Dexamethasone for Management of Cytokine Release Syndrome Associated With Talquetamab in Patients With Relapsed/Refractory Multiple Myeloma

To the Editors,

1.

Cytokine release syndrome (CRS) is a systemic inflammatory response commonly associated with T‐cell‐redirecting therapies including chimeric antigen receptor (CAR) T‐cell therapy and T‐cell‐engaging bispecific antibodies (BsAbs) [1, 2]. CRS manifestations include fever and organ dysfunction characterized by hypotension and dyspnea, which can be life‐threatening. Pharmacologic treatment includes antipyretics, corticosteroids, and/or tocilizumab; however, initial treatment strategies vary by severity and institutional protocol [3, 4].

Consensus guidelines for toxicity management of CD20 × CD3 BsAbs for B‐cell lymphomas recommend antipyretics and dexamethasone prior to use of tocilizumab for low‐grade (Grade 1–2) CRS [5]. Conversely, the International Myeloma Working Group (IMWG) consensus guidelines for toxicity management of BsAbs utilized in multiple myeloma (MM) recommend tocilizumab for initial treatment of low‐grade CRS prior to dexamethasone based on prior clinical trial experience with B‐cell maturation antigen‐directed BsAbs [6].

Talquetamab is a G protein‐coupled receptor class C Group 5 member D (GPRC5D)‐directed T‐cell‐engaging BsAb indicated for treatment of relapsed/refractory MM (RRMM) [7]. In the phase I/II MonumenTAL‐1 trial, CRS was a frequently observed adverse event, occurring in up to 80% of patients [8]. Due to CRS risk, step‐up doses (SUD) and premedications with acetaminophen, antihistamine, and dexamethasone 16 mg are standard. Most patients who developed CRS presented with low‐grade CRS; only four patients experienced Grade 3 [8]. In MonumenTAL‐1, most patients (63% and 54%) received tocilizumab as initial CRS treatment, while only 3% and 7% in the weekly and biweekly cohorts received corticosteroid treatment. Recent evidence supports dexamethasone as initial CRS management with teclistamab, though similar data is lacking with talquetamab [9]. Therefore, we evaluated the outcomes of dexamethasone as initial management for talquetamab‐induced CRS.

This retrospective multicenter observational study included 211 patients across seven US academic medical centers with RRMM treated with standard of care talquetamab between August 2023 and June 2025. All centers obtained institutional review board approval, which granted waiver of consent, and the study was conducted in accordance with the Declaration of Helsinki. CRS and immune effector cell‐associated neurotoxicity syndrome (ICANS) were graded using the American Society of Transplantation and Cellular Therapy criteria [10]. Treatment responses were evaluated using IMWG criteria save for 24‐h urine tests as these are not routinely performed to assess response among participating institutions. High‐risk cytogenetics were defined as the presence of t(4;14), t(14;16), deletion 17p, and/or gain/amplification 1q on fluorescence in situ hybridization testing.

Talquetamab was administered subcutaneously as SUDs of 0.01 and 0.06 mg/kg followed by weekly doses of 0.4 mg/kg or an additional SUD of 0.4 mg/kg followed by biweekly dosing of 0.8 mg/kg per package insert. SUDs were separated by 2–3 days (days 1,4,7 ± 10 or 1,3,5 ± 7). All patients were premedicated per package insert during the SUD phase. Prophylactic measures including tocilizumab or additional dexamethasone were ordered per physician discretion. Talquetamab was administered continuously until disease progression or used as bridging therapy to CAR T‐cell therapy. CRS was managed per institutional protocol or physician discretion. Tocilizumab was dosed at 8 mg/kg (maximum 800 mg). Dexamethasone treatment doses varied by institution, ranging from 4 to 20 mg. To assess dexamethasone's efficacy for talquetamab‐induced CRS management, this study compared patients who received dexamethasone‐first as their initial intervention versus those who received tocilizumab‐first as their initial intervention. Patients may have also received supportive care including antipyretics, oxygen, and fluids. Those managed by supportive care only or who received dexamethasone and tocilizumab simultaneously were excluded from analysis. Statistical tests included Fisher's exact test or Kruskal–Wallis.

