Pretreatment with Tocilizumab Prior to the CD3 Bispecific Cevostamab in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Showed a Marked Reduction in Cytokine Release Syndrome Incidence and Severity

Trudel, Suzanne; Bahlis, Nizar J.; Spencer, Andrew; Kaedbey, Rayan; Otero, Paula Rodríguez; Harrison, Simon; Wong, Chihunt; Goodman, Grant R.; Nakamura, Rin; Choeurng, Voleak; Cooper, James Fenimore; Mateos, María‐Victoria

doi:10.1182/blood-2022-159381

Cited by 29 publications

(20 citation statements)

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“…Taken together, our findings add to an emerging body of evidence that patients treated with new T‐cell–engaging therapies commonly experience CRS and benefit from supportive therapy with tocilizumab 3,5,18,20,22,23 . In particular, intervention with tocilizumab in patients who experience CRS appears to reduce the likelihood of subsequent CRS events without compromising efficacy of teclistamab.…”

Section: Discussionsupporting

confidence: 52%

“…In addition, the results positively reflect study protocol recommendations (i.e., administering tocilizumab for grade ≥2 CRS) and the need for prompt intervention, commonly experience CRS and benefit from supportive therapy with tocilizumab. 3,5,18,20,22,23 In particular, intervention with tocilizumab in patients who experience CRS appears to reduce the likelihood of subsequent CRS events without compromising efficacy of teclistamab. Further research in larger numbers of patients is needed to clarify the optimal timing of tocilizumab administration and its potential impact on treatment delays, hospitalization, and response rates.…”

Section: Discussionmentioning

confidence: 99%

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Detailed overview of incidence and management of cytokine release syndrome observed with teclistamab in the MajesTEC‐1 study of patients with relapsed/refractory multiple myeloma

Martin

Mateos

Nooka

et al. 2023

Cancer

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Background Teclistamab, a B‐cell maturation antigen × CD3 bispecific antibody, demonstrated an overall response rate of 63.0% in 165 heavily pretreated patients with relapsed or refractory multiple myeloma in the phase 1/2 MajesTEC‐1 study. Cytokine release syndrome (CRS), a known manifestation of T‐cell redirection, was observed in 119 of 165 patients (72.1%). Methods Patients received once‐weekly teclistamab 1.5 mg/kg subcutaneously after two step‐up doses (0.06 and 0.3 mg/kg). CRS was graded according to American Society for Transplantation and Cellular Therapy criteria and managed according to the study protocol, including use of tocilizumab and/or steroids. Results Most cases of CRS occurred during the step‐up dosing schedule of teclistamab and were grade 1 (50.3% of patients) or grade 2 (21.2% of patients); a single case of grade 3 CRS was reported in a patient with concurrent grade 3 pneumonia. All CRS cases resolved and none led to treatment discontinuation. Overall, 33.3% of patients had >1 CRS event; CRS recurrence was reduced when tocilizumab was administered for the first CRS event compared with when it was not (20.0% vs. 62.2%, respectively). Baseline characteristics such as tumor burden and cytokine levels did not appear to predict CRS incidence or severity. Conclusions Findings of this study support the need for preemptive planning and prompt management of CRS in patients treated with T‐cell–engaging bispecific antibodies. Intervention with tocilizumab for CRS appears to decrease the likelihood of patients experiencing subsequent CRS events without compromising response to teclistamab. Plain language summary Cytokine release syndrome (CRS), observed in 72.1% of patients treated with teclistamab in the MajesTEC‐1 study, was mostly grade 1 or 2 and manageable, without requiring treatment discontinuation. Most CRS occurred during the step‐up schedule, requiring vigilance during treatment initiation. Ensure fever is resolved and patients have no signs of infection before initiating the teclistamab step‐up schedule or administering the next teclistamab dose, to avoid exacerbating CRS. Tocilizumab reduced the risk of subsequent CRS in patients receiving it for their first CRS event (20.0% vs. 62.2% in those not receiving it), without affecting response to teclistamab. No baseline characteristics, including tumor burden or cytokine levels, appeared to clearly predict for CRS occurrence or severity.

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Detailed overview of incidence and management of cytokine release syndrome observed with teclistamab in the MajesTEC‐1 study of patients with relapsed/refractory multiple myeloma

Martin

Mateos

Nooka

et al. 2023

Cancer

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“…52 Prophylactic tocilizumab 2 hours before the first dose of cevostamab was explored, resulting in 36% of patients experiencing CRS, compared with 90% from a historical comparison cohort. 53 Continued refinement of supportive care, including premedications, alternative dosing strategies, and prophylactic tocilizumab, may further reduce the incidence of this complication in patients receiving CAR T-cell and BsAb therapy. Anti-GPRC5D CAR T Phase II 47 MajesTEC-1 10 MonumenTAL-1 31 ABBV-383 Phase I ICANS can include a range of symptoms and signs, including headache, confusion, somnolence, seizures, and coma.…”

