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A phase II trial of TBL-12 sea cucumber extract in patients with untreated asymptomatic myeloma

2016; Wiley; Volume: 180; Issue: 2 Linguagem: Inglês

10.1111/bjh.14314

1365-2141

Ajai Chari, Amitabha Mazumder, K. H. Vincent Lau, Donna Catamero, Zachary Galitzeck, Sundar Jagannath,

Proteoglycans and glycosaminoglycans research

The sphingolipids/glycosides in sea cucumbers have several antitumour properties (Zou et al, 2003) including anti-angiogenesis (Tian et al, 2005), direct tumour cytotoxicity (Sugawara et al, 2006) and, of particular relevance to multiple myeloma (MM), the inhibition of osteoclastogenesis (Kariya et al, 2004). TBL-12, a sea cucumber extract, has been commercially available since 1981 and has been used by human subjects as a food supplement without any reported toxicities (Taiyeb-Ali et al, 2003). We investigated the safety and efficacy of TBL-12 in patients with asymptomatic (smouldering) MM (ASMM) in this pilot phase II study. Inclusion criteria included ≥10% bone marrow plasmacytosis and no associated hypercalcaemia, renal insufficiency, anaemia, lytic bone lesions or recurrent infections. Patients were also required to have a serum monoclonal protein ≥10 g/l and/or urine M-spike ≥200 mg/24 h, Karnofsky performance status ≥80%, no active infections, and be receiving steroids less than the equivalent of 10 mg prednisone daily for other medical conditions. This study was approved by the St. Vincent's and Mt. Sinai institutional review boards and all subjects provided written informed consent prior to study participation. Subjects were given open label TBL-12, formulated as a liquid gel (manufactured by Unicorn Pacific Corporation, Port Vila, Vanuatu) and kept frozen until the time of consumption. Patients ingested 2 units of 20 ml twice per day, for a total of 80 ml per day. Disease parameters were monitored monthly and treatment was continued until disease progression as defined by standard International Myeloma Working Group (IMWG) criteria for serological progression or due to end organ symptoms, whichever occurred sooner. A total of 20 patients participated in this study; baseline characteristics and risk stratification were based on previously published criteria (Kyle et al, 2007; Dispenzieri et al, 2008; Mateos et al, 2013) (Table 1). Based on Kyle et al (2007), this population was at high risk for disease progression (PD) with 14 patients having a serum M-spike ≥30 g/l and ≥10% bone marrow plasma cells (BMPC). With the additional high-risk criteria of a serum free light chain (FLC) ratio 8, as defined by Dispenzieri et al (2008), 13 patients were high risk. Of the 7 remaining patients, characterized as intermediate risk by the Dispenzieri criteria, 4 had markedly elevated FLC ratios (range 307–12 357) and one had a 9·2 g urine M-spike and, under current criteria, would be defined as a light chain smouldering MM (>0·5 g/24 h urine M-spike and ≥10% BMPC) (Kyle et al, 2014). Finally, although immunophenotyping was not performed in this study, 16 patients met the high-risk criteria by serum or urine paraprotein criteria alone and the remaining 4 were intermediate risk, as defined by Mateos et al (2013). Of note, many patients met the criteria for active myeloma based on the new IMWG consensus criteria (Rajkumar et al, 2014), including 4 with bone marrow plasmacytosis ≥60% and 10 patients with an involved:uninvolved serum FLC ratio of ≥100, which are associated with 95 and 80% risk of progression at 2 years, respectively. A total of 12 patients had one or both of these criteria. Compliance was excellent and the treatment was well tolerated with only grade 1 nausea. There was one severe adverse event, a pneumococcal pneumonia requiring hospitalisation, which was felt to be unrelated to study treatment. One subject came off study due to non-compliance at Cycle 6 and 2 subjects came off study at Cycles 8 and 51 because they re-located and were no longer able attend follow-up appointments. Patients completed between 2 and 64 cycles. Two patients remained on study at the time of administrative study closure, when they had completed 61 and 64 cycles. The best response to date has been a minimal response (MR) for 5 cycles. A total of 15 patients came off study for PD after a median of 15 cycles (range 2–54). The reasons for PD included hypercalcaemia (n = 1), acute renal insufficiency (n = 1, after 2 cycles with 9·2 g urine M-spike at screening), anaemia (n = 8, 1 after 3 cycles with 90% BMPC at screening), recurrent infections (n = 1), serological PD greater than 25% from baseline (n = 2), and new lytic lesions on magnetic resonance imaging and positron-emission tomography-computed tomography (n = 2). There have been 2 deaths to date, neither while on study treatment. The remaining 18 patients remain alive and therefore the median overall survival has not been reached, with follow-up ranging from 16 to 72 months. The median progression-free survival (PFS) by Kaplan–Meier survival analysis for all patients was 33 months (Figure 1). The median PFS for the 13 high-risk patients based on the criteria of Dispenzieri et al (2008) was 29 months; the median PFS for the 7 intermediate risk patients was not reached. These compare favourably to the expected PFS for these groups of 24 and 60 months respectively (Dispenzieri et al, 2008). The median PFS of the 16 high-risk patients as defined according to Mateos et al (2013) was 28·5 months, which was better than the 21 months observed for the control arm of that study (Mateos et al, 2013). Finally, the median PFS for 12 patients meeting the recent IMWG criteria for active myeloma was 11 months. Four of these patients remain asymptomatic even after a median of 10 years from diagnosis. An additional patient, considered intermediate risk according to Dispenzieri et al (2008), has remained asymptomatic for 7·5 years. TBL-12 was well tolerated in this pilot study of high- and standard-risk ASMM patients, with a median PFS that compares favourably to the expected outcomes of high-risk ASMM patients (Dispenzieri et al, 2008) and the observation group reported by Mateos et al (2013). Larger prospective studies are required to further define the efficacy of TBL-12 in ASMM. Additionally, the absence of death, including in those four patients defined as having active myeloma by IMWG criteria that remained asymptomatic 6 years after study enrollment, further highlights the importance of prospective randomized phase 3 studies to determine if there is any overall survival benefit from early intervention in ASMM. The following authors received research funding from the identified companies: AC from Array BioPharma; AC from Novartis; AC from Millennium/Takeda; AC from Celgene; AC from Amgen-Onyx; AC from Janssen. Drug supply was provided by Unicorn Pacific Corporation (Port Vila, Vanuatu), which manufactures TBL-12. AC provided conceptualization, methodology, validation, formal analysis, investigation, resources, data curation, original draft creation, review and edits of the manuscript, visualization, supervision and project administration of the project. AM provided conceptualization, methodology, review and edits of the manuscript and research investigation of the project. KL provided formal analysis of the data, provision of study materials, research data management and creation of the tables and figures, review and edits of the manuscript, and preparation of the data presentation. DC provided research and investigation process, resources, review and edits of the manuscript, and visualization of the project. ZG provided formal analysis of the data, resources, data management, review and edits of the manuscript and visualization of the project. SJ provided conceptualization, methodology, research and investigation process, review and edits of the manuscript, supervision and funding acquisition of the project. All co-authors gave final approval of the published version. The following authors have served as paid consultants within the past 2 years for the identified companies: AC for Array BioPharma; AC, JS for Novartis; AC, AM for Millennium/Takeda; AC, AM for Amgen-Onyx; AC, AM for Celgene; AC, JS for Janssen; JS for Bristol Myer Squibb, AM for Teva Pharma; AM for Ipsen Biopharm. The following authors have no conflicts to disclose: KL, DC, and ZG.