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Clinical Cancer Research 13, 6162, October 15, 2007. doi: 10.1158/1078-0432.CCR-07-0807
© 2007 American Association for Cancer Research
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Cancer Therapy: Clinical

Novel Therapy with 2-Methoxyestradiol for the Treatment of Relapsed and Plateau Phase Multiple Myeloma

S. Vincent Rajkumar1, Paul G. Richardson2, Martha Q. Lacy1, Angela Dispenzieri1, Philip R. Greipp1, Thomas E. Witzig1, Robert Schlossman2, Carolyn F. Sidor3, Kenneth C. Anderson2 and Morie A. Gertz1

Authors' Affiliations: 1 Division of Hematology, Mayo Clinic, Rochester, Minnesota; 2 Dana-Farber Cancer Institute, Boston, Massachusetts; and 3 EntreMed, Rockville, Maryland

Requests for reprints: S. Vincent Rajkumar, Division of Hematology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905. Phone: 507-538-0591; Fax: 507-266-4972; E-mail: rajks{at}mayo.edu.


   Abstract
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 Abstract
Patients and Methods
 Results
 Discussion
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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: 2ME2 was administered orally at a dose of 1,000 mg daily. Sixty patients (31 men and 29 women) were treated. After 39 patients were accrued, the dose was 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 (grade 1-2); 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 at 1, 2, and 3 years were 24%, 17%, and 11%, 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 2ME2 was inadequate. A new formulation with better 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 17ß-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.


   Patients and Methods
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Eligibility. Patients were eligible to enter on the study if they had previously treated symptomatic myeloma in relapse or in plateau phase. To be considered plateau phase, patients must have been previously treated with at least one conventional or high-dose chemotherapy regimen, be off all therapy for at least 4 weeks, and have M-protein concentrations that are stable (<20% variations) for at least 4 weeks before registration. Patients were required to have monoclonal bone marrow plasma cells, measurable disease defined as serum monoclonal protein >10 g/L, and urine monoclonal protein ≥200 mg/24 h. Patients also needed to have hemoglobin >70 g/L, platelet count >25 x 109/L, absolute neutrophil count >0.75 x 109/L, bilirubin and creatinine less than twice the upper limit of normal, aspartate aminotransferase and alanine aminotransferase <2.5 times the upper limit of normal, alkaline phosphatase <5.0 x upper limit of normal, international normalized ratio or prothrombin time ≤1.2, and activated partial thromboplastin time within normal limits. Patients with active infection, uncontrolled heart failure, or other serious medical or psychiatric illness, another active malignancy with the exception of superficial skin carcinoma, or Eastern Cooperative Oncology Group performance score of 3 or 4 were excluded. Also excluded were patients who had undergone major surgery within 21 days of starting therapy and patients with myocardial infarction or with symptomatic uncontrolled coronary disease within 3 months before registration. Pregnant or nursing women were not eligible for the study. Women of child-bearing potential needed to agree to use effective barrier contraceptive methods during study; a serum pregnancy test within 72 h before the initiation of 2ME2 therapy was required for women of child-bearing potential. Patients were required to be at least 18 years of age. The study was approved by the Mayo Clinic and the Dana-Farber Cancer Institute Institutional Review Boards in accordance with federal regulations and the Declaration of Helsinki. All patients gave written informed consent.

Treatment schedule. 2ME2 was administered orally at a dose of 1,000 mg daily. After the first 39 patients were accrued, based on the results of other ongoing phase I trials (22), the protocol was amended and the dose of 2ME2 was increased to 800 mg twice daily for the remaining patients. Patients from the initial cohort who were on study at that point were also allowed to escalate the dose to 800 mg twice daily (n = 9). The treatment cycle length was 28 days; cycles were repeated every 4 weeks until disease progression or unacceptable toxicity. Concurrent use of corticosteroids, chemotherapy, or other antimyeloma therapy was not permitted. Patients were allowed to be treated with chronic low-dose steroids (to a maximum of 10 mg of prednisone a day, or equivalent) if they were given for disorders other than myeloma (e.g., adrenal insufficiency or rheumatoid arthritis). Bisphosphonates and erythropoietic agents were permitted.

