I asked some of the world’s best myeloma specialists what they considered to be their favorite myeloma abstracts from ASH 2017. I am so pleased to provide the myeloma patient community with this series of blog posts reporting on the “Best of the Best ASH 2017 Myeloma Abstracts”.
Dr. Paul Richardson is the RJ Corman Professor of Medicine at Harvard Medical School, Clinical Program Leader, and Director of Clinical Research at the Jerome Lipper Multiple Myeloma Center, Dana Farber Cancer Institute, Boston, Massachusetts. Dr. Richardson currently holds leadership positions in several professional bodies and serves on the Editorial Board of the Journal of Clinical Oncology, the Journal of Oncology, The Oncologist, Clinical Cancer Research, and the British Journal of Hematology. Dr. Richardson has published more than 280 original articles, and more than 180 reviews, chapters, and editorials in leading peer-reviewed journals including the New England Journal of Medicine, Blood, Journal of Clinical Oncology, Leukemia, Clinical Cancer Research, and British Journal of Haematology. His primary research interest is in novel therapies, and he has been a leader in the clinical development of bortezomib, lenalidomide and pomalidomide. He has pioneered the development of lenalidomide, bortezomib, and dexamethasone (so called RVD), which is now one of the most widely used combinations nationwide in the upfront treatment of myeloma.
Dr. Richardson has chosen Abstract 3135 as one of his favorite ASH abstracts.
Dr. Richardson states, In Relapsed Refractory Multiple Myeloma – Selinexor in combination with Bortezomib and Dexamethasone (SVT) has better tolerability and impressive activity in heavily pretreated relapsed refractory multiple myeloma patients.”
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A single drug has shown outstanding results in relapsed or refractory myeloma patients: selinexor. In myeloma it is more common to give the drugs in combination. In the graph below, you can see selinexor used with Velcade and dex compared to other popular myeloma therapies. Selinexor can bring some drugs like bortezomib back to life and can even lower the instance of side effects like peripheral neuropathy. For example, neuropathy in the Selinexor/Velcade/dex combination was only 25% of Velcade/dex alone (see graph below). And from someone who lives with neuropathy, I can tell you I would love to have 1/3 or 1/4 the problems I live with every day!
Introduction – Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound. Twice weekly bortezomib in combination with dexamethasone (Vd) is an established therapy in relapsed and refractory multiple myeloma. While the activity of bortezomib in combination with other agents is effective, prolonged use is limited due to peripheral neuropathy (50-60%) as well as acquired resistance to bortezomib. Strategies to identify new dosing regimens with high response rates, improved tolerability and the ability to overcome resistance are needed. Pre-clinical studies have shown that selinexor can restore sensitivity of bortezomib-resistant myeloma, inhibiting tumor growth and increasing survival in mice with myeloma. In this clinical trial (NCT02343042), we investigated the safety, tolerability and efficacy of the combination of selinexor, bortezomib and low dose dexamethasone (SVd) in patients with relapsed refractory myeloma.
Methods – This phase 1b/2 dose escalation study was designed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose for SVd. The study enrolled patients with RRMM after ≥ 1 prior therapy. Patients with prior exposure or refractory to proteasome inhibitors were included, provided they were not refractory to bortezomib as a last therapy. Selinexor was independently dosed escalated in once-weekly (100 mg) or twice-weekly (80 mg) regimens.
Results – 42 patients were enrolled; 22 in the dose escalation and 20 in the phase 2 recommended dose cohort. Median age was 64 years, median of 3 prior lines of therapy. The maximum tolerable dose was not reached. Common treatment related grade 1/2 adverse events (AEs) included: anorexia (57%), nausea (55%), fatigue (48%), and vomiting (26%). Grade 3/4 AEs included: thrombocytopenia (40%), neutropenia (19%) and anemia (12%). Importantly, peripheral neuropathy (PN) across all patients was limited to 6 patients (14%) of which 5 had prior bortezomib exposure. Based on tolerability and efficacy, the phase 2 dose of SVd is selinexor 100 mg, bortezomib 1.3 mg/m2 and dex 40 mg, or (40% less bortezomib and 25% less dex compared to the standard, approved schedule for Vd). Among the 18 patients with non-PI(protesome inhibitor) refractory MM and ≤ 3 lines of prior therapy, the ORR was 83% and Clinical Benefit rate was 89%; the median follow up was 10 months and Progression Free Survival (PFS) was not reached. Among the 19 patients with protesome Inhibitor (PI) (bort, ixazomib or carfilzomib) refractory MM, the ORR was 42% Clinical Rate of 68%. The median follow up was 9.2 months and the median PFS was 9 months.
Conclusions – Selinexor in combination with weekly bortezomib and dex is well tolerated and highly active in RRMM. The ORR of 83% and periphrial neuropathy rate of 13% in protesome inhibitor (PI) non-refractory MM with 1-3 lines of prior therapy compares favorably to the previously reported ORR of 63% and >40% PN for Vd demonstrated in previous phase III trials. The high ORR with SVd is achieved with 40% less bortezomib and 25% less dex and no overt major organ toxicities. Furthermore, in patients with PI refractory MM, the ORR of 42% and Clinical Benefit Rate of 68% support pre-clinical findings that selinexor re-sensitizes and overcomes resistance to PIs. SVd has shown durable responses regardless of prior PI sensitivity status and has an improved side effect profile. This data supports the ongoing phase 3 BOSTON study examining SVd vs Vd.
Dr. Richardson also noted: “Other very promising data were reported on a variety of novel agents including antibody drug conjugates (ADC) targeting BCMA, venetoclax, isatuximab (combined with pomalidomide and dexamethasone) and melflufen/dexamethasone.” Thank You Dr. Richardson for all you do for the myeloma patient community.