Real-world analysis of teclistamab in 123 RRMM patients from Germany

Teclistamab, a B-cell maturation antigen (BCMA) × CD3 directed bispecific antibody, has shown high response rates and durable remissions in the MAJESTEC-1 trial in patients with relapsed and refractory multiple myeloma (RRMM). We retrospectively assessed efficacy and tolerability in 123 patients treated at 18 different German centers to determine whether outcome is comparable in the real-world setting. Most patients had triple-class (93%) or penta-drug (60%) refractory disease, 37% of patients had received BCMA-directed pretreatment including idecabtagene vicleucel (ide-cel) CAR-T cell therapy (21/123, 17.1%). With a follow-up of 5.5 months, we observed an overall response rate (ORR) of 59.3% and a median progression-free survival (PFS) of 8.7 months. In subgroup analyses, we found significantly lower ORR and median PFS in patients with extramedullary disease (37%/2.1 months), and/or an ISS of 3 (37%/1.3 months), and ide-cel pretreated patients (33%/1.8 months). Nonetheless, the duration of response in ide-cel pretreated patients was comparable to that of anti-BCMA naive patients. Infections and grade ≥3 cytopenias were the most frequent adverse events. In summary, we found that teclistamab exhibited a comparable efficacy and safety profile in the real-world setting as in the pivotal trial.


INTRODUCTION
Bispecific antibodies and CAR-T cells are currently altering the therapeutic landscape of relapsed and refractory multiple myeloma (RRMM).In clinical trials, novel immune therapies have displayed high response rates, resulting in durable remissions lasting over a year [1][2][3][4][5].
With regard to CAR-T cell treatment with idecabtagene vicleucel (ide-cel) however, some discrepancies were observed in real-world conditions compared to the KarMMa trial with progression free survival times of 8.5 months vs. 12.1 months (optimal dose group) and overall survival times of 12.5 months vs. 19.4months, respectively [2,6].This may be due to the trial´s strict entry criteria and generally observed benefits for patients treated in clinical trials, regardless of the treatment arm.
It is unclear whether such discrepancies also exist for teclistamab, a B-cell maturation antigen (BCMA) x CD3 bispecific antibody [7] which was approved for treatment of RRMM in several countries in 2022.In the MAJESTEC-1 trial, an overall response rate of 63% was observed with a median progression free survival of 11.3 months and median overall survival of 18.3 months [8].Cytokine release syndrome and neurotoxicity appeared to be well manageable with grade 3 or 4 events in less than 1% of treated patients [8,9].Yet, the majority of patients experienced infections (76.4%) and therapy-induced neutropenia (70.9%) or other cytopenias [8].Inclusion criteria of the MAJESTEC-1 trial comprised stable blood counts and kidney function [8].We anticipated variations in the real-world patient cohort treated with teclistamab and sought to evaluate the effectiveness and tolerability in a representative group with access to both CAR-T and ADC therapy.

METHODS
This is an investigator-initiated retrospective study including 123 patients from 18 German centers who had received at least one full treatment dose of teclistamab between July 2022 and October 2023.Patient records were analyzed retrospectively.After step up doses of 0.06 and 0.3 mg/kg, teclistamab was applied weekly at doses of 1.5 mg/kg according to the label.Patients were evaluated retrospectively for meeting selected key inclusion criteria of the MAJESTEC-1 trial at screening for teclistamab (Supplementary Table 1).Outcomes were assessed according to the IMWG response criteria [10].In addition, near complete remission was defined as serological complete remission lacking bone marrow assessment, as this was not always part of clinical routine.In patients with non-secretory disease, response evaluation was based on radiological criteria as previously described [10].High-risk cytogenetic aberrations were defined as the presence of del(17p), t(4;14) and/or t (14;16).Time-to-event analyses were conducted using the Kaplan-Meier method.For comparison of survival amongst subgroups, the log-rank test and Cox regression analysis were performed for univariable and multivariable analyses, respectively.Chi square tests were used to analyze differences in overall response rates between groups.
This retrospective study was approved by the local Ethics Committees (20230404 01 and 23-11299-BO).

