Defining the Rates of Cytokine Release Syndrome Associated with Talquetamab Step-up Doses

Abstract

Purpose:

Talquetamab is a G protein-coupled receptor class C group 5 member D T-cell engaging antibody, approved for relapsed/refractory multiple myeloma. In MonumenTAL-1 clinical trial, cytokine release syndrome (CRS) occurred at a frequency of 77%; however, there was no assessment of CRS rates by step-up dose. The primary objective of this study was to characterize CRS rates after each talquetamab step-up dose in a real-world setting.

Patients and Methods:

Patients with relapsed/refractory multiple myeloma who completed the talquetamab weekly or biweekly step-up dosing schedule between September 2023 and November 2024 were identified via institutional database. CRS rate after each talquetamab step-up dose was compared using Chi-square/Fisher exact. Kruskal Wallis test was used to compare difference in median time to CRS onset. Multivariate logistic regression analysis was performed to identify predictors of CRS.

Results:

Fifty patients completed the talquetamab step-up dosing phase during the study period; CRS occurred at a rate of 80%. Pairwise comparisons revealed significant differences in CRS rates between the fourth dose (4%) and each of step-up dose 1 (28%, p=0.014) and 2 (34%, p=0.003). The only CRS event with fourth dose was grade 1. The median time to onset of first CRS did not differ significantly between step-up doses (p=0.441). Prior exposure to T-cell redirecting therapy had no impact on CRS incidence (odds ratio: 0.20; 95% CI:0.03–1.10).

Conclusion:

Our findings suggested that the fourth talquetamab dose could be administered in outpatient settings given its high tolerability. The reduced hospitalization period for talquetamab step-up dosing could reduce healthcare expenses.

Introduction

Although the prognosis for patients with multiple myeloma has improved significantly in recent years, the disease remains incurable.^[1,2] Its clinical trajectory, typified by increasingly shorter periods of remission, supports the need for the discovery of novel agents as evidenced by real world data.^[3,4] Final analysis of the LocoMMotion study demonstrated that patients with relapsed/refractory multiple myeloma (RRMM) progressing after the standard therapeutic drug classes (proteasome inhibitors, immunomodulatory agents, anti-CD38 monoclonal antibodies) had the shortest progression free survival (median: 4.6 months) and overall survival (13.8 months).^[4]

An intricate interplay exists between the bone marrow microenvironment and myeloma cells which promotes the evasion of immune system/surveillance and disease progression.^[5] This explains the growing interest in developing novel approaches such as T-cell redirecting therapies (chimeric antigen receptor T-cells, CAR T-cells and T-cell engaging antibodies) that have the potential to restore and modulate immune function to more effectively treat the disease.^[6,7] Shortly after their regulatory approval and advent into clinical practice, T-cell redirecting therapies have unequivocally become the mainstay of treatment of RRMM; one such example is talquetamab which is the first-in-class T-cell engaging antibody directed against the G protein-coupled receptor class C group 5 member D (GPRC5D) antigen, heavily expressed on myeloma cells. Its approval came about following the results of the phase I MonumenTAL-1 study which enrolled patients with RRMM progressing after a median of at least 5 prior lines of therapy.^[8] Talquetamab demonstrated unprecedented clinical efficacy in this setting where the overall response rates were 70% and 64% with the approved subcutaneous doses of 0.4 mg/kg weekly and 0.8 mg/kg every 2 weeks, respectively. Additionally, more than half of the patients achieved a very good partial response with either dose. By virtue of T-cell engagement, one of the most frequent early onset side effects of talquetamab was cytokine release syndrome (CRS), observed in about 72% of the patients primarily during the step-up dosing phase of treatment. Notably, CRS was mild in its severity (grades 1 and 2) with less than 1% of patients in the overall cohort experiencing severe CRS (grades 3 and 4). Per manufacturer package insert, it is recommended that patients be hospitalized throughout the period of the step-up dosing phase of talquetamab for CRS monitoring.^[9] This translates into a hospital stay of at least 9 days after which patients can continue treatment in outpatient settings on a weekly or biweekly dosing schedule.

Currently, there is a gap in our knowledge of the CRS rates after each talquetamab step-up dose. This study sought to characterize these CRS rates in a real-world setting to discern whether patient hospitalization is required for the entire period of the ramp up or step-up dosing schedule.

Methods

Patient identification and selection

Our institutional plasma cell disorders database was queried to identify patients who received talquetamab as the standard of care for RRMM during the period of September 2023 until November 2024. Patients were included in the final analysis if they completed the step-up dosing schedule as illustrated in the study design flowchart (Figure 1). This study was approved by the institutional review board and conducted according to the Declaration of Helsinki and the Belmont report.

