Dexametasone для управления CRS в связи с teclistamab у пациентов с повторной/редактированной множественной миеломой.

TO THE EDITOR:

Cytokine release syndrome (CRS) is a systemic inflammatory response triggered by the activation of T-cells and is commonly seen in patients receiving immune effector cell therapies such as chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies (BsAbs) which target varying tumor antigens such as CD19, CD20, B-cell maturation antigen (BCMA), or GPRC5D depending on the type of malignancy. CRS characteristics include fever, hypotension, and dyspnea due to increases in inflammatory mediators such as interleukin-6, interferon-γ, and tumor necrosis factor, which can be life-threatening if left untreated [ 1 ]. Although the grading of CRS associated with BsAbs is well established, management of CRS associated with BsAbs may vary depending on disease type, product, and institutional protocol and generally includes the use of antipyretics, hydration, oxygen, tocilizumab, and/or corticosteroids [ 2 , 3 ].

In April 2024, a panel of lymphoma experts published new consensus recommendations for toxicity management associated with CD3xCD20 BsAbs used in B-cell non-Hodgkin lymphomas (NHL). Owning to years of prior experience managing BsAb-related CRS, the committee supports the use of antipyretics and dexamethasone before tocilizumab for patients with grade 1-2 CRS and reserves tocilizumab for patients with refractory CRS that persist after the use of antipyretics and dexamethasone [ 4 ].

Subsequently, in May 2024, the International Myeloma Working Group (IMWG) published consensus guidelines for BsAbs used in multiple myeloma (MM), which differed from the lymphoma consensus by recommending tocilizumab prior to dexamethasone in patients with grade 1-2 CRS. The IMWG consensus was largely based on prior experience with BCMA-targeting BsAbs and favored initial tocilizumab due to its rapid reduction in CRS symptoms and decreased incidence of recurrent CRS [ 5 ]. The consensus also states that evidence of initial CRS management with steroids is very scarce [ 5 ]. Additionally, Martin, et al described CRS management in the MajesTEC-1 trial and found CRS was primarily managed with tocilizumab, with only nine patients receiving dexamethasone monotherapy [ 6 , 7 ]. Although consensus recommendations for NHL and MM may differ, there remains a lack of data for steroids as initial treatment of BsAb-related CRS. In an effort to support outpatient adoption and reduce costs, we sought to determine the efficacy and safety of utilizing dexamethasone for CRS management in patients receiving teclistamab for relapsed/refractory multiple myeloma (RRMM).

We retrospectively analyzed data from six US academic medical centers which included 243 patients with RRMM who initiated teclistamab commercially or as part of an expanded access protocol between August 2022 and July 2024. All centers obtained institutional review board approval, which granted a waiver of consent, and the study was conducted in accordance with the Declaration of Helsinki. Responses to therapy were evaluated using IMWG criteria with the exception of 24-hour urine tests which are not routinely performed to assess response at the participating institutions [ 8 ]. CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded using the American Society for Transplantation and Cellular Therapy criteria [ 2 ]. Extramedullary disease (EMD) was defined as bone-independent tumors and did not include paraskeletal plasmacytomas. High-risk cytogenetics were defined as the presence of deletion 17p, t(4;14), t(14;16) and/or amplification/gain 1q on fluorescence in situ hybridization testing at any time point before teclistamab initiation.

Teclistamab was administered subcutaneously as step-up doses of 0.06 mg/kg and 0.3 mg/kg followed by weekly doses of 1.5 mg/kg per the package insert. Step-up doses were separated by 2 to 3 days (days 1,4,7 or 1,3,5) and administered either in the inpatient or outpatient setting based on institutional preference. During the step-up dosing period, all patients were premedicated with acetaminophen, diphenhydramine, and dexamethasone per the package insert. Patients received toxicity management and supportive care per institutional protocols. Tocilizumab was dosed at 8 mg/kg (max 800 mg) and was not utilized as prophylaxis (ie: before step-up doses). Dexamethasone doses varied by institution and ranged from 4 mg to 20 mg.