Among the total population (n = 211), the median age was 66 years (range 34–87) and 55% were male (Table 1). Median prior lines of therapy were 6 (range 2–14) and 87% were triple‐class refractory. Talquetamab was used as bridging therapy in 53 patients (25%). Most patients (91%) received biweekly talquetamab after SUDs. Twenty‐seven patients (13%) received prophylactic tocilizumab and 20 (9%) received additional dexamethasone prophylaxis during the SUD period.

TABLE 1.

Baseline characteristics and safety/efficacy outcomes.

	All (n = 211)	Dexamethasone (n = 46)	Tocilizumab (n = 42)	p
Characteristic	Median (range) or n (%)
Age, years	66 (34–87)	65 (46–85)	68 (50–80)	0.14
Age > 70 years	68 (32%)	11 (24%)	15 (36%)	0.09
Male sex	115 (55%)	23 (50%)	23 (55%)	0.57
Race
Non‐Hispanic White	168 (80%)	36 (78%)	34 (81%)	0.79
Non‐Hispanic Black	37 (18%)	10 (22%)	5 (12%)	0.27
Other	6 (3%)	0	3 (7%)	0.11
ECOG PS b
0 or 1	157 (74%)	33 (72%)	31 (74%)	0.99
2	40 (19%)	8 (17%)	6 (14%)	0.78
3 or 4	11 (5%)	2 (4%)	5 (12%)	0.25
R‐ISS stage III	72 (34%)	10 (22%)	16 (38%)	0.16
High‐risk cytogenetics	125 (59%)	29 (63%)	24 (57%)	0.66
Prior lines of therapy	6 (2–14)	6 (3–14)	6 (2–10)	0.69
Extramedullary disease	63 (30%)	15 (33%)	10 (24%)	0.48
LDH prior to SUD1	210 (71–1281)	245 (102–1108)	190 (71–1026)	0.11
Triple‐class refractory	183 (87%)	39 (85%)	638 (90%)	0.53
Penta drug refractory	99 (47%)	17 (37%)	22 (52%)	0.2
Prior BCMA‐DT	126 (60%)	22 (48%)	24 (57%)	0.4
SUD Schedule
Days 1,3,5,7	133 (63%)	17 (37%)	36 (86%)	< 0.0001
Days 1,4,7,10	52 (25%)	19 (41%)	5 (12%)	0.0035
Other	26 (12%)	10 (22%)	1 (2%)	0.008
Dosing schedule
Weekly	18 (9%)	6 (15%)	0 (0%)	0.03
Biweekly	193 (91%)	40 (85%)	42 (100%)	0.03
Talquetamab as bridge	53 (25%)	11 (24%)	12 (29%)	0.64
Safety and efficacy outcomes	Median (range) or n (%)
CRS any grade (out of 211)	129 (61%)	46 (100%)	42 (100%)
CRS Grade 1	92 (43%)	32 (70%)	22 (52%)	0.13
CRS Grade 2	34 (16%)	12 (26%)	19 (45%)	0.08
CRS Grade 3/4	3 (1%)	2 (4%)	1 (2%)	0.99
Timing of CRS a
SUD1	35 (17%)	16 (35%)	10 (24%)	0.35
SUD2	56 (27%)	25 (54%)	18 (43%)	0.29
SUD3	62 (29%)	25 (54%)	18 (43%)	0.29
First full dose	15 (7%)	5 (11%)	3 (7%)	0.72
Dose delay due to CRS	53 (25%)	16 (35%)	20 (48%)	0.28
Duration of delay, days	1 (0.5–15)	1 (1–5)	1 (1–15)	0.96
Recurrent CRS with next dose	39 (18%)	23 (50%)	6 (14%)	< 0.005
Duration of CRS, days	1 (0–8)	1 (1–5)	1 (1–5)	0.78
ICANS any grade (out of 211)	29/211 (14%)	12 (26%)	10 (24%)	0.99
ICANS Grade 1	15 (7%)	6 (13%)	5 (12%)	0.99
ICANS Grade 2	7 (3%)	4 (9%)	3 (7%)	0.99
ICANS Grade 3	4 (2%)	2 (4%)	2 (5%)	0.99
ICANS Grade 4	3 (1%)	0	0
Response rates (all) b	n = 195	n = 42	n = 41
ORR	150 (77%)	36 (86%)	37 (90%)	0.74
≥ VGPR	98 (50%)	22 (52%)	23 (56%)	0.83
Response (non‐bridge) b	n = 145	n = 33	n = 29
ORR	108 (75%)	28 (85%)	27 (93%)	0.43
≥ VGPR	82 (57%)	18 (55%)	20 (69%)	0.30

