Contributions
Abstract: EP965
Type: E-Poster Presentation
Session title: Myeloma and other monoclonal gammopathies - Clinical
Background
Fc receptor-homolog 5 (FcRH5), an immunoglobulin (Ig) domain-containing type I membrane protein, is expressed exclusively in the B-cell lineage; and has been identified as a desirable target for the treatment of MM [1]. The humanized IgG-based T-cell-engaging bispecific antibody cevostamab (anti-FcRH5xCD3; BFCR4350A) binds to the most membrane-proximal domain of FcRH5 on myeloma cells and to cluster of differentiation 3 (CD3) on T cells resulting in efficient immunological synapse formation and potent T-cell-directed killing of myeloma cells. Cevostamab showed promising activity and manageable toxicity as monotherapy in the GO39775 Phase 1 dose escalation study (NCT03275103) enrolling RRMM patients (pts) [2].
Aims
To analyse pre-treatment FcRH5 target expression by response to therapy and pts baseline characteristics (prior therapy, cytogenetic risk status), in the cevostamab Phase I study.
Methods
Bone marrow aspirates (BMA) were collected prior to receiving cevostamab treatment. FcRH5 cell surface expression on myeloma cells was assessed using flow cytometry and the levels of expression (reported as molecules of equivalent soluble fluorochrome [MESF]) were compared between pts by prior therapy and stratified by cytogenetic risk status (determined by FISH). The clinical cut-off date (CCOD) used for the current analyses was August 18, 2020.
Results
As of CCOD, 53 pts (median age: 62.0 years [range: 33–80]) had enrolled in the study. Median number of prior lines of therapy was 6 (range: 2–15). Prior treatments included proteasome inhibitors (PIs), 100% (94.1% refractory); immunomodulatory drugs (IMiDs), 100% (98.0% refractory); anti-CD38 mAbs, 81% (92% refractory); and 86% of pts received autologous stem cell transplant. Overall, 72% of pts were triple-class refractory (≥1 PI, ≥1 IMiD, and ≥1 anti-CD38 mAb), and 94% of pts were refractory to their last therapy. In pts who received ≥3.6mg/20mg doses, the ORR was 53% (18/34); response was consistent in pts with exposure to prior daratumumab and anti-BCMA agents. FcRH5 expression was detected on myeloma cells in all pts with adequate BMA samples for biomarker evaluation (n=44). Prior therapy and the number of lines of treatment did not appear to affect FcRH5 expression. Of the pts with evaluable samples for cytogenetics (n=28), 25 pts were high risk [HR; 1q21, t(4;14), t(4,16) or del(17p)] and 3 standard risk (SR). Baseline FcRH5 expression stratified by cytogenetic risk showed a trend towards higher expression in pts with HR cytogenetics; median (min, max) MESF was 6329 (352, 44409) in HR and 2591 (766, 4560) in SR. Expression levels were consistent in HR pts with 1q21 vs no 1q21, t(4,14) vs no t(4,14) and d(17p) vs no d(17p). No clear correlations were observed between response to cevostamab and baseline expression levels of FcRH5.
Conclusion
Response to cevostamab was observed irrespective of FcRH5 expression levels in pts with RRMM assessed to date. Prior therapy did not affect the expression levels of FcRH5. There was a trend towards higher expression levels in pts with high-risk cytogenetics. These data further confirm FcRH5 as a promising target for MM therapeutics.
References: 1.Li et al. Cancer Cell 2017;31:383–95; 2.Cohen et al, ASH 2020
Keyword(s): Bispecific, Immune therapy, Multiple myeloma, Phase I
Abstract: EP965
Type: E-Poster Presentation
Session title: Myeloma and other monoclonal gammopathies - Clinical
Background
Fc receptor-homolog 5 (FcRH5), an immunoglobulin (Ig) domain-containing type I membrane protein, is expressed exclusively in the B-cell lineage; and has been identified as a desirable target for the treatment of MM [1]. The humanized IgG-based T-cell-engaging bispecific antibody cevostamab (anti-FcRH5xCD3; BFCR4350A) binds to the most membrane-proximal domain of FcRH5 on myeloma cells and to cluster of differentiation 3 (CD3) on T cells resulting in efficient immunological synapse formation and potent T-cell-directed killing of myeloma cells. Cevostamab showed promising activity and manageable toxicity as monotherapy in the GO39775 Phase 1 dose escalation study (NCT03275103) enrolling RRMM patients (pts) [2].
Aims
To analyse pre-treatment FcRH5 target expression by response to therapy and pts baseline characteristics (prior therapy, cytogenetic risk status), in the cevostamab Phase I study.
Methods
Bone marrow aspirates (BMA) were collected prior to receiving cevostamab treatment. FcRH5 cell surface expression on myeloma cells was assessed using flow cytometry and the levels of expression (reported as molecules of equivalent soluble fluorochrome [MESF]) were compared between pts by prior therapy and stratified by cytogenetic risk status (determined by FISH). The clinical cut-off date (CCOD) used for the current analyses was August 18, 2020.
Results
As of CCOD, 53 pts (median age: 62.0 years [range: 33–80]) had enrolled in the study. Median number of prior lines of therapy was 6 (range: 2–15). Prior treatments included proteasome inhibitors (PIs), 100% (94.1% refractory); immunomodulatory drugs (IMiDs), 100% (98.0% refractory); anti-CD38 mAbs, 81% (92% refractory); and 86% of pts received autologous stem cell transplant. Overall, 72% of pts were triple-class refractory (≥1 PI, ≥1 IMiD, and ≥1 anti-CD38 mAb), and 94% of pts were refractory to their last therapy. In pts who received ≥3.6mg/20mg doses, the ORR was 53% (18/34); response was consistent in pts with exposure to prior daratumumab and anti-BCMA agents. FcRH5 expression was detected on myeloma cells in all pts with adequate BMA samples for biomarker evaluation (n=44). Prior therapy and the number of lines of treatment did not appear to affect FcRH5 expression. Of the pts with evaluable samples for cytogenetics (n=28), 25 pts were high risk [HR; 1q21, t(4;14), t(4,16) or del(17p)] and 3 standard risk (SR). Baseline FcRH5 expression stratified by cytogenetic risk showed a trend towards higher expression in pts with HR cytogenetics; median (min, max) MESF was 6329 (352, 44409) in HR and 2591 (766, 4560) in SR. Expression levels were consistent in HR pts with 1q21 vs no 1q21, t(4,14) vs no t(4,14) and d(17p) vs no d(17p). No clear correlations were observed between response to cevostamab and baseline expression levels of FcRH5.
Conclusion
Response to cevostamab was observed irrespective of FcRH5 expression levels in pts with RRMM assessed to date. Prior therapy did not affect the expression levels of FcRH5. There was a trend towards higher expression levels in pts with high-risk cytogenetics. These data further confirm FcRH5 as a promising target for MM therapeutics.
References: 1.Li et al. Cancer Cell 2017;31:383–95; 2.Cohen et al, ASH 2020
Keyword(s): Bispecific, Immune therapy, Multiple myeloma, Phase I