Figure 1.

Flow diagram of retrospective study design.

Treatment/data collection

Talquetamab treatment was initiated using the step-up dosing schedule recommended/outlined by the manufacturer. The decision to administer talquetamab, either inpatient or outpatient, was guided by the eligibility criteria for T-cell engaging antibody administration set forth by the providers of multiple myeloma service/team at our institution. Briefly, patients who received the step-up doses in outpatient settings wore wearable devices which allowed for continuous real-time monitoring of vital signs, oxygen saturation and physical activity. Additionally, telehealth visits were scheduled and conducted 24 hours after each talquetamab step-up dose where patients were thoroughly evaluated for any signs and symptoms of CRS or immune effector cell-associated neurotoxicity syndrome (ICANS). Alternatively, patients who were hospitalized to receive the talquetamab step-up doses underwent vital sign checks every 4 hours and immune effector cell-associated encephalopathy assessment at least once every 24 hours for CRS and ICANS monitoring. Institutional guidelines were implemented in the event patients developed CRS and/or ICANS.

Regardless of the setting, all patients were pre-medicated with acetaminophen 650 mg, diphenhydramine 25 mg and dexamethasone 16 mg about 30 minutes prior to the administration of each step-up dose of talquetamab. For outpatient talquetamab administration, patients were provided with a single dose of dexamethasone. All step-up doses were separated by at least 48 hours to allow for CRS/ICANS monitoring.

A retrospective chart review was performed to collect patient demographics, disease characteristics, prior lines of therapy (including types of prior T-cell redirecting therapies), start date/time of each talquetamab step-up dose, and CRS onset/grades (according to the American Society for Transplantation and Cellular Therapy, ASTCT grading criteria).^[10]

Statistical analysis

All baseline characteristics were described either as median (range) or frequencies (percentage). The Chi-square/Fisher exact test (with 1 degree of freedom) was used to compare differences in the rates of CRS and grades between each talquetamab step-up dose. Differences in the time to onset of CRS between the step-up doses were compared using the Kruskal-Wallis test. Multivariate logistic regression analysis was performed to identify factors that could impact CRS incidence with talquetamab step-up dosing (prior exposure to T-cell redirecting therapy, high risk cytogenetics, absolute lymphocyte count, etc.). All statistical analyses were performed using IBM SPSS statistics (version 23.0).

Results

A total of 53 patients received commercial talquetamab during the study period; only 3 patients were excluded for not completing the step-up dosing phase of treatment. One of these 3 excluded patients opted to enroll in a clinical trial whereas the other two developed complications (not related to CRS or other treatment related adverse effects) after the administration of the first step-up dose of talquetamab; these complications were hypoxia (secondary to worsening pleural effusion that necessitated therapy cessation and patient transfer to the ICU for management), and the other was pneumonia (requiring treatment with broad spectrum antibiotics accompanied with episodes of supraventricular tachycardia/atrial fibrillation).

Of the 50 patients included in the analysis, 27 received the biweekly step-up dosing schedule. Talquetamab step-up doses were administered to 4 patients (8%) in the outpatient setting whereas the rest were hospitalized for treatment initiation. Baseline characteristics were summarized in Table 1; 34 patients received prior T-cell redirecting therapy (CAR T-cells and/or T-cell engaging antibodies).

Table 1.

Baseline characteristics of 50 patients who completed talquetamab step-up dosing phase.

Parameter	N=50
Median age, years	66 (range: 41-85)
Gender, % (n)
- Male	46 (23)
Race, % (n)
- White	62 (31)
- Black	18 (9)
Weight, kg	70.3 (range: 44.5-131.6)
Multiple myeloma type, % (n)
- Free kappa light chain	10 (5)
- Free lambda light chain	6 (3)
- IgA kappa	8 (4)
- IgA lambda	8 (4)
- IgG kappa	42 (21)
- IgG lambda	26 (13)
High risk cytogenetics*, % (n)	54 (27)
Median prior lines of therapy	7 (range: 4-16)
Extramedullary disease, % (n)	44 (22)
Elevated LDH (prior to T-cell engaging antibody), % (n)	44 (22)
Prior T-cell redirecting therapies, % (n)	68 (34)
- CAR T-cells	50 (22)
- T- cell engaging antibodies	36 (16)
. BCMA directed	30 (13)

^*presence of any of the following, t(4;14), t(14;16), t(14;20), TP53 mutations, 17p deletions, and 1q gain/amplifications

