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

The sphingolipids/glycosides in sea cucumbers have several antitumour properties (Zou et al, 2003) including antiangiogenesis (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 I). 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 <0 125 or >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 tomographycomputed 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 correspondence