NovelTherapy with 2-Methoxyestradiol for the Treatment of Relapsed and Plateau PhaseMultiple Myeloma

Purpose: 2-Methoxyestradiol (2ME2) is an endogenous product of estradiol metabolism with antiangiogenic and antineoplastic properties.We report on the first phase II trial of 2ME2 in multiple myeloma. Experimental Design: 2ME2was administeredorally at a dose of1,000mgdaily. Sixty patients (31men and 29women)were treated. After 39 patients were accrued, the dosewas increased to 800 mg twice daily for the remaining patients. Results: Thirty-one patients had relapsed or refractory multiple myeloma, and 29 had plateau phase multiple myeloma. Median age was 60 years (range, 27-84 years). Therapy was well tolerated. Common adverse events included anemia (35%), fatigue (35%), nausea (25%), diarrhea (20%), hot flushes (20%), headache (17%), muscle cramps (15%), and upper respiratory tract infection (15%). Most adverse events were mild (grade1-2); 12% experienced grade 3-4 adverse events. Median time to progression was 3.8 months, with 5.6 months for plateau phase disease and 2.3 months for relapsed multiple myeloma. Estimated progression-free survival rates for all patients at1, 2, and 3 years were 24%,17%, and11%, respectively.Three patients, all with plateau phase disease, have been on study for over 4 years without progression at 50, 60, and 63 months, respectively. Minor response was noted in 2 patients. Conclusions: Although no partial responses have been seen thus far, the minor responses and prolonged stable disease seen with 2ME2 therapy are promising. Plasma levels indicate that the dose of 2ME2was inadequate. A new formulationwithbetter bioavailability will be tested soon in multiple myeloma. Multiple myeloma is a clonal plasma cell proliferative disorder that remains incurable in most patients (1). Significant advances have occurred in the biology and treatment of myeloma in the last decade (2). However, despite the use of conventional chemotherapy (3), autologous stem cell transplantation (4, 5), and newer highly effective agents including thalidomide, bortezomib, and lenalidomide (6–11), most patients still relapse and succumb to their myeloma. There is thus a significant and continuing need for novel, relatively nontoxic and active agents for the treatment of the disease. 2-Methoxyestradiol (2ME2) is a natural metabolite of the endogenous estrogens 17h-estradiol and 2-hydroxyestradiol (12–14). It has shown promising antitumor effects in preclinical studies (15). 2ME2 directly induces tumor cell apoptosis (16) in addition to also possessing potent antiangiogenic properties (12, 17–19). Because angiogenesis is increased in myeloma, and given the dual antitumor and antiangiogenic properties of 2ME2, we hypothesized that the agent may be of therapeutic benefit in this disease. In preclinical studies, 2ME2 has shown direct antitumor activity on myeloma cell lines and primary myeloma cells by induction of apoptosis and G2-M cell cycle arrest (20). In addition, it has shown the ability to overcome drug resistance in myeloma cells (21). I.p. injection of 2ME2 suppresses myeloma xenograft growth in murine models, an effect that is sustained even after cessation of therapy (20). The goal of this phase II clinical trial was to determine the efficacy and safety of 2ME2 in patients with relapsed or plateau phase multiple myeloma.