Response and toxicity criteria. The response criteria used were standard Eastern Cooperative Oncology Group criteria (10); as a modification, a category of minor response was also defined. An objective response was defined as a ≥50% decrease in the serum and urine monoclonal protein levels from baseline. Patients with measurable disease only in the urine needed to have a >90% reduction in 24-h urine monoclonal protein excretion to be considered a response. For objective response criteria to be met, there had to be no new bone lesions, no increase in existing lytic lesions, no recurrence or persistence of hypercalcemia, no increase in any existing plasmacytomas, and no new plasmacytomas. For patients in whom serum monoclonal protein levels were felt unreliable, as in the case of small ß migrating paraproteins, the appropriate serum immunoglobulin levels were used. A complete response was defined as a complete disappearance of the monoclonal protein in the serum and urine by immunofixation studies and 3% or fewer plasma cells on bone marrow examination. Patients seeming to meet complete response criteria except for the lack of repeat bone marrow examination, presence of >3% plasma cells, or clusters of plasma cells on bone marrow examination were considered to have near complete response. Meeting objective response criteria, but not the criteria for complete response or near complete response, was defined as partial response. Disease that does not satisfy the criteria for response, complete response, or progression was classified as no response. Among nonresponders, patients with a >25% reduction in serum or urine monoclonal protein levels were considered as having minor response. All responses needed to be confirmed at least 2 weeks apart by two consecutive determinations.

Disease progression required two of the following four criteria: (a) increase in serum monoclonal protein ≥50% above the lowest response level, or a increase in level by >2 g/dL; (b) increase in urine monoclonal protein by 50% above the lowest remission value, or increase in excretion by ≥2 g/24 h; (c) increase in size of soft tissue plasmacytoma by >50%; and (d) definite appearance of bone lesions, or increase in the size of existing bone lesions by >50%.

The National Cancer Institute Common Terminology Criteria for Adverse Events, version 2, was used to grade adverse events as well as to assign perceived attribution of these events to the study treatment regimen. By these criteria, toxicity was defined as an adverse event considered being possibly, probably, or definitely related to treatment.

Statistical design and analysis. All efficacy and toxicity analysis were conducted on an intent to treat basis. The primary end point of this trial was objective response. This trial was designed with a one-stage design to accrue 60 patients to assess the response rate and safety of 2ME2 in the setting of relapsed and plateau phase multiple myeloma. Ninety-five percent confidence intervals for the objective response probability were calculated using exact binomial 95% confidence intervals. The Fisher exact test was used to compare differences in nominal variables. For continuous variables, the Wilcoxon rank-sum test was used for unpaired comparisons and the Wilcoxon signed rank test was used for paired comparisons. The Kaplan-Meier method was used to estimate overall survival, progression-free survival, and time to progression (23). Progression-free survival was defined as time from start of the treatment to disease progression or death. Time to progression was defined as time from start of treatment to disease progression, with deaths due to causes other than progression censored (24). The maximum grade for each type of adverse event along with perceived causality was recorded and reported for each patient. Toxicity incidence was estimated and summarized using frequency and descriptive techniques.


   Results
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 Patients and Methods
 Results
Discussion
 References
 
Sixty patients (31 men and 29 women) were registered to the study from February 6, 2001 through March 10, 2005, and all were evaluable for response and toxicity. Thirty-six patients were treated at Mayo Clinic and 24 at Dana-Farber Cancer Institute. Median age was 60 years (range, 27-84 years). Thirty-one patients had relapsed or refractory myeloma and 29 had plateau phase disease. Additional patient characteristics at study entry are presented in Table 1 .