Patient characteristics
123 patients have received at least one full dose of teclistamab in 18 German centers from July 2022 to October 2023.Therapy had been discontinued during step-up dosing in another three other patients due to cytopenias, rapidly progressive disease or infections.Patient characteristics are shown in Table 1 in comparison to the patient cohort in the MAJESTEC-1 trial.Our cohort comprised higher proportions of patients with EMD, ISS of 3, high bone marrow infiltration and triple-class or penta-drug refractory disease.Most patients treated with teclistamab in our cohort had no remaining treatment options and many didn't meet clinical trial eligibility criteria.
The patients were heavily pretreated with a median of 6 (range 3-14) prior lines of therapy.Of the 123 patients, 49 (39.8%) had undergone polychemotherapy regimens like PACE, including 22 patients (17.9%) with therapy within the last two months before teclistamab initiation.The vast majority (92.6%) had triple-class refractory disease and 60.2% of patients had penta-drug refractory disease.A substantial proportion of 39.0% would not have met the inclusion criteria of the MAJESTEC-1 trial shown in Supplementary Table 1.37.4% (45/123) of the patients had received BCMAdirected pretreatment, among them 17.1% (21/123) with ide-cel, 18.7% (23/123) with belantamab mafodotin, and single patients with both or a BCMA-directed study medication.The median time between the last BCMA-directed treatment and the initiation of teclistamab was 6.0 months in anti-BCMA-pretreated patients.

Efficacy
In our real-world study, 59.3% of patients responded to treatment with teclistamab achieving partial remission or better (Fig. 1).22.0% reached a complete or near complete response, 26.0% had a very good partial remission and 11.4% partial remission.13.0% did not respond but maintained stable disease, 25.2% showed primary progressive disease.Median time to response was 1.0 months, median time to best response 1.6 months.With a median follow-up of 5.5 months, median progression free survival (PFS) time was 8.7 months (with still 55% censored events at data cut-off).Median duration of response (DOR) and median overall survival (OS) times were not reached (Fig. 1).

Efficacy in BCMA pretreated patients and high-risk subgroups
The ORR for patients with BCMA-directed pretreatment was lower at 54.8% compared to anti-BCMA naive patients with an ORR of 64.5%.Notably, this disparity was exclusively attributable to patients pretreated with ide-cel (n = 21) who had an ORR of only 33.3% (p < 0.01, chi-square test) (Fig. 2).In contrast, the ORR for patients with belantamab pretreatment (73.9%) was comparable to the ORR in anti-BCMA naive patients (64.5%) (Fig. 2).Patients pretreated with ide-cel exhibited a significantly lower median PFS of 1.8 months (p = 0.01, log-rank test).However, the DOR was not reached in patients with PR or better and did not differ from that of patients naive to ide-cel (p = 0.54, log-rank test) (Fig. 2).At data cutoff, six out of seven responding patients with ide-cel pretreatment remained in remission.Interestingly, among the four long-term responders (benefiting for >8 months), one patient had demonstrated primary refractory disease to ide-cel, and the other three patients all experienced early relapse (<180 days).Three of the 21 patients had undergone ide-cel pretreatment only shortly (<1.5 months) before teclistamab initiation, two of them achieving VGPR with teclistamab treatment.Response rates to teclistamab did not differ between patients with an interval between CAR-T cell treatment and teclistamab initiation of more or less than 3 months (33% vs. 20%, p = 0.57, chi-square test) or 6 months (22% vs. 36%, p = 0.49, chi-square test), respectively.
In further subgroup analyses, patients with EMD and an ISS of 3 at teclistamab initiation showed a significantly inferior ORR and progression free survival time in univariable and multivariable analysis (see Tables 2 and 3 and Fig. 2).Bone marrow infiltration ≥60% was not included in multivariable analysis due to limited case numbers, but showed significantly inferior PFS and ORR in univariable analysis.In contrast, there was no significant difference in ORR and PFS time between patients with penta-refractory disease compared to those without penta-refractory disease and between patients who received polychemotherapy within the last two months compared to those who did not.Furthermore, ORR and PFS did not significantly differ among patients with different cytogenetic risk profiles (see Tables 2 and 3 and Supplementary Fig. 1).Of note, PFS of patients treated with ide-cel showed a trend towards inferior outcomes in the multivariable analysis, albeit the limited case numbers (p = 0.07, n = 21).

