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

Background 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. Methods 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. Case 1: Penta-refractory RRMM patient. Basic data: 72 y/o, male, IgG lambda, high-risk (HR) cytogenetics: no, extramedullary manifestations: no, prior lines: 8. Case 2: 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. Case 3: 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. Results 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. Conclusion 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.