Cevostamab for relapsed/refractory multiple myeloma

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, antibody–drug conjugate, and bispecific antibodies allowed).
• An Eastern Cooperative Oncology Group performance score of 0–1.

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.

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*

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.
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

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.

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 2–3 CRS symptoms in the DSU cohort compared with 73.3% in the SSU cohort.

CRS, cytokine release syndrome; DSU, double step-up; SSU, single step-up.
*Adapted from Trudel, et al.^3
†3.6/target dose (10.8–198 mg).
^‡0.3/3.6/target dose (60–160 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).

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, 6.0–18.4). 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.