Introduction
FDA (Food and Drug Administration) fast track program facilitates the development and accelerated review of new drugs aimed at treating life-threatening conditions and having the potential to address unmet medical needs. FDA fast track drugs (2019) for relapsed refractory MM include selective exportin-1 (XPO-1) inhibitors, first generation Selinexor / KPT-330 (S) and second generation KPT-8602, and an anti-B-cell maturation antigen (BCMA) bispecific T-cell engager (BiTE), AMG-420. The aim of our study is to analyze published literature for updates in clinical data viz efficacy and toxicity of these new agents in pts with RRMM.
Methods
Following PRISMA guidelines, we performed a comprehensive literature search on articles published after 2014 using Pubmed, Embase, Cochrane and Web of Science. Fifty-eight articles were identified initially and after a detailed scrutiny, we finalized 8 studies involving 299 RRMM patients and summarized the data using absolute values and percentages. Chimeric antigen receptor (CAR) T-cell therapy was excluded from our manuscript.
Results
Selinexor / KPT-330: A total of 6 studies (Table 1) involving 258 RRMM pts were included. In a phase Ib/II study by Bahlis et al., S was given in combination with bortezomib (V) and dexamethasone (d) to 22 pts with 4 median prior lines of therapy. The overall response rate (ORR) was 77% with complete response (CR) in 5%, partial response (PR) in 50% and very good partial response (VGPR) in 23% pts. In another phase Ib/II study by the same author, SVd was given to 42 pts with 3 median prior therapies. In 40 evaluable pts, ORR was 63% with CR in 8%, PR in 33%, and VGPR in 23%. The progression free survival (PFS) was 9 months. In a phase I/II study by Broijl et al., S (45 or 30 mg/m2) was given in combination with Vd to pts with median 3 prior treatments. Among 5 evaluable pts who received 45 mg/m2 of S, PR was observed in 80% and VGPR was observed in 40% pts. OS was 100% and 75% at 12 and 24 months respectively and PFS was 17 months. In pts who received S (30 mg/m2) with Vd, PR was observed in 67% and VGPR was observed in 17% pts. OS was 75% at 12 months and PFS was 10 months. In a phase II study by Vogl et al, 79 pts received S (80 mg) in combination with d (20 mg), both orally and twice weekly. Median prior therapies received were 7. In 78 evaluable patients, the ORR was 21% with PR in 15% and VGPR in 5%. OS and PFS were 9.3 and 2.3 months respectively. In a phase I study by Chen et al., 84 pts having received 6 median prior therapies were included. S was given either alone or in combination with d. Fourteen pts were rendered ineligible for response. ORR was 4% for pts who received single-agent S and 22% for those who received S+d. PR was observed in 4% of single-agent S pts. Among S+d pts, all responses were observed in S (45 mg/m2) plus d (20 mg) group (ORR 50%) with CR in 8% and PR in 42% pts. In a phase I study by Jakobowiak et al., 18 pts with median 3 prior therapies were included. S in combination with carfilzomib (CFZ) and d were given. Among 16 evaluable patients, PR was observed in 63% and VGPR was observed in 25% pts. On July 3, 2019, FDA granted accelerated approval to selinexor.
KP-8602: In a phase I/II trial by Cornell et al., involving 6 pts, KP-8602 (5 mg PO QDx5) in combination with dexamethasone (20 mg 2QWK) was given for 28 days. they had received 6 median prior lines of therapy. PR was observed in 16% of the pts.
AMG-420: In a phase I study by Topp et al., 35 pts with median 4 prior lines of therapy were included. Single-agent AMG-420 (0.2-800 µg/day) was given. CR was observed in 17% pts. The highest dose at which a CR was observed was 400 µg/day. It was also the dose at which maximum number of pts showed a CR (n=3, 9%). A partial response (PR) and a very good partial response (VGPR) was also observed in 1 patient each i.e. 3%.
Conclusion
Combination regimens of SVd has superior efficacy as compared to S monotherapy. Major adverse events reported with both single-agent and combination regimens are hematological i.e. thrombocytopenia, neutropenia and anemia. KP-8602 has promising efficacy in limited pts and appear to have better adverse effect profile. AMG-420 has shown promising activity and tolerability in RRMM pts at a dose of 400 µg/day with no major toxicities at this dose. The published data on these drugs is scarce, still emerging and warrants further investigation.
Anwer:In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.
Author notes
Asterisk with author names denotes non-ASH members.
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