Abbreviations: ECOG PS = Eastern Cooperative Oncology Group Performance Status, BCMA‐DT = B‐cell maturation antigen directed therapy, CAR = chimeric antigen receptor, CRS = cytokine release syndrome, ICANS = immune effector cell‐associated neurotoxicity syndrome, LDH = lactate dehydrogenase, ORR = overall response rate, R‐ISS = Revised International Scoring System, High‐risk cytogenetics = t(4;14), t(14;16), deletion 17p, and/or gain/amplification 1q, SUD = step‐up dose, VGPR = very good partial response.

^a Values may not total 100%, patients may have experienced CRS following more than one SUD.

^b Analyzed among patients with data available.

CRS occurred in 129 (61%) patients, including 92 (43%) experiencing Grade 1 and 34 (16%) Grade 2 (Table 1). Three patients experienced grade ≥ 3 CRS. CRS occurred after SUD1 (17%), SUD2 (27%), SUD3 (29%), and first full‐dose (7%), respectively. Fifty‐three patients (25%) experienced a SUD delay due to CRS (median 1 day, 0.5–15) and 39 (18%) experienced recurrent CRS with a subsequent SUD. Median CRS duration was 1 day (range 0–8). ICANS occurred in 29 patients (14%) and was primarily low‐grade.

Of patients who experienced CRS, dexamethasone was the first intervention in 46 (36%), tocilizumab in 42 (33%), and supportive care only in 37 (29%). Four patients received dexamethasone and tocilizumab simultaneously. Baseline characteristics between the dexamethasone‐first and tocilizumab‐first groups were well‐balanced (Table 1). Differences were present between SUD schedules and dose frequency, though differences are likely attributed to institutional practice variability. The median initial dexamethasone dose was 10 mg (range, 4–20 mg).

In the dexamethasone‐first cohort, 32 (70%), 12 (26%), and 2 (4%) patients experienced grade 1, 2, and 3 CRS, respectively. For patients with grade 1 CRS, 16 (50%) had CRS resolution with a single dexamethasone dose, 9 (25%) resolved following repeated dexamethasone doses (median 2 repeat doses, range 1–6), and 6 (19%) required tocilizumab for CRS resolution (Table 2). One patient in this group died after SUD2 due to respiratory failure versus pulmonary embolism, and CRS resolution was not assessable. Both Grade 3 cases in the dexamethasone‐first cohort were managed with repeat dexamethasone doses, tocilizumab, and vasopressors to attain CRS resolution. For Grade 2, 5 (42%) patients attained CRS resolution following a single dexamethasone dose, though 6 (50%) would ultimately need a dose of tocilizumab for CRS resolution.

TABLE 2.

Pharmacologic interventions for CRS management.

Dexamethasone first a , n = 46
Necessary intervention to achieve CRS resolution	All‐grade CRS	Grade 1 CRS, n = 32	Grade 2, n = 12
Single dex dose	21 (46%)	16 (50%)	5 (42%)
Repeat dex doses	10 (22%)	9 (25%)	1 (8%)
Single toci dose	12 (26%)	5 (16%)	6 (50%)
Repeat toci doses	2 (4%)	1 (3%)	0
Tocilizumab first a , n = 42
Necessary intervention to achieve CRS resolution	All‐grade CRS	Grade 1, n = 22	Grade 2, n = 19
Single toci dose	30 (71%)	17 (77%)	13 (68%)
Repeat toci doses	5 (12%)	2 (9%)	3 (16%)
Single dex dose	2 (5%)	0	2 (11%)
Repeat dex doses	5 (12%)	3 (14%)	1 (5%)

Note: Resolution of G1 CRS following a single dexamethasone dose versus a single tocilizumab dose (50% vs. 77%, p = 0.6381). Resolution of G1 CRS following a single dexamethasone dose versus a single tocilizumab dose (42% vs. 68%, p = 0.2623).

