Real-World MajesTEC-1 Trial Shows Comparable Findings in R/R Multiple Myeloma

The use of teclistamab in the real-world phase 2 MajesTEC-1 analysis showed similar safety and efficacy for patients with relapsed/refractory multiple myeloma.

Consistent results were reported with teclistamab-cqyv (Tecvayli) including overall response and safety for patients with relapsed/refractory multiple myeloma in the phase 2 MajesTEC-1 (NCT04557098) based on results presented at the 2023 American Society of Hematology (ASH) Annual Meeting and Exposition.¹

“Teclistamab appeared well tolerated and effective in this real-world heavily pre-treated [relapsed or refractory multiple myeloma] patient population, where the majority did not meet the eligibility criteria for the MajesTEC-1 trial and had high risk disease features,” Danai Dima, a third-year fellow in the Department of Hematology-Oncology, Cleveland Clinic, Taussig Cancer Center, said during a presentation of the data. “…While teclistamab was associated with early responses, durability and deepening of these responses need to be determined with longer follow-up in our real-world population.”

Real-World Efficacy Results

In the 104 patients evaluated in the retrospective analysis, the overall response rate (ORR) was 66%, compared with 63% in the MajesTEC-1 trial, including a complete response (CR) or better in 29% and 39.4%, respectively. Further, very good partial response (VGPR) occurred in 17% of patients in the analysis, compared with 19.4% in the trial, partial responses were observed in 20% and 4.2%, minimal response in 0% and 1.2%, and stable disease in 9.5% and 16.4%.

A higher number of patients in the real-world analysis (24.5%) experienced progressive disease, compared with those in the phase 2 trial (14.5%).

Dima highlighted subgroups of interest, with more than half experiencing an overall response to teclistamab in the retrospective analysis: those 70 or older (71%), non-Hispanic Black patients (71%), those with penta-refractory (68%) and triple-refractory disease (64%), patients with a high risk for cytogenetics (63%), those ineligible for the MajesTEC-1 trial (60%), and individuals having received prior BCMA therapy (59%).

Next, the investigators evaluated response rates to teclistamab in 56 patients who received prior BCMA-directed therapy, compared with the type they had previously received–including CAR T-cell therapy (n = 42), antibody-drug conjugates (n = 24), and other investigational agents (n = 4). In total, 43 patients received at least 1 prior BCMA-directed therapy, 12 who received 2, and just 1 patient who was given 3.

Patients in the real-world study who experienced an overall response reported a longer amount of time from their last BCMA-directed therapy to the initiation of treatment with teclistamab, compared with the MajesTEC-1 trial (339 days vs 205 days; P = .072). When evaluating those who started treatment with teclistamab within 3 months of their last BCMA-directed therapy, those in the retrospective study induced a lower ORR, compared with those on the phase 2 trial (42.9% vs 64.3%, respectively; P = .27) and a lower VGPR or better (35.7% vs 47.6%; P = .64). Lastly, among those treated with teclistamab after 6 months following previous BCMA-directed therapy, lower ORRs (47.4% vs 64.9%, respectively; P = .33) and VGPRs or better (35.7% vs 47.6%; P = .57) were also lower within the real-world cohort. Dima noted none of these reached statistical significance.

Further, after a median follow-up of 3.8 months, 46 patients in the real-world study had progressed on the agent. Median progression-free survival (PFS) was 5.4 months (95% CI, 3.4 months-not reached [NR]). At data cutoff, 29 patients died, with the majority occurring after disease progression (n = 21; 86%). Median overall survival was not reached, while the 6- and 10-month rates were 70% (95% CI, 61%-80%) and 67% (95% CI, 57%-79%), respectively.

Lastly, according to a multivariate analysis of the real-world data, the investigators identified ECOG performance status of 2 or more (P = .002), extramedullary disease (P = .001), and 4 or more prior lines of therapy (P = .035) were associated with inferior ORR with teclistamab, while ECOG performance status of 2 or more (P < .001), extramedullary disease (P = .003), and age of 70 years or older (P = .027) were associated with inferior PFS.

Real-World Safety Results

In the retrospective analysis, any grade cytokine release syndrome (CRS) occurred in 64% of patients, which was comparable to the 72% in the MajesTEC-1 trial, Dima said. Median time to onset of CRS was 3.5 days (range, 1-8) and lasted for a median duration of 1 day (range, 1-6).

Any grade immune effector cell-associated neurotoxicity syndrome (ICANS) was seen in 14% of patients, compared with 14.5% in the MajesTEC-1 trial, with the median time to onset being 5 days (range, 1-10) and median duration of 2 days (range, 1-30).

“The incidence of severe CRS and ICANS was low, so were the rates of recurrence suggesting possibly feasible outpatient teclistamab step-up dosing administration, as well as administration of teclistamab in the community practice after the initial step-up dosing,” Dima added.

On day 30, hematologic toxicities, which occurred in 99 patients, included leukopenia (any grade, 63%; grade 3-4, 19%), neutropenia (47%; 21%), anemia (71%; 16%), and thrombocytopenia (61%; 19%).

On day 60, hematologic toxicities, which occurred in 60 patients, included leukopenia (any grade, 42%; grade 3-4, 7%), neutropenia (42%; 15%), anemia (50%; 10%), and thrombocytopenia (47%; 8%).