Safety
Safety outcomes were comparable to those observed in the MAJESTEC-1 trial.During step-up dosing, 58.5% of patients developed CRS and 7.3% neurotoxic events in the form of immune-effector cell-associated neurotoxicity syndrome (ICANS).Tocilizumab was administered in 23.6% and dexamethasone in 16.2% of patients.Like in the MAJESTEC-1 trial, grade ≥3 events for CRS and ICANS were rare (Table 4).The median hospital stay for step-up dosing was 10 days.Seven patients (5.7%) required intensive care unit support for management of CRS or ICANS, infections or other complications.Frequent adverse events observed included infections and cytopenias.Any kind of infection occurred in 54.5% of the patients, 49.3% of them (26.8% of all patients) requiring hospitalization for grade ≥3 infections.In all centers, patients treated with teclistamab received continuous PJP and HSV prophylaxis.IVIG substitution was used as primary and/or secondary infection prophylaxis with different approaches in different participating centers.Additionally, a majority (53.7%) of patients experienced grade ≥3 cytopenias of any kind according to CTCAE (Table 4).G-CSF and TPO agonizts were used in 22.0% and 3.3% of patients, respectively.Treatment interruptions of more than two and four weeks occurred in 33.1% and 19.8% of patients, respectively.

DISCUSSION
In this real-world analysis across multiple centers, we observed outcomes in 123 RRMM patients that were similar to those seen in the pivotal trial.For instance, the ORR of 64.5% in our BCMA-naive group was nearly equal to the ORR of 63% in MAJESTEC-1 [8].It is noteworthy that almost half of our patients did not meet the key inclusion criteria of the clinical trial.PFS was slightly lower at 8.7 months (vs.11.3 months in MAJESTEC-1), but follow-up was limited to a median of 5.5 months and 55% of the data were censored at the time of data cut.Lower CR rates in our real-world analysis (22% vs. 39% in the MAJESTEC-1 trial) can also be attributed to a shorter median follow-up time, as responses have been shown to deepen over time.We also observed markedly poorer outcomes among patients with EMD, an ISS of 3, and/or ≥60% bone marrow infiltration.While patient characteristics such as age, gender, and lines of pretreatment remained consistent with the pivotal trial, our real-world group was enriched by high risk features such as ISS 3, high risk cytogenetic aberrations, EMD, or high bone marrow infiltration.The off-the-shelf availability of teclistamab likely contributed to the similar outcomes in the pivotal trial and our real-world analysis.The ability to initiate treatment quickly in rapidly evolving disease settings is a major benefit of bispecific antibodies compared to CAR-T cell therapy.Both our real-world analysis and the MAJESTEC-1 demonstrated decreased efficacy of teclistamab in patients with EMD.EMD is an established risk factor [11] and seems to hold its negative prognostic impact in the era of T-cell based immunotherapy [3,12,13].In line with this assumption, Zanwar et al. recently reported a median PFS of only 2.9 months in patients with EMD treated with bispecific antibodies [14].Furthermore, we found a high tumor load to be associated with an inferior outcome.Lower efficacy of bispecific antibodies in these settings has been previously reported in preclinical models of BCMA x CD3 bispecific antibodies [15] and is well described for the CD19 x CD3 bispecific antibody blinatumomab in acute lymphoblastic leukemia [16][17][18].Likewise, the CD3 x BCMA-directed bispecific antibody elranatamab showed lower efficacy in patients with EMD and an ISS of 3 [4,19].The mechanisms of impaired efficacy of bispecific antibodies in patients with high tumor burden and EMD remain incompletely understood.Altered conditions that hinder the entry of specific T-cells into the tumor lesions may play a role in EMD [20] as well as an increased degree of T-cell exhaustion in patients with abundant tumor cell counts [16,21].
A key question in this context is whether debulking chemotherapy can enhance response in patients with high tumor load.23 patients in our cohort had received polychemotherapy such as PACE in the two months before teclistamab treatment.The median PFS of this group was not significantly different from that of other patients, considering the limited number of cases.At the same time, chemotherapy may affect T-cell fitness as described for ide-cel [22] or CD19 bispecifics [23].