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  		Table 1. Patient characteristics

 
Response to therapy. Fifty-five patients have gone off study and five remain on therapy. Reasons for discontinuing study therapy included disease progression (46 patients), toxicity felt to be possibly related to therapy (4 patients), patient preference (4 patients), and death on study (1 patient; reported as unrelated to study medication).

Median time to progression was 3.8 months; 5.6 months for plateau phase disease and 2.3 months for relapsed myeloma (Fig. 1A ). Estimated progression-free survival rates for all patients at 1, 2, and 3 years were 24%, 17%, and 11%, respectively (Fig. 1B). Three patients, all with plateau phase disease, have been on study for more than 4 years without progression at 50, 60, and 63 months, respectively. A further two patients, both with plateau phase disease, have each been on study for >3 years and >18 months, respectively. Additionally, 17 patients were on study for at least 6 months (28%), 10 for at least 1 year (17%), and 6 for at least 2 years (10%). Thus far, no partial responses have been seen and 2 (3%) patients, both with plateau phase disease, met criteria for minor response (Table 2 ).


Figure 1
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  		Fig. 1. Kaplan-Meier estimate of time to progression (A) and progression-free survival (B) on 2ME2 therapy for relapsed and plateau phase myeloma.

 

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  		Table 2. Best confirmed response to therapy

 
Adverse effects. 2ME2 was well tolerated with minimal attributable toxicity. Five patients withdrew from study due to adverse events (hypertension, seizure, transient ischemic attack, small bowel obstruction, and renal insufficiency); these adverse events were either not associated or of unknown association with study drug. One patient died on study (due to hyperkalemia, encephalopathy, myocardial infarction, and disease progression), which was not considered to be treatment related. Major adverse events seen in this trial, reported in 5% or more of all patients, regardless of grade, are listed in Table 3 and represent the most severe toxicity associated with each patient. 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 (grade 1-2); grade ≥3 adverse events occurred in 12% of patients (Table 3).


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  		Table 3. Major hematologic and nonhematologic adverse events

 
Among patients with elevated liver enzymes, four patients had elevated aspartate aminotransferase (two with grade 1-2, two with grade 3) and alanine aminotransferase (one with grade 1, two with grade 3, and one with grade 4), whereas four patients had only elevated aspartate aminotransferase (all grade 1-2) and one patient had only elevated alanine aminotransferase (grade 1). Elevated liver enzymes were reversible, resolving to grade 1 or less at time of study termination in all but one patient. In one patient, elevated enzymes resolved to grade 1 when dose was held, but returned to grade 2 (aspartate aminotransferase) and grade 3 (alanine aminotransferase) with resumption of drug.

Plasma drug levels. Plasma drug levels were assessed in 33 patients. In these patients, 2ME2 and 2ME1 levels were measured before the daily dose (nadir level). The nadir levels were between 1 and 2 ng/mL for 2ME2. 2ME1 levels were between 8 and 20 ng/mL (PPD). No significant change was seen with the dose escalation to 800 mg twice daily.


   Discussion
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 Abstract
 Patients and Methods
 Results
 Discussion
References
 
Recent advances in myeloma therapy have shown the benefit of targeting both the myeloma cell and its microenvironment (25, 26). Bone marrow angiogenesis is a major microenvironmental factor that is felt to be important for myeloma cell growth and survival (27). Increased angiogenesis is characteristic of progressive myeloma and is associated with disease stage (28), plasma cell proliferative rate (27), and prognosis (29). 2ME2 is a novel estrogen metabolite that is directly cytotoxic to myeloma cells and has potent antiangiogenic properties, but is without myelosuppression or neurotoxicity (20, 21). These features make 2ME2 an attractive therapeutic candidate for myeloma.

We show in this phase II trial that 2ME2 is safe and well tolerated. Although no partial responses were observed, prolonged stable disease in some patients with plateau phase myeloma is promising. Importantly, no significant neuropathy, myelosuppression, or thromboembolic disease was seen with 2ME2 therapy. Indeed, the side effect profile was remarkably benign, with the added advantage of treatment being administered orally.

