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Impact of treatment modality and route of administration on rates of CRS in RRMM

May 10, 2024
Learning objective: After reading this article, learners will be able to cite a new clinical development in relapsed/refractory multiple myeloma.

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B-cell maturation antigen (BCMA)-directed immunotherapies for the treatment of relapsed/refractory multiple myeloma (RRMM) are often associated with high response rates compared with standard of care treatments. However, they are often also accompanied by cytokine elevation, which can lead to cytokine release syndrome (CRS). The incidence of CRS associated with BCMA-directed therapies is well established but rarely stratified by modality and administration route.1

Here, we summarize a meta-analysis by Soltantabar et al.1 published in Clinical Pharmacology and Therapeutics on the impact of treatment modality and the route of administration of immunotherapies on the incidence of CRS in RRMM.

Study design1

  • In this meta-analysis, data were collected on the incidence of CRS from trials including patients with RRMM treated with BCMA-directed chimeric antigen receptor (CAR) T-cell or bispecific antibody (bsAb) therapies.
  • The weighted proportion of Grade ≥3 CRS events were compared by modality of treatment and administration (intravenous/subcutaneous).
  • Data were also collected on the rate and agent used to manage CRS, as well as onset and duration.

Key findings1

  • In total, 1,560 patients enrolled across 36 studies were included in this study.
  • A higher incidence of CRS was associated with the use of CAR T-cell therapies compared with bsAbs, in all grades of CRS (Figure 1).
    • Rates of CRS also varied significantly by dose level per agent (Table 1).
  • CAR T-cell therapies were also associated with a longer median duration of CRS at 5 days vs 2 days with bsAbs.
  • The incidence of any-grade CRS following treatment with BsAbs was comparable between intravenous and subcutaneous administration routes at 58% vs 59%, respectively.
  • However, a lower incidence of Grade ≥3 CRS was observed in patients who received subcutaneous bsAbs at 0% vs 4% intravenous.
    • The number of studies investigating the subcutaneous administration route was limited; therefore, more research is needed to draw conclusions.
  • Tocilizumab and corticosteroids were more commonly used to manage CRS in patients treated with CAR T-cell therapies than bsAbs.
    • CAR T-cell therapy: 44% and 13%, respectively.
    • BsAb therapy: 25% and 13%, respectively.

Figure 1. CRS rates associated with CAR T-cell and bispecific antibody therapies* 

bsAbs, bispecific antibody; CAR, chimeric antigen receptor.
*Data from Soltantabar, et al.1

Table 1. Incidence of CRS by agent and dose level*


Dose level

Any grade CRS, %

Grade ≥3 CRS, %


12/32/76 mg



4/20/76 mg



44/76 mg; no premed



44/76 mg premed



1,000 μg/kg (76 mg)



600 μg/kg (44 mg)




5/20/50 mg IV



5/20/200 mg IV




3/6/10 mg SC



3/6/30 mg SC



3/6/10 mg IV




40 mg IV



60 mg IV



CRS, cytokine release syndrome; IV, intravenous; SC, subcutaneous.
*Adapted from Soltantabar, et al.1

Key learnings1

  • Data collected in this meta-analysis provide evidence to suggest there are significant variations in the incidence of CRS associated with BCMA-targeted immunotherapies.
  • A higher incidence of CRS was associated with CAR T-cell therapies compared with bsAbs.
  • These data provide some evidence that subcutaneous administration of BCMA-directed immunotherapies could be associated with decreased rates of higher grade CRS, highlighting administration routes as key for further research.

  1. Soltantabar P, Sharma S, Wang D, et al. Impact of treatment modality and route of administration on cytokine release syndrome in relapsed or refractory multiple myeloma: a meta-analysis. Clin Pharmacol Ther. 2024. Online ahead of print. DOI: 1002/cpt.3223.


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