In total, 31 patients experienced an infection, including severe infections (46%), infections of the respiratory system (69%), bacterial infections (41%), viral infections (51%), and fungal infections (3%) after a median onset of 46 days (range, 1-218).

Patients were subsequently hospitalized for infection (n = 16), cytopenia (n = 3), symptom control (n = 6), neurotoxicity (n = 2), and acute kidney injury (n = 1).

Dose delays (n = 12) and treatment discontinuation (n = 5) most commonly occurred as a result of infection.

“Cytopenias and infections remain a challenge; therefore, close monitoring, supportive care, and prophylactic measures with growth factors, antimicrobials, IVIG, and vaccinations are important,” Dima said.

MajesTEC-1 Trial

In the phase 2 trial, 165 patients who had relapsed or refractory myeloma after at least 3 therapy lines were treated with teclistamab at a subcutaneous injection dose of 1.5 mg/kg by body weight after receiving step-up doses of 0.06 mg/kg and 0.3 mg/kg. ORR served as the primary end point.²

After a median follow-up of 14.1 months, the ORR was 63.0%, including a 39.4% experiencing a CR or better. Further, median duration of response with teclistamab was 18.4 months (95% CI, 14.9 to not estimable [NE]), while the median PFS observed was 11.3 months (95% CI, 8.8-17.1). Further, common adverse events were comprised of cytokine release syndrome in 72.1% of the patients, neutropenia in 70.9%, anemia in 52.1%, and thrombocytopenia in 40.0%; while infections occurred in 76.4% of patients and neurotoxic events in 14.5%.

Based on these results, the FDA approved the BCMA-targeted bi-specific T-cell engager in October 2022.3

Further Evaluation of Teclistamab

Although the results of the phase 2 MajesTEC-1trial led to approval of the agent, the investigators noted that it had stringent eligibility criteria and may not have been representative of those patients treated in the real-world setting. For example, Dima explained, patients at the Cleveland Clinic often present with significant organ dysfunction, significant comorbidities, severe cytopenias, high-risk disease characteristics, and have had prior BCMA-directed therapy exposure.

Therefore, the investigators aimed to evaluate the real-world outcomes of patients with relapsed or refractory myeloma who were treated with commercially-available teclistamab or those in an expanded access program with the drug from August 2022 to August 2023, across 5 academic centers in the US. The primary outcomes were safety and efficacy; in particular, they homed in on those who would have been ineligible for the phase 2 trial that led to the drug’s approval in the United States, as well as patients who presented with high-risk disease features.

The data cutoff for the real-world analysis was August 15, 2023.

In the analysis, patients had received step-up doses of teclistamab in 2 different schedules based on institutional preference:

• Standard: 0.03 mg.kg on day 1, 0.6 mg/kg on day 4, and 1.5 mg/kg on day 7.
• Condensed: 0.03 mg/kg on day 1, 0.6 mg/kg on day 3, and 1.5 mg/kg on day 5.

Patients in the retrospective analysis were a median 66.5 years (range, 35-87), including 32% older than 70, compared with 64 years (range, 33-84) in the MajesTEC-1 trial. Further, compared with the phase 2 trial, a higher number of patients in the multicenter analysis had R-ISS stage III disease (31% vs 12%, respectively), high-risk cytogenetics (59% vs 26%), extramedullary disease (42% vs 17%), triple-refractory disease (92% vs 78%), and penta-refractory disease (64% vs 30%). In addition, 33% of patients in the real-world analysis had an ECOG performance status of 2 or more, while more patients in the phase 2 trial (82% vs 58%, respectively) underwent a prior autologous stem cell transplant (ASCT).

“We can clearly see that our patient population had a high proportion of patients with high-risk features,” Dima highlighted. “Certainly, our study included patients who would not qualify for the MajesTEC-1 trial. Half of these patients met one [exclusion] criteria, and the other half met 2 or more exclusion criteria for the [trial].”

The investigators highlighted the reasons for MajesTEC-1 trial ineligibility, and the number of patients who met that criteria in the real-world analysis, including prior anti-BCMA therapy (53%), poor performance status (33%), any baseline cytopenia (31%), renal dysfunction (13%), liver dysfunction (5%), cardiac dysfunction (4%), plasma cell leukemia (2%), amyloidosis (1%), central nervous system involvement (4%), and ASCT received less than 12 weeks before (1%).

“Efforts to balance risks and benefits with limited treatment duration, longer intervals between doses and possibly cessation of therapy for these patients who have achieved deep remissions to allow for recovery of the immune repertoire should become areas of interest for future clinical trials,” Dima concluded.

References

1. Dima D, Davis JA, Ahmed N, et al. Real-World Safety and Efficacy of Teclistamab for Patients with Heavily Pretreated Relapsed-Refractory Multiple Myeloma. Blood. 2023;142(1):91. doi:10.1182/blood-2023-180421.
2. Moreau P, Garfall AL, van de Donk NWCJ,et al. Teclistamab in Relapsed or Refractory Multiple Myeloma. New Eng J Med. 2022;387:495-505. doi:10.1056/NEJMoa2203478.
3. Janssen News Release. U.S. FDA Approves TECVAYLI™ (teclistamab-cqyv), the First Bispecific T-cell Engager Antibody for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma. Published: October 25, 2022. https://prn.to/3SAtXoO. Accessed; December 9, 2023.