Of the 243 patients included, the median age was 69 years (range 32–89), 51% were female, and 72% were non-Hispanic White (Table 1 ). The median prior lines of therapy were 5 (range 3–18), and 87% of patients were triple-class refractory. Seventy-four percent of the patients would have been excluded from the MajesTEC-1 trial, most commonly due to receipt of prior BCMA therapy (39%), ECOG ≥ 2 (32%), baseline cytopenia (8%), and renal insufficiency (7%). Eleven patients (5%) received step-up doses in an outpatient setting. Table 1 Patient/Treatment Characteristics and Safety/Efficacy Outcomes. All patients N = 243 Dexamethasone N = 33 Tocilizumab N = 38 P -value Characteristics Median (range) or n, (%) Age, years 69 (32–89) 69 (37–85) 68 (43–88) 0.92 Age > 70 years 99 (41) 12 (36) 16 (42) 0.64 Female sex 123 (51) 17 (52) 22 (61) 0.63 Race Non-Hispanic White 174 (72) 21 (64) 27 (71) 0.61 Non-Hispanic Black 59 (24) 12 (36) 10 (27) Hispanic 6 (3) 0 1 (2) Asian 3 (1) 0 0 ECOG PS 0 or 1 159 (68) 27 (82) 29 (77) 0.77 2 51 (22) 5 (15) 7 (18) 3 24 (10) 1 (3) 2 (5) R-ISS stage III 52/161 (32) 9/22 (41) b 8/29 (28) b 0.39 Baseline marrow plasma cell involvement, % b 40 (0–95) 55 (7–90) 38 (0–95) 0.41 High-risk cytogenetics a 130 (53) 16/32 (50) b 21/33 (64) b 0.31 Prior lines of therapy 5 (3–18) 6 (3–18) 6 (3–13) 0.6 Extramedullary disease 82 (33) 10 (30) 9 (24) 0.6 Triple-class refractory 212 (87) 26 (79) 31 (82) 0.78 Penta-class refractory 95 (39) 7 (21) 22 (58) 0.0013 Prior BCMA-DT 94 (39) 13 (39) 16 (42) 1 CAR T 62 (26) 11 (33) 12 (32) 0.81 ADC 33 (14) 2 (6) 7 (18) 0.16 BsAb 5 (2) 1 (3) 0 0.46 Step up dosing schedule Days 1, 3, 5 120 (49) 21 (64) 9 (24) 0.0008 Days 1, 4, 7 117 (48) 12 (36) 29 (76) 0.0008 Other 6 (3) 0 0 Safety Outcomes Median (range) or n , (%) CRS, any grade 133 (55) 33 (100) 38 (100) Grade 1 98 (41) 28 (85) 26 (68) 0.16 Grade 2 32 (13) 5 (15) 12 (32) 0.16 Grade 3+ 3 (1) 0 0 Timing of CRS Step-up dose 1 60 (25) 20 (61) 18 (47) 0.8 Step-up dose 2 60 (25) 19 (58) 16 (42) 0.62 First full dose 51 (21) 13 (39) 8 (21) 0.29 Repeat CRS after subsequent dose 32/133 (24) 14 (42) 6 (16) 0.018 Subsequent dose delay 31 (13) 9 (27) 8 (21) 0.59 Subsequent dose delay for grade 1 CRS only 21 (8) 6 (18) 5 (13) 0.74 Duration of CRS, days 1 (0.5–6) 1 (1–4) 1 (1–4) 0.19 Hospital days (day 1,3,5 step-up) 7 (6–35) 7 (6–10) 7 (7–12) 0.59 Hospital days (day 1,4,7 step-up) 9 (8–25) 9 (9-21) 9 (8–25) 0.55 Delay of discharge >48 h after final step-up dose due to any grade CRS 61 (25) 10 (30) 14 (37) 0.61 Delay of discharge >48 h after final step-up dose due to grade 1 CRS 43 (18) 8 (24) 9 (24) 1 ICANS, any grade 31 (13) 4 (12) 3 (8) 0.7 Grade ≥3 7 (3) 0 0 Efficacy Outcomes Median (range) or n , (%) ORR 156/237 (66) 24 (73) 28 (74) 1 ≥CR 89/237 (38) 16 (49) 19 (50) 1 VGPR 34/237 (14) 4 (12) 6 (16) 0.74 PR 33/237 (14) 4 (12) 3 (8) 0.69 Median PFS, months 6 Not reached 6.7 0.195 Median OS, months 14.3 Not Reached Not Reached 0.64 ECOG PS Eastern Cooperative Oncology Group Performance Status, BCMA-DT B-cell maturation antigen directed therapy, R-ISS Revised International Scoring System, ADC antibody-drug conjugate, ICANS immune effector-cell associated neurotoxicity syndrome. a Defined as Del17p, t(4;14), t(14;16), and/or gain/amplification 1q. b Analyzed among patients who had data available. p values that are statistically significant are shown in bold.

