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Cevostamab for relapsed/refractory multiple myeloma

Mar 8, 2022
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Cevostamab targets the membrane-proximal domain of Fc receptor homolog 5 (FcRH5), which is expressed exclusively on B-lineage cells. Cevostamab, as an FcRH5/CD3 bispecific antibody, has shown promising activity in heavily pre-treated patients with relapsed/refractory multiple myeloma (RRMM). Cevostamab received orphan drug designation last year from both the U.S. Food and Drug Administration (FDA)1 and the European Medicines Agency (EMA)2.

During the 63rd American Society of Hematology Annual Meeting and Exposition, Suzanne Trudel3 presented the updated safety and efficacy data from a phase I study (NCT03275103) of cevostamab in patients with RRMM.

Study design

Inclusion criteria for the trial were as follows:

  • Patients with RRMM who had exhausted other treatment options (prior CAR T-cell, antibodydrug conjugate, and bispecific antibodies allowed).
  • An Eastern Cooperative Oncology Group performance score of 01.

Cevostamab was given intravenously for 17 cycles. To reduce cytokine release syndrome (CRS)/infusion reactions, Cycle 1 (C1) step-up dosing (Figure 1) was used, along with corticosteroid premedication in C1−2 and acetaminophen and diphenhydramine premedication in C1−17. Patients were hospitalized for ≥72 hours after each C1 infusion.

Figure 1. Cevostamab administration with single and double step-up dosing schemas*

A Single step-up and B double step-up dosing schemas of cevostamab administration.
C, Cycle; D, Day.
*Adapted from Trudel, et al.3
All doses in mg.

Results

The baseline characteristics of this heavily pretreated group of patients with RRMM are shown in Table 1. There was a high prevalence of patients with high-risk cytogenetics, with 70.5% having gain of 1q21. In total, 88.8% of patients were refractory to previous agents and had been treated with a median of six prior lines of therapy. Patients remained on the study for a median of 8.8 months (range, 0.2−37.2 months).

Table 1. Patient characteristics*

Characteristic, % (unless otherwise stated)

Total (N = 161)

Median age (range), years

64 (33−82)

Male

58.4

High-risk cytogenetics

 

              1q21 gain

70.5

              t(4;14)

55.6

              t(14;16)

13.5

              del(17p)

2.2

Extramedullary disease

21.1

Median time since first MM therapy (range), years

6.1 (0.3−22.8)

Median number of prior lines of therapy (range)

6 (2−18)

Prior anti-CD38 antibody

88.2

Prior anti-BCMA

33.5

Prior ADC

16.8

Prior bispecific antibody

8.1

Triple-class refractory

84.5

Penta-drug refractory§

68.3

Refractory to previous therapy

88.8

ADC, antibody drug conjugate; BCMA, B-cell maturation antigen; MM, multiple myeloma.
*Adapted from Trudel, et al.3
Percentage of patients with conclusive assay results.
≥1 immunomodulatory drug, ≥1 proteasome inhibitor, and ≥1 anti-CD38 antibody.
§
≥2 immunomodulatory drugs, ≥2 proteasome inhibitors, and ≥1 anti-CD38 antibody.

Safety

The most common Grade 3 and 4 adverse events (AEs) were:

  • Neutropenia
  • Anemia
  • Thrombocytopenia
  • Lymphopenia
  • Infection

A total of 99.4% of patients experienced an AE during the study, with 32.9% at Grade 3 and 28.6% at Grade 4. Fatal AEs were recorded in 3.7% and one death was classified as cevostamab-related and recorded as due to hemophagocytic lymphohistiocytosis. Treatment discontinuation occurred in 13% of patients due to AEs, with 4.3% being related to cevostamab.

CRS

CRS was first seen in C1 and occurred within 24 hours of administration in 70% of patients. In 85% of patients, CRS then resolved within 48 hours. The profile of CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) grades across the cohort is shown in Figure 2. Only one patient with ICANS + CRS did not have a resolution of their ICANS symptoms. This patient subsequently discontinued treatment due to disease progression. Most patients with CRS were managed with tocilizumab only (37.3%), while 21.7% had only steroids, and 20.0% were treated with both agents.

Figure 2. Patients who experienced CRS and ICANS after cevostamab infusion*

CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome.
*Data from Trudel, et al.3

 
In the two-dose cohorts, different CRS profiles were seen (Figure 3). In the C1 single step-up (SSU) cohort, 88.4% of patients experienced CRS compared with 79.5% in the double step-up (DSU) cohort. The DSU profile appeared to be improved, with 52.3% of patients with Grade 23 CRS symptoms in the DSU cohort compared with 73.3% in the SSU cohort.

Figure 3. CRS incidence in the SSU and DSU cohorts*

CRS, cytokine release syndrome; DSU, double step-up; SSU, single step-up.
*Adapted from Trudel, et al.3
3.6/target dose (10.8198 mg).
0.3/3.6/target dose (60160 mg).

Efficacy

A response was observed in patients at the ≥20 mg target dose (n = 143).

Responses were more frequent at the higher dose level (132−198 mg), with an overall response rate (ORR) of 56.7%, compared with 36.1% for the lower dose cohort (20−90 mg) (Figure 4).

Figure 4. Best response to treatment*

CR, complete response; PR, partial response; sCR, stringent CR; VGPR, very good partial response.
*Adapted from Trudel, et al.3


The median time to first response was 1 month (range, 0.7−5.9 months), and responses were seen to deepen over time, with a median time to best response of 2.1 months (range, 0.7−11.4 months). Only ten patients who achieved a very good partial response or better were evaluable for measurable residual disease (at 10−5 threshold), of which seven achieved measurable residual disease negativity.

Response duration

The median duration of response for the whole cohort was 11.5 months (95% confidence interval, 6.018.4). In the C1 SSU cohort, the median follow-up was 14.3 months (range, 2.7−31.8 months), whereas in the C1 DSU cohort, the median follow-up was 6.5 months (range, 4.8−21.4 months).

Conclusion

The safety profile of cevostamab was improved with the C1 DSU dosing schedule compared with the SSU, with a reduced CRS incidence recorded in the former. In addition, the ORR was increased at the 132−198 mg dose level compared with the 20−90 mg dose level. In this heavily pretreated cohort, which included patients with previous exposure to CD38 and BCMA-targeted agents, an ORR of 54.8% was achieved in the C1 DSU group, indicating cevostamab may be a beneficial treatment for this group and deserves further assessment in a phase II study.

  1. U.S. Food and Drug Administration. Search orphan drug designations and approvals https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=799220. Accessed Mar 4, 2022.
  2. European Medicines Agency. EU/3/21/2424: Orphan designation for the treatment of multiple myeloma. https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-21-2424. Published Apr 13, 2021. Accessed Mar 4, 2022.
  3. Trudel S. Cevostamab monotherapy continues to show clinically meaningful activity and manageable safety in patients with heavily pre-treated relapsed/refractory multiple myeloma (RRMM): updated results from an ongoing phase I study. Oral abstract #157. 63rd American Society of Hematology Annual Meeting and Exposition; Dec 11, 2021; Atlanta, US.

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