P-084: Venetoclax monotherapy is feasible and efficient in patients with bcl-2 overexpressing relapsed/refractory multiple myeloma at high-risk sites: a case series

Abstract

<h3>Background</h3> Patients with relapsed/refractory multiple myeloma (RRMM) after numerous treatment lines represent a difficult to treat population and prognosis is poor especially in case of extramedullary manifestations that involve high-risk sites such as the central nervous system (CNS). Venetoclax is an oral, selective bcl-2 inhibitor with a beneficial pharmacological profile and penetrance into the CNS. Recent studies demonstrated high responses to venetoclax in RRMM patients with t(11;14) or high bcl-2 expression on a transcriptional level. However, the prognostic and predictive value of bcl-2 expression is still under debate. Especially, detection of bcl-2 protein expression by immunohistochemistry (IHC) is not well established as a biomarker in RRMM. Here, we present three cases of bcl-2 IHC positive RRMM patients with high-risk manifestations that showed deep end enduring treatment responses to venetoclax monotherapy. <h3>Methods</h3> We report on three consecutive RRMM patients treated between 2019 and 2021. At initial diagnosis none of the patients had a t(11;14). At relapse FISH was not evaluated but two of three patients showed a strong cyclin D1 expression. In all patients, IHC staining of MM cells in bone marrow biopsies and cerebrospinal fluids demonstrated a strong and homogeneous bcl-2 protein expression at relapse, respectively. Venetoclax was dosed up to 800 mg daily and all patients remained on this dose level. <b>Case 1:</b> Penta-refractory RRMM patient. Basic data: 72 y/o, male, IgG lambda, high-risk (HR) cytogenetics: no, extramedullary manifestations: no, prior lines: 8. <b>Case 2:</b> RRMM patient with CNS involvement. Basic data: 61 y/o, male, IgM lambda, HR cytogenetics: no, extramedullary manifestations: soft tissue, intraspinal, meningeal, intracerebral, prior lines: 7. <b>Case 3:</b> RRMM patient with extramedullary relapse after auto-allo-SCT. Basic data: 71 y/o, male, asecretory, HR cytogenetics: del(17p), extramedullary manifestations: soft tissue, prior lines: 6. <h3>Results</h3> Regarding the first case, two months after venetoclax beginning, IgG levels dropped to normal range reaching a VGPR (Duration of response (DOR) is 7 months). In the second case a CR was achieved in PET-CT and MRI scans 5 months after beginning of venetoclax treatment (DOR 15 months). A follow-up PET-CT staging of the third case showed a CR of the previously described extramedullary manifestations three months after venetoclax dosing. There were no hematological adverse events in any of the cases. <h3>Conclusion</h3> Venetoclax monotherapy was well-tolerated in these three RRMM patients without any severe hematologic or infectious adverse events. Moreover, even in the two patients with extramedullary high-risk manifestations, treatment responses were deep and long lasting. Future studies should systematically investigate the value of bcl-2 protein expression as a prognostic and predicitive biomarker in RRMM patients.