The overall incidence of CRS with talquetamab was 80% (n=40), of which 22% (n=11) were recurrent i.e. recurring after step-up doses 2 (73%, n=8) and 3 (27%, n=3). The CRS rates after step-up doses 1, 2 and 3 were 28%, 34% and 16%, respectively (Figure 2). The fourth talquetamab dose (first full dose) was associated with the lowest CRS rate (4%, n=1), thereby translating into a statistically significant difference when compared to step-up doses 1 (p=0.014) and 2 (p=0.003). Grade 2 CRS occurred in 4%, 12%, 4% and 0% of patients with step-up doses 1, 2, 3 and the fourth dose, respectively (Figure 3).

Figure 2.

Breakdown of rates of cytokine release syndrome following each talquetamab step-up dose.

Figure 3.

Grades of cytokine release syndrome associated with each talquetamab step-up dose.

The median time to CRS onset did not differ significantly between the step-up doses where it was 20.0 hours (range: 9.5–39.5 hours) with step-up dose 1, 17.0 hours (range: 8.0–48.0 hours) with step-up dose 2, 31.5 hours (range: 8.0–48.0 hours) with step-up dose 3 and 30.5 hours with the fourth dose (p=0.441, Figure 4). Of the 40 detected CRS events, 28 (70%) were treated with tocilizumab (in addition to acetaminophen) including 9 (23%) of the 11 recurrent events. All the CRS events resolved within 2 hours of intervention, and none were persistent.

Figure 4.

Median time to onset of cytokine release syndrome after each talquetamab step-up dose.

Two of the 4 patients who received outpatient talquetamab developed grade 1 CRS, one after step-up dose 1 and the other after step-up dose 2. Both patients were treated with tocilizumab and observed in the emergency department for 24 hours.

There was no statistically significant difference in CRS rates with talquetamab between patients who received prior T-cell redirecting therapies vs. those who did not p=0.130, Figure 5). Multivariate regression analysis did not demonstrate any association between CRS rates and any of these covariates, high-risk cytogenetics, elevated LDH, absolute lymphocyte count, etc. (Table 2). The rate of ICANS/neurotoxicity with talquetamab was 6% (n=3); one of these events occurred 24 hours after step-up dose 1 and the remaining two occurred 24 and 48 hours after the administration of step-up dose 3; their respective grades were 1 (n=1) and 2 (n=2). Management of ICANS/neurotoxicity entailed antiseizure prophylaxis with levetiracetam 500 mg twice daily in addition to dexamethasone 10 mg every 6 hours or 12 hours (depending on severity). ICANS score improved and returned to baseline after 24 hours in two patients and 12 days in the third patient (who developed ICANS after the third dose of talquetamab which was administered according to the weekly step-up dosing schedule).

Figure 5.

Differences in rates of cytokine release syndrome during the talquetamab step-up dosing phase based on prior exposure to T-cell redirecting therapy.

Table 2.

Results of multivariate regression analysis to identify predictors of CRS with talquetamab step-up doses.

Parameter	Odds Ratio	95% Confidence Interval
Gender (female vs. male)	1.90	0.45-9.00
Race (Caucasian vs. others)	0.70	0.30-1.80
High risk cytogenetics*	2.00	0.50-8.20
LDH elevation (yes vs. no)	1.30	0.30-6.60
% plasma cells, bone marrow (≤ 40% vs. > 40%)	1.50	0.10-31.70
Extramedullary disease (yes vs. no)	0.50	0.10-2.10
Absolute lymphocyte count (< 0.5 vs. ≥ 0.5)	1.50	0.30-7.50
T-cell redirecting therapy (yes vs. no)	0.20	0.03-1.10

^*: presence of any of the following, t(4;14), t(14;16), t(14;20), TP53 mutations, 17p deletions, and 1q gain/amplifications

Discussion

T-cell redirecting therapies including T-cell engaging antibodies such as talquetamab have changed the treatment landscape of RRMM. Despite their widespread use in this setting, treatment initiation remains limited to centers which have the necessary expertise and infrastructure to manage early onset complications, in particular CRS and ICANS/neurotoxicity. As stated previously, most of the CRS events tended to occur during the step-up dosing phase of treatment. Nonetheless, there is a paucity of data pertaining to the frequency of these events following each talquetamab step-up dose.^[8]