This trial was launched at a time when antiangiogenic strategies for hematologic malignancy were still early in terms of clinical trial design. In retrospect, the trial offers valuable lessons that now may seem more obvious when testing antiangiogenic strategies in relapsed myeloma patients. Although angiogenesis was a target, we lacked a clear biomarker to determine whether or not the dose administered was having an adequate effect on the target. As a result, it is difficult to determine in this study whether the lack of major response is related to inadequate dose, insignificant pharmacologic activity of the agent in myeloma, or low bioavailability. In future studies, biomarkers of 2ME2 effect, such as up-regulation of the expression of death receptor 5 protein, will be incorporated (30).

Based on pharmacokinetic studies, we hypothesize that the primary reason that major responses were not observed in this study is most likely related to the low bioavailability of the preparation of 2ME2 used in this trial. The levels achieved in this study (1-2 ng/mL) were >10-fold lower than concentrations needed to cause apoptosis and growth arrest in in vitro models (20). We believe that the low concentrations achieved were related to poor bioavailability of the formulation, and that it could not be solved by increasing the administered dose. These findings are similar to another trial that used the same formulation in which steady-state AUC and trough concentrations of 2ME2 increased linearly up to 400 to 600 mg/d, but doses above 400 to 600 mg/d did not produce any meaningful increase in 2ME2 levels (31). A similar finding has also been observed in a phase II study of 2ME2 in prostate carcinoma, lending support to this hypothesis (32). In murine xenograft models, we used a more bioavailable liposomal preparation of 2ME2 and observed major antimyeloma effects (20). A new formulation of 2ME2 with 5- to 10-fold better bioavailability has been identified. Phase I studies have been completed, and phase II studies are being initiated in various tumor types including myeloma.

The mechanism of the antitumor and antiangiogenic activities of 2ME2 that occur in the setting of relatively minimal effects on normal cells has been studied intensely, resulting in the description of several specific effects (33). The apoptotic and antiangiogenic effects of 2ME2 have been shown to be related to its ability to up-regulate expression of death receptor 5, activate caspases, and destabilize microtubules through binding to the colchicine binding site and, subsequently, down-regulate hypoxia-inducible factor 1{alpha} and downstream proangiogenic factors and to its capacity to generate reactive oxygen species (30, 34–39). 2ME2 also sensitizes cancer cells to Fas-mediated apoptosis (40). Additionally, 2ME2 treatment of tumor cell lines causes down-regulation of cyclin D1 by disrupting the binding of activating transcription factor 2 to cyclin D1 promoter (41). This property is of particular importance in myeloma because up-regulation of cyclins is hypothesized as a universal occurrence that functions as the main driver of plasma cell proliferation (26). Finally, 2ME2 has also been shown to inhibit osteoclast differentiation and induce apoptosis, a property that is of relevance to multiple myeloma (42).

2ME2 is a promising antineoplastic agent with properties that make it of considerable interest for the treatment of myeloma. As shown in this phase II trial, 2ME2 therapy is well tolerated in the treatment of relapsed and plateau phase myeloma. The unexpectedly long periods of stable disease in a subset of patients despite the use of a suboptimal and less bioavailable version of the drug is of significant interest and justifies the need for further clinical investigation with 2ME2 in myeloma using a formulation with improved bioavailability. Combination approaches warrant study as do maintenance strategies, and novel 2ME2 analogues being developed are also of interest (43).


   Acknowledgments
 
We thank Cato Research, Durham, NC, for providing assistance with data analysis.


   Footnotes
 
Grant support: EntreMed; National Cancer Institute grants CA93842, CA100080, CA62242, CA50947, and CA78378; Doris Duke Distinguished Clinical Research Award (K.C. Anderson); the Multiple Myeloma Research Foundation; and the Leukemia and Lymphoma Society.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 4/ 6/07; revised 7/17/07; accepted 8/ 8/07.


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 Abstract
 Patients and Methods
 Results
 Discussion
 References
 

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