Abbreviation: CRS = cytokine release syndrome.

^a Patients may have also received supportive care concurrently (antipyretics, fluids, oxygen).

In the tocilizumab‐first cohort, 22 (52%), 19 (45%), and 1 (2%) patients experienced Grade 1, 2, and 4 CRS, respectively (Table 1). For patients with Grade 1 CRS in the tocilizumab‐first group, 17 (77%) resolved with one dose, 2 (9%) resolved with two doses, and 3 patients (14%) resolved following the addition of dexamethasone (Figure 1). In the Grade 2 group, 13 (68%) of patients had CRS resolution after a single tocilizumab dose, with only 3 (16%) and 3 (16%) patients requiring repeat tocilizumab doses or the addition of dexamethasone, respectively. There was no difference in patients whose Grade 1 CRS resolved following a single dose of dexamethasone first (50% vs. 77%, p = 0.6381) or Grade 2 CRS (42% vs. 68%, p = 0.2623) versus tocilizumab‐first (Table 2). One patient in the tocilizumab‐first group experienced Grade 4 CRS which resolved following repeated tocilizumab, dexamethasone, and vasopressors.

FIGURE 1.

Sankey diagrams of Grade 1 and Grade 2 CRS treatment. (A) Sankey diagram of Grade 1 CRS occurrences and management strategies. (B) Sankey diagram of Grade 2 CRS occurrences and management strategies. CRS = cytokine release syndrome.

Median duration (1 day, p = 0.96) and incidence (35% and 48%, p = 0.28) of SUD delays were similar in the dexamethasone and tocilizumab cohorts, respectively. CRS recurrence after a subsequent SUD was more common among those who received dexamethasone as initial CRS management (50% vs. 14%, p < 0.005); however, repeat events were all low‐grade and resolved with repeated dexamethasone and/or tocilizumab. All patients who had CRS recurrence on subsequent SUDs experienced either the same or a lower grade CRS, except for two patients who were both in the group treated with tocilizumab first. There were no unifying features among patients with recurrent CRS—baseline characteristics and management strategies were heterogenous. There was no difference in ICANS incidence in those who received dexamethasone first (26% vs. 24%; p = 0.99).

There were no significant differences between dexamethasone and tocilizumab cohorts for hospitalization duration during SUD (9 vs. 10 days; p = 0.34) or intensive care unit admission during SUD (7% vs. 9%; p = 0.70). At a median follow‐up of 9.2 months, the overall response rate (ORR) of all patients was 77%, with 50% of patients achieving a very good partial response (VGPR) or better. Best ORR was similar between dexamethasone and tocilizumab groups (86% vs. 90%, p = 0.74). Among 27 patients who received prophylactic tocilizumab, CRS occurred in 14 (52%) patients and was primarily Grade 1. Of those 14 patients who received prophylactic tocilizumab and still experienced CRS, 2 received dexamethasone as their initial treatment, 5 received tocilizumab as their initial treatment, and the other 7 were managed with supportive care only. Twenty patients received dexamethasone prophylaxis beyond the package insert recommendations; 13 (65%) experienced CRS, with 92% being Grade 1.

Our findings suggest that Grade 1 CRS with talquetamab may safely be treated first with dexamethasone, prior to tocilizumab, with most cases resolving without the need for tocilizumab. For patients experiencing Grade 2 CRS, dexamethasone may also be an effective first pharmacologic intervention; however, interpretation is limited by small sample size given only 12 patients received dexamethasone first in this setting and 50% eventually required tocilizumab for CRS resolution. While there was no significant difference in resolution of Grade 1 or 2 CRS following a single initial dexamethasone dose and single initial tocilizumab dose, these differences could be clinically and operationally meaningful in an outpatient setting. Dexamethasone may be easier for patients to administer in the outpatient to try to remain outpatient and avoid the need for additional health care resource utilization. Whereas tocilizumab may require a patient visit to a health care setting for intravenous administration, the advantage is that a single dose may also reduce the need for any additional intervention for that CRS episode or for future SUDs. Nonetheless, dexamethasone is inexpensive and accessible, so given its success resolving Grade 1 CRS in the absence of uncontrolled diabetes, it is a low‐risk and effective first approach towards managing Grade 1 CRS. Replacing the 17 initial tocilizumab doses utilized for Grade 1 CRS used in our study with dexamethasone would have yielded a cost savings of $108 358 (average wholesale price); though it is possible future costs may be offset by the accessibility of biosimilars.