Overall, CRS occurred in 133 patients (55% of the population). Forty-one percent of patients experienced a grade 1 event and 13% experienced a grade 2 event. Two grade 3 and one grade 4 CRS events occurred and resolved with dexamethasone, tocilizumab, and vasopressor support in the intensive care unit but did not lead to treatment discontinuation. CRS occurred after the first step-up, second step-up, and first treatment doses in 25%, 25%, and 21% of patients, respectively. Recurrent CRS (ie: after subsequent teclistamab doses) was observed in 13% of patients. ICANS was observed in 13% of patients, with three percent experiencing grade 3-4 events. At a median follow-up of 8.8 months, the overall response rate (ORR) was 66%, with 38% achieving a complete response or better. Median progression-free survival (PFS) and overall survival (OS) were 6 and 14.3 months, respectively.

Of the 133 patients who experienced CRS, dexamethasone was used in 31 patients (23%), tocilizumab in 38 (29%), 30 patients (23%) received both dexamethasone and tocilizumab, and 34 (25%) received supportive care only (observation, acetaminophen, oxygen and/or hydration) for CRS management.

In the 30 patients who received both dexamethasone and tocilizumab, nine received dexamethasone prior to tocilizumab, seven of these were due to concern for concomitant ICANS. The remaining two received subsequent tocilizumab due to persistent CRS not resolved with dexamethasone and are included in the dexamethasone group. Of the remaining 21 patients who received both tocilizumab and dexamethasone, 12 received the drugs simultaneously, four received dexamethasone for ICANS, and the remaining five received tocilizumab first due to physician discretion ( n = 2 for grade 1 CRS, n = 2 for grade 2 CRS, n = 1 for grade 3 CRS).

When comparing the dexamethasone and tocilizumab monotherapy groups, baseline patient and disease characteristics were similar except for penta-class refractory disease, which was significantly higher in the tocilizumab group ( p = 0.0013) (Table 1 ).

Of the 33 patients who experienced CRS in the dexamethasone group, the majority (85%) experienced grade 1 events (Fig. 1 ). Five patients (15%) experienced grade 2 events, with two receiving supplemental oxygen and one receiving a fluid bolus in addition to dexamethasone. Fourteen patients (42%) who received dexamethasone for initial CRS experienced recurrent CRS after a subsequent teclistamab dose. However, all subsequent events were of the same or lower grade and resolved with a median of one (range 1–4) additional dexamethasone dose. Dexamethasone 10 mg was used for 73% of CRS events with doses ranging from 4 mg to 20 mg. The median number of dexamethasone doses was one (range 1–5) with ten patients (30%) requiring a second dose for recurrent CRS. In five patients (15%) who required more than two doses, dexamethasone 10 mg was scheduled every 6 h until CRS resolution. The median duration of CRS was one day (range 1-4) and step-up doses were delayed a median of one day (range 1–5) in 27% of the patients. Fig. 1 CRS management strategies and efficacy outcomes. A Sankey diagram of grade 1 CRS incidence and management strategies. B Sankey diagram of grade 2 CRS incidence and management strategies. C Best ORR stratified by CRS management strategy. D PFS stratified by CRS management strategy.

Eleven patients initiated step-up in the outpatient setting; five experienced grade 1 CRS and were managed as outpatients with dexamethasone or supportive care and one was admitted for management of grade 2 CRS with tocilizumab. No patients who initiated step-ups in the outpatient setting received tocilizumab prophylaxis.

In the tocilizumab group, 68% and 32% of patients experienced grade 1 and 2 events, respectively. The majority (92%) of patients received one dose of tocilizumab with three patients requiring multiple (range 2–5) doses. Six patients (16%) experienced recurrent CRS after a subsequent teclistamab dose with a median CRS duration of one day (range 1–4). Step-up doses were delayed a median of one day in 21% of patients who received tocilizumab treatment. There was no difference in ICANS incidence between the groups ( p = 0.7).

Best ORR was 73% in the dexamethasone group and 74% in the tocilizumab group with the majority of patients in both groups achieving a very good partial response or better (Fig. 1 ). Median PFS was not reached in the dexamethasone group and was 6.7 months in the tocilizumab group ( p = 0.195) (Fig. 1 ). Treatment-related mortality was not observed in either group.

As shown in previous real-world studies [ 9 – 13 ], our findings reinforce the efficacy and safety of teclistamab in a real-world population of which 74% would have been ineligible for the MajesTEC-1 trial [ 7 ]. Although only eleven patients received step-up doses in the outpatient setting, all but one who experienced CRS were safely managed with dexamethasone in the outpatient setting.

