Marizomib for CNS-Multiple Myeloma

Marizomib, a natural marine product, is an irreversible proteasome inhibitor (PI) that has distinct advantages over the currently approved PIs in that it irreversibly inhibits all three enzymatic activities of the proteasome and has been demonstrated to cross the blood brain barrier. Several studies have demonstrated that marizomib (MRZ) penetrates and can be retained in the CNS and that it substantially inhibits proteasome activity in the brain; radiolabeled MRZ showed 30% CNS biodistribution compared with blood levels in rats; it elicits a significant anti-tumor effect in a rodent model of malignant glioma; and pharmacological inhibition of proteasome activity has been observed in primate brains. MRZ is currently under clinical investigation in relapsed-refractory multiple myeloma and grade IV malignant glioma. CNS-multiple myeloma (MM) is a rare manifestation of extra-medullary disease with very limited therapeutic options. Its prevalence is increasing as anti-myeloma therapies become more effective at treating systemic disease, resulting in the CNS becoming a sanctuary site for the disease further highlighting the urgent unmet clinical need in this patient population. MRZ has demonstrated encouraging activity in non-CNS-MM, and has emerging clinical activity in glioma making it a potentially promising CNS-MM therapeutic intervention.

To date 3 patients have been treated under compassionate use protocol with MRZ for CNS-involved MM. Two of these patients have received sufficient doses of MRZ in combination with DEX to evaluate its activity in this indication. MRZ was dosed initially at 0.5mg/m² and then increased to 0.7mg/m²once tolerability had been established on the schedule currently in use on the glioma study (days 1, 8, and 15 of a 28 day cycle as a 10 minute infusion). Both patients, who had received prior cranio-spinal radiotherapy and intrathecal chemotherapy with no response, have tolerated MRZ well with no unexpected adverse events. The first patient had an 89% reduction in cerebrospinal fluid (CSF) plasmacytosis and 77% serum LDH reduction. After 5 months daratumumab was added to MRZ and further clinical improvement was observed (resolution of double vision and becoming fully ambulatory). Six months after MRZ initiation the patient progressed clinically and stopped treatment. Clinical symptoms disappeared in the second patient in the second month of MRZ with complete resolution of CSF plasmacytosis and CSF monoclonal spike. The patient is currently undergoing the 4th cycle of treatment with sustained resolution of saddle anesthesia and no further signs of cauda equina symptoms. Collectively, these cases provide preliminary evidence that MRZ may have utility as a therapeutic for CNS-MM and also demonstrate that combination of MRZ and daratumumab may provide benefit in this indication. Follow up is ongoing on the second patient and more mature data will be presented on this patient and any additional patients subsequently treated under compassionate use for CNS-MM.