAL-1 study of talquetamab, a GPRC5DxCD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma. Accessed July 23, 2024. https://library.ehaweb.org/eha/2024/eha2024-congress/420979/leo.rasche.long-term.efficacy.and.safety.results.from.the.phase.1.2.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Asearch%3D%23p915
14. Johnson & Johnson. TALVEY® (talquetamab-tgvs) demonstrates highly durable, longer-term responses in patients with relapsed or refractory multiple myeloma. Published June 24, 2024. Accessed July 23, 2024. https://www.jnj.com/media-center/press-releases/talvey-talquetamab-tgvs-demonstrates-highly-durable-longer-term-responses-in-patients-with-relapsed-or-refractory-multiple-myeloma
15. European Hematology Association. Talquetamab, a GPRC5DxCD3 bispecific antibody, in combination with pomalidomide in patients with relapsed/refractory multiple myeloma: safety and efficacy results from the phase 1B MonumenTAL-2 study. Accessed August 23, 2024. https://library.ehaweb.org/eha/2024/eha2024-congress/420975/emma.searle.talquetamab.a.gprc5dcd3.bispecific.antibody.in.combination.with.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Asearch%3D%23p911
16. Janssen Science. TALVEY - MonumenTAL-3 (MMY3002) Study. Accessed July 23, 2024. https://www.janssenscience.com/products/talvey/medical-content/talvey-monumental3-mmy3002-study
17. International Standard Randomised Controlled Trial Number Registry. A study comparing talquetamab plus pomalidomide, talquetamab plus teclistamab, and elotuzumab, pomalidomide, and dexamethasone or pomalidomide, bortezomib, and dexamethasone in participants with relapsed or refractory myeloma who have received an anti-CD38 antibody and lenalidomide. Accessed July 23, 2024. https://www.isrctn.com/ISRCTN74178658
18. Johnson & Johnson. A study of ciltacabtagene autoleucel and talquetamab for the treatment of participants with high-risk multiple myeloma (MonumenTAL-8). Accessed August 23, 2024. https://globaltrialfinder.janssen.com/trial/64407564MMY2008
19. ClinicalTrials.gov. A study comparing talquetamab to belantamab mafodotin in participants with relapsed/refractory multiple myeloma (MonumenTAL-5). Accessed August 23, 2024. https://clinicaltrials.gov/study/NCT05461209
20. Plieth J. T cell engagers enter new pivotal studies. ApexOnco Oncology Pipeline. Accessed August 23, 2024. https://www.oncologypipeline.com/apexonco/t-cell-engagers-enter-new-pivotal-studies