Interestingly, our study and the MAJESTEC-1 trial revealed no differences in outcomes between patients with high-risk cytogenetics and those without.Even patients with two or more high-risk cytogenetic aberrations, categorized as having "ultra high-risk disease", for whom other therapies have reported significantly inferior outcomes [24], did not exhibit differences in response rates or PFS time in our study.However, the presence of high-risk cytogenetics is likely to be underreported in our real-world cohort,  as bone marrow punctures including cytogenetic analyses are not always part of clinical routine.Another clinically relevant observation was the efficacy of teclistamab in patients previously treated with anti-BCMA therapies.Initial reports already described lower response rates to teclistamab treatment after BCMA-directed CAR-T cell therapies [25].Our study also observed lower response rates and PFS in patients pretreated with ide-cel.However, the duration of response in patients achieving a PR or better (7/21) was similar to ide-cel naive patients.Therefore, we believe that teclistamab continues to be a valuable treatment option for patients pretreated with ide-cel -a setting with limited therapeutic options.BCMA-loss, as previously described [26][27][28][29][30] may be one potential mechanism for primary resistance to teclistamab after BCMA therapy, although drivers of resistance may be heterogeneous [31].Interestingly, all four patients with longterm remissions following teclistamab experienced only limited benefit to ide-cel treatment.In these patients, CAR-T productintrinsic issues including insufficient T-cell expansion may play a role.Future efforts to pre-identify non-responders will be important to avoid futile and costly BCMA-directed retreatment, and antigen expression testing could help in this setting.However, the frequency of (functional) BCMA loss has yet to be determined and a standard approach to testing for these aberrations is missing.In contrast, patients treated with Belantamab did not exhibit distinct outcomes.In patients enrolled in the DREAMM-1 and DREAMM-2 trials, BCMA loss was not reported [32], thus reinforcing the idea that the pressure on the clonal architecture is lower with antibody drug conjugates.
Safety was comparable to that observed in MAJESTEC-1.Neurotoxicity and cytokine release syndrome appeared to be low-grade in the majority of cases and well manageable.However, infections were frequent and posed a significant challenge in the treatment with teclistamab.The infection rate of 54.4% in this real-world analysis was lower than that reported in the MAJESTEC-1 trial, likely due to the shorter follow-up in our study [8].The high rates of infections require close monitoring and adequate preventive measures [33,34].
In conclusion, teclistamab displays a similar safety and efficacy profile to that in the MAJESTEC-1 trial and is a valuable treatment option for RRMM.Further studies are warranted to evaluate a potential role of teclistamab in less advanced treatment lines or newly diagnosed MM.

Fig. 1
Fig. 1 Rate of response in 123 patients and Kaplan-Meier analysis of response duration and of progression-free and overall survival.Panel A shows the rates of near complete response and complete response (CR), very good partial response (VGPR), and partial response in 123 patients who were treated with teclistamab.Panel B illustrates progression-free survival and Panel C overall survival among the 123 patients.Panel D shows the duration of response to teclistamab therapy in the 73 patients who had an overall response (partial response or better).Tick marks indicate censored data.Bands indicate confidence bands around survival curves.

Table 1 .
Patient characteristics at baseline in comparison to MAJESTEC-1.

Table 2 .
Univariable and multivariable models of the association of selected patient characteristics with PFS.

Table 3 .
Association of selected patient characteristics with the overall response rate.