A Phase I/II Study of TACI-Ig To Neutralize APRIL and BLyS in Patients with Refractory or Relapsed Multiple Myeloma or Active Previously-Treated Waldenström’s Macroglobulinemia.

Background: APRIL (A Proliferation-Inducing Ligand) and BLyS (B Lymphocyte Stimulator) are potent survival factors for normal B cells and are over-expressed in plasma cell malignancies. BLyS binds to 3 members of the TNF-R family of receptors, TACI, BCMA and BAFF-R, whereas APRIL binds to TACI and BCMA and also to heparan sulfate proteoglycans such as syndecan-1, which is expressed by most plasma cells. APRIL and BLyS are produced by the malignant myeloma cells themselves, as well as by cells within the tumor environment, resulting in the enhanced survival of the malignant cells via both an autocrine and paracrine loop. In vitro, a blockade of BLyS and APRIL has been shown to induce myeloma-cell apoptosis. In the present clinical trial we have used a soluble receptor fusion protein comprised of the extracellular domain of TACI and the Fc portion of a human IgG (TACI-Ig) to neutralize both APRIL and BLyS in patients with multiple myeloma (MM) or Waldenström’s macroglobulinemia (WM). The aim was to determine the tolerability, the pharmacokinetics (PK), the pharmacodynamics and the biological activity of TACI-Ig.

Methods: The trial is an open-label, dose-escalation study followed by a classical Simon 2-stage trial designed to determine the maximum tolerated dose as well as the optimal biologic dose of TACI-Ig, in patients with refractory or relapsed MM or active WM. Eligible patients are enrolled in sequential cohorts to receive five weekly subcutaneous injections of TACI-Ig at 2, 4, 7 or 10 mg/kg. Patients who demonstrate at least stable disease after the first cycle are allowed to receive 2 additional treatment cycles. PK is assessed after the 1st and 5th dosing. Usual safety parameters are assessed, including measurement of potential anti-TACI-Ig antibodies. The biological activity assessment comprises M-protein, beta 2-microglobulin, soluble syndecan-1, lymphocyte subpopulation counts (by flow cytometric analysis), polyclonal immunoglobulins, serum and urinary free light chains and CRP. Evaluation of response is assessed using modified Bladé criteria at the end of cycles 1 and 3.

Results: Preliminary results of the first 3 cohorts of the dose-escalation study are reported. Six MM patients and 3 WM patients have entered the trial. No dose limiting toxicity has been observed and no SAE related to study drug has been reported to date. Mild injection site erythema (1 patient) is the only drug-related toxicity reported to date. Two MM patients and 1 WM patient demonstrated a stabilization of disease through the end of the third cycle, 3 MM patients and 1 WM patient demonstrated progressive disease after the first cycle and 1 MM and 1 WM patient have not been fully evaluated yet. Polyclonal immunoglobulins in 6/9 (5 MM and 1 WM) patients and soluble syndecan-1 in 2/5 MM patients show a decrease during treatment, while CRP levels are not affected.

Conclusions: Treatment with TACI-Ig was well tolerated at the dose levels tested so far. A biological response in accordance with the expected TACI-Ig mode of action is observed in this heavily treated refractory population. Accrual of patients at higher dose levels is ongoing and will be presented.