A Phase II Trial of TBL12 Sea Cucumber Extract in Patients with Untreated Asymptomatic Myeloma

Background:

There is currently no standard therapy for patients with asymptomatic multiple myeloma. Lenalidomide/dexamethasone has been studied in a phase III trial of high-risk patients with asymptomatic or “smoldering” myeloma; this regimen was found to delay time to progression and improve survival rates with mild to moderate toxicity, including DVT and myelosuppression. In this trial, the median time to progression was found to be 21 months in the control group.

TBL12 sea cucumber extract has been shown to have a number of antitumor properties, including anti-angiogenesis and direct tumor cytotoxicity. In our independent cytotoxicity assays using cell culture models of human myeloma cells, TBL12 effectively reduced myeloma cell growth in a dose-dependent manner with minimal toxicity and appeared to induce a programmed cell death based on cellular changes seen (i.e. nuclear condensation). Based on these preclinical results, we sought to investigate the efficacy and toxicity of TBL12 in delaying the progression of asymptomatic multiple myeloma in an FDA-sponsored clinical trial.

Methods:

Twenty patients were enrolled in the study. TBL12 was administered orally at a dose of 2 units (of 20 mL each) twice a day, in 4 week cycles, until disease progression. Disease progression was determined according to standard International Myeloma Working Group criteria. The primary endpoint was the median duration of response, defined as the median amount of time that the patients received the TBL12 medication.

Results:

Of the 20 patients enrolled in the study, 5 patients were taken off the TBL12 protocol due to either personal choice or noncompliance. Among the remaining 15 patients, the length of follow-up ranged from 8.5 months to 31 months, with a median follow-up period of 21 months. The trial was stopped in December 2013. Five of the patients developed progressive disease while receiving TBL12; four of these patients developed new lytic bone lesions and one patient progressed by paraprotein measurement. Including all original 20 patients in the study, the median duration of response was 19.75 months. Excluding the 5 patients who were taken off the TBL12 protocol due to either personal choice or noncompliance, the median duration of response was 21 months.

Toxicities observed during the trial were mostly grade 1 or 2 and were generally unrelated to the medication. There were two grade 3 adverse events: one chest pain episode that was unlikely to be related to the medication and one cellulitis episode that was unrelated to the medication. Examples of grade 2 toxicities included: anxiety/depression, fatigue, tooth infection, leukopenia, vaginal infection, lower back pain, rib pain, sinus infection, bronchial infection, and pneumonia. Examples of grade 1 toxicities included: dizziness, joint pains, colds (URIs), flu, stomach pain, fatigue, headaches, nausea, tremor, tingling, radicular pains, weakness and diarrhea. There were no grade 4 adverse events observed. None of the patients died while receiving TBL12. The patients reported improvement in quality of life measures, which will be discussed.

Conclusions:

TBL12 may be a promising therapeutic agent in halting the progression of asymptomatic multiple myeloma. In vitro correlations of response with marrow T cell subsets, cytokines and angiogenesis are ongoing and will be presented. Given the minimal toxicities associated with this drug, additional studies to further elucidate the time to progression, response patterns, and overall survival rates associated with TBL12 in asymptomatic multiple myeloma patients would be worthwhile.