To our knowledge, this is the first study to define and characterize these events in a real-world clinical setting. Our results suggested that CRS was not only an infrequent event after the administration of the fourth talquetamab (first full) dose but also tended to be mild in severity (grade 1). Generally, CRS grade 1 could be easily offset with antipyretics such as acetaminophen. The patient reported herein had an isolated event with the temperature spiking to 38 °C (100.4 °F, grade 1 CRS) following the fourth dose. This event resolved on its own without any clinical intervention, thereby providing support for the safe administration of the fourth talquetamab dose (of the biweekly step-up dosing schedule) in outpatient settings without the need for additional monitoring. Alternatively, step-up dose 2 was associated with the highest CRS rates (34%; n=17); approximately a third of which were grade 2 prompting treatment with tocilizumab to mitigate it and thereby avoid prolonged hospitalization. Correlative analyses to investigate whether CRS events were predictive of better response to talquetamab, were not performed because this topic was not within the scope of this paper. However, the study by Firestone et al demonstrated an improved progression free survival among the group of patients who developed CRS with teclistamab during the step-up dosing phase.^[11] Whether this association is also noted with talquetamab is a question that requires further investigation

Our findings could be practice-changing, as they provide sufficient evidence to support early patient discharge specifically, reducing the length of hospitalization required to complete the step-up dosing phase of treatment with talquetamab by at least 2 days (48 hours). The implications of this reduction include decreased health care expenditures by avoiding the additional costs incurred due to prolonged hospitalization (at least 9 days). This could be particularly beneficial for institutions operating under the Medicare Prospective Payment System (PPS), where reimbursement is a predetermined, fixed amount based on the Diagnosis Related Group (DRG) model. To better contextualize the significance of our results, Table 1S (in supplemental information) was generated to estimate and compare the differences in cost between the current standard of practice (at least 9 days of hospitalization) for talquetamab step-up dosing and our proposed model (at least 7 days of hospitalization followed by outpatient administration of first dose). Of note, the estimations provided in Table 1S reflect PPS-exempt costs and may differ under PPS.

Most of the patients included herein received a T-cell redirecting therapy (CAR T-cells or T-cell engaging antibodies), which was subsequently switched to talquetamab upon disease progression. Although CRS rates in this patient population (T-cell redirecting therapy experienced) were numerically lower compared to those with no prior T-cell redirecting therapy exposure, the difference did not reach statistical significance. This was contrary to what was previously reported in an observational study involving teclistamab where the risk of CRS was approximately 4-fold higher in the T-cell redirecting therapy naïve patient population (based on multivariate analysis).^[12] Sample size might not explain this discrepancy given the fact that both studies included a small number of patients. Whether the target antigen (BMCA vs. GPRC5D) was the culprit or the reason for this observation, further investigation might be warranted to discern the impact of prior T-cell redirecting therapy on the incidence of CRS with talquetamab. Furthermore, none of the covariates included in our multivariate logistic regression model predicted CRS. Baseline blood concentrations of inflammatory markers and cytokines (ferritin, C-reactive protein, interleukin-6, etc.) were not incorporated because it was not customary to measure them upon therapy initiation. This might represent one of the major limitations of this study.

There have been some ongoing efforts aimed at operationalizing outpatient step-up dosing of T-cell engaging antibodies such as talquetamab.^[13,14] These entailed utilizing wearable technologies to monitor patients closely, and prophylactic tocilizumab to reduce the occurrence of CRS.^[15–17] Although the former approach has been investigated with CAR T-cells, it could also be applied for approved T-cell engaging antibodies such as talquetamab. Our observations could help facilitate and promote the operationalization of outpatient talquetamab step-up dosing since CRS monitoring following the fourth dose (full dose) did not appear to be necessary. Furthermore, the wearable devices could be safely disconnected earlier during the talquetamab step-up dosing phase i.e. at the time of administration of the fourth dose, which would most likely translate into improved patient convenience.

In conclusion, our real-world data indicated that the talquetamab first full dose was well tolerated, characterized by a significantly low incidence and severity of CRS events. Reducing the length of hospital stay with the talquetamab step-up dosing schedule, and administration of the fourth talquetamab dose (first full dose) in outpatient settings could be considered in clinical practice. This would most likely lead to reductions in healthcare expenditure through cost avoidance.

Context Summary.

Key Objective:

Define the rates of cytokine release syndrome (CRS) after each talquetamab step-up dose for treating relapsed refractory multiple myeloma in the real-world.

Knowledge generated:

The fourth talquetamab dose (first treatment dose) was well tolerated and associated with a significantly low rate of CRS (4%; all grade 1).

Relevance:

Our findings suggest that the duration of hospitalization for the administration of talquetamab step-up doses could be reduced. This will most likely minimize healthcare expenditure.