Section: Toxicitymentioning

confidence: 99%

Chimeric Antigen Receptor T-Cell and Bispecific Antibody Therapy in Multiple Myeloma: Moving Into the Future

Holstein

Grant

Wildes

2023

JCO

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Historically, the outcomes for individuals with triple-class refractory and penta-drug refractory multiple myeloma (MM) have been poor because of a dearth of effective treatment options. However, the advent of chimeric antigen receptor (CAR) T-cell and T-cell redirecting bispecific antibody (BsAb) therapies has led to unprecedented response rates and durations of response in heavily relapsed/refractory (R/R) populations. Currently, two B-cell maturation antigen (BCMA)–directed CAR T-cell therapies (idecabtagene vicleucel and ciltacabtagene autoleucel) as well as one BCMA/CD3 BsAb (teclistamab) have been approved for late-line (greater than four previous lines) R/R MM in the United States. The purpose of this review is to analyze the recent data for these approved therapies as well as provide an overview of other related CAR T-cell and BsAb therapies under development, including non–BCMA-targeting agents. We review efficacy and safety considerations, with particular focus on cytokine release syndrome, neurotoxicity, and infection risk. The relative merits and limitations of each class of therapy are discussed, as well as the areas of unmet need with respect to optimal sequencing and supportive care measures. We examine the factors that challenge equitable access to these novel therapies across minoritized racial, ethnic, and socioeconomic populations. Although it is evident that CAR T-cell and BsAb therapies will transform treatment paradigms in MM for years to come, significant work remains to identify the optimal utilization of these novel therapies and ensure equitable access.

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“…Administration of the IL‐6 receptor blocking antibody, tocilizumab, prior to the first dose of cevostamab significantly reduced the CRS rate [53]. There was no negative effect of tocilizumab on efficacy of cevostamab, but there was a higher rate of neutropenia [53]. Tocilizumab as CRS prophylaxis has the potential to enable outpatient administration of BsAbs.…”

Section: What Is the Adverse Event Profile Of A T‐cell Redirecting Bi...mentioning

confidence: 99%

“…These properties of ABBV-383 are likely related to the low affinity binding to CD3 on the T-cells, while BCMA-binding occurs with high affinity, which also translated into antitumor activity with minimal cytokine release in preclinical studies [52]. Administration of the IL-6 receptor blocking antibody, tocilizumab, prior to the first dose of cevostamab significantly reduced the CRS rate [53]. There was no negative effect of tocilizumab on efficacy of cevostamab, but there was a higher rate of neutropenia [53].…”

Section: Cytokine-release Syndromementioning

confidence: 99%

T‐cell redirecting bispecific antibodies in multiple myeloma: Current landscape and future directions

O'Neill

Donk

2023

eJHaem

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T‐cell engaging bispecific antibodies (BsAbs) have substantial activity in heavily pretreated patients with multiple myeloma (MM). The overall response rate obtained with B‐cell maturation antigen (BCMA)‐targeting BsAbs is approximately 60%–70%, including a high proportion of patients achieving very good partial response or complete response. Comparable efficacy is seen with BsAbs targeting GPRC5D or FcRH5. Cytokine release syndrome is frequently observed with BsAb treatment, but mostly during the step‐up doses and the first full dose. Early intervention with IL‐6 receptor blocking antibodies (e.g., tocilizumab) prevents escalation to severe manifestations. Infections are also common during treatment and related to the extent of exposure to immune suppressive anti‐MM agents, as well as development of hypogammaglobulinemia due to elimination of normal plasma cells, and probably because of T‐cell exhaustion resulting from continuous BsAb‐mediated T‐cell activation. Adequate monitoring for infections and institution of infectious prophylaxis are essential. Patients treated with GPRC5D‐targteing BsAbs often develop skin and nail disorders and loss of taste, which is likely related to GPRC5D expression in cells that produce hard keratin. Currently ongoing studies are aiming at further improving these results by evaluating BsAbs in combination with other drugs, such as immunomodulatory agents and anti‐CD38 antibodies, as well as the application of BsAbs in earlier lines of therapy, including patients with newly diagnosed disease. We expect that the outcomes of patients with MM will further improve by the introduction of this novel type of T‐cell immunotherapy.

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Pretreatment with Tocilizumab Prior to the CD3 Bispecific Cevostamab in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Showed a Marked Reduction in Cytokine Release Syndrome Incidence and Severity

Cited by 29 publications

References 0 publications

Detailed overview of incidence and management of cytokine release syndrome observed with teclistamab in the MajesTEC‐1 study of patients with relapsed/refractory multiple myeloma

Detailed overview of incidence and management of cytokine release syndrome observed with teclistamab in the MajesTEC‐1 study of patients with relapsed/refractory multiple myeloma

Chimeric Antigen Receptor T-Cell and Bispecific Antibody Therapy in Multiple Myeloma: Moving Into the Future

T‐cell redirecting bispecific antibodies in multiple myeloma: Current landscape and future directions

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