More importantly, our findings suggest patients experiencing grade 1 CRS with teclistamab may safely be treated with as few as one dexamethasone 10 mg dose without the need for additional tocilizumab. It may be premature to suggest dexamethasone alone for managing patients who experience grade 2 CRS, as our data only included five of these patients; however, all five patients responded to dexamethasone and/or additional supportive care without the need for tocilizumab. Although we found more patients in the dexamethasone group experienced repeat CRS after a subsequent teclistamab dose (42% vs 16%, p = 0.018), all repeat events were of the same or lesser grade and all but two events were managed with repeat dexamethasone administration. Additionally, the higher number of recurrent CRS events in the dexamethasone group did not lead to differences in the duration of CRS, rates of subsequent dose delay, median number of hospital days, or rates of delayed hospital discharge between the groups (Table 1 ).

The potential for utilizing dexamethasone for low-grade CRS treatment is especially relevant as both tertiary centers and small practices seek to implement effective strategies for outpatient initiation of teclistamab. Prophylactic tocilizumab is one strategy that may aid in implementation of outpatient teclistamab [ 14 , 15 ]. The combination of tocilizumab for CRS prophylaxis and dexamethasone for CRS management may also serve as an effective method for outpatient teclistamab administration. For practices without immediate access (logistically or financially) to tocilizumab, the use of dexamethasone may prevent unwarranted admissions and allow patients with low-grade CRS to be managed in an outpatient setting.

A total of 44 tocilizumab doses were administered with 26 of the doses being utilized for grade 1 CRS. Utilization of tocilizumab for grade 1 CRS alone represents a cost of $165,724 using the average wholesale price (AWP) for the branded product [ 16 ]. In contrast, substitution of 26 doses of tocilizumab with 26 dexamethasone 10 mg doses would have saved $165,642 based on an AWP of $3.13 for each 10 mg dose of dexamethasone [ 17 ]. These cost savings are particularly intriguing when considering the median number of hospital days and rate of delayed hospital discharge were similar between the groups. Aspects such as availability of an oral formulation and ease of use should also be taken into account when considering dexamethasone for CRS treatment.

Additionally, response rates, PFS, and OS in dexamethasone group were not affected by the use of additional corticosteroids which may help dispel the theory that corticosteroids reduce T-cell induced proliferation and tumor lysis with immune effector cell therapies [ 18 , 19 ].

Our observations have several limitations worth highlighting. Although response rates were similar to the MajesTEC-1 trial and other real-world studies, an inherent limitation is the retrospective nature of our study. There were institutional differences in the step-up dosing schedule and toxicity management, but this is reflective of variability seen in real-world practice. Although response assessments were based on IMWG criteria, they were conducted by investigators and not an independent review committee. Our data only included patients receiving teclistamab so extrapolation to patients receiving talquetamab or elranatamab should be considered with caution. Although our findings support CRS management with dexamethasone, a group of patients in our study were managed solely with acetaminophen and supportive care which may indicate not all patients require escalation to dexamethasone or tocilizumab. Further research with a larger sample size is needed to confirm these findings and elucidate any potential subgroup differences in outcomes of patients with differing disease characteristics.

In conclusion, 55% of patients with RRMM receiving teclistamab experienced CRS, although it should be emphasized only one percent of patients experienced a grade 3+ event. Our findings suggest patients experiencing grade 1 CRS with teclistamab may safely be treated with as few as one dexamethasone 10 mg dose as an alternative to management with tocilizumab which may facilitate outpatient initiation of step-up doses.

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Author contributions

JAD and VN planned the project, contributed patients and data, interpreted data, and prepared the manuscript. JS, MR, DCM, CC, KJ, CBW, KG, KMG, SA, HH, JM, GE, JK, JR, and ZM contributed patients and data, interpreted data, and approved the final manuscript.

Data availability

Data may be made available upon request to the corresponding author.

Competing interest

JAD: consultancy: Janssen. MR: consultancy: Janssen. ZM: consultancy: Janssen, Pfizer, Sanofi. SA: Research Funding: GSK, AMGEN, Karyopharm; Honoraria: Janssen. KJ: consultancy: Pfizer, Janssen (J&J), and BioLineRx. CBW: consultancy: Pfizer. JK: honoraria GPCR Therapeutics, Legend Biotech; Consultancy: Janssen.

Ethics approval and consent to participate

All centers obtained institutional review board approval, which granted a waiver of patient consent, and the study was conducted in accordance with the Declaration of Helsinki. All centers obtained institutional review board approval, reference # Pro00122996.

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