Although a higher incidence of subsequent CRS was observed among patients who received dexamethasone first compared with tocilizumab, all events were low‐grade, and successfully managed with additional dexamethasone or tocilizumab. While this did not translate into significant differences in treatment delays or health care resource utilization, it is possible that given a longer half‐life and duration of effect, tocilizumab treatment could minimize CRS recurrence and need for additional CRS management with future doses [11].

Response rates and depth of response were not significantly impacted with the use of additional corticosteroids, which further supports the feasibility of dexamethasone as an initial CRS management strategy. Similar results were previously reported with teclistamab [9], and these additional findings may further ease concerns that corticosteroids may reduce T‐cell‐mediated immune responses with BsAbs.

This study has several limitations worth noting. Firstly, an inherent limitation is the retrospective nature of this analysis. Initial CRS management choice was determined by institutional protocol and clinician discretion, rather than predefined criteria. While baseline characteristics were similar, we did not propensity score match patients or do a multivariate analysis to account for differences. There were also differences in SUD schedules and additional prophylaxis medications to minimize CRS risk beyond package insert recommendations. Prophylactic tocilizumab was not a routine practice standard at the time of study inclusion, though guidelines have since incorporated the use of prophylactic tocilizumab prior to the first SUD step of MM multiple BsAbs. Thus, limited dexamethasone use in the prophylactic tocilizumab patients, and the trend towards management with either tocilizumab or supportive care only treatment likely represents variability in institutional practice. While our findings support dexamethasone as an initial treatment option for low‐grade CRS, there was variability in the dexamethasone dosing used, so it is difficult to ascertain the optimal dose. However, the median initial dexamethasone dose used across institutions was 10 mg, which aligns with the IMWG guideline dose recommendations when utilizing dexamethasone for CRS management.

Although recurrent CRS occurred more frequently in those who received dexamethasone first, events remained low‐grade and manageable, with efficacy comparable to the tocilizumab group. Given the advantages of dexamethasone regarding availability and cost, these findings underscore its feasibility as initial management for talquetamab‐induced low‐grade CRS.

Author Contributions

J.M., D.C.M., and J.A.D. analyzed the data and wrote the first draft of the manuscript. All authors contributed patients, edited, and approved the final manuscript.

Funding

The authors have nothing to report.

Ethics Statement

All centers obtained institutional review board approval, which granted waiver of consent, and the study was conducted in accordance with the Declaration of Helsinki.

Conflicts of Interest

J.M. reports consulting: GSK; K.J. reports consulting: Pfizer, Janssen (J&J), and BioLineRx; M.R. reports consulting: Janssen; V.R.N. reports employment: Genmab; consulting/advisor: Lilly, GSK; S.A. reports consulting: Amgen, GSK, Karyropharm, Janssen; D.K.H. reports consulting: BMS, Janssen, legend Biotech, Pfizer, Karyopharm; Research: BMS, Karyopharm, Adaptive Biotechnologies, 6 and Pentecost Myeloma Research Center; A.G.‐C. reports consulting Amgen, Sanofi, BMS, Janssen, Pfizer; D.S. reports consulting BMS, GSK, Sanofi, Johnson & Johnson, Pfizer, Opna Bio, Genentech, Abbvie, Legend Biotech; Z.M. reports consulting for Janssen, Pfizer, Sanofi; J.K. reports consulting: GPCR, Janssen, Prothena, Legend Biotech; research: Prothena, Ascentage, Janssen, Karyopharm, GPCR; J.A.D. reports consulting BMS, GSK, Janssen.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.