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Version of Record online: 22 SEP 2010
Copyright © 2010 American Cancer Society
Volume 117, Issue 2, pages 336–342, 15 January 2011
How to Cite
Niesvizky, R., Ely, S., Mark, T., Aggarwal, S., Gabrilove, J. L., Wright, J. J., Chen-Kiang, S. and Sparano, J. A. (2011), Phase 2 trial of the histone deacetylase inhibitor romidepsin for the treatment of refractory multiple myeloma. Cancer, 117: 336–342. doi: 10.1002/cncr.25584
This article is a U.S. Government work and, as such, is in the public domain in the United States of America.
Presented in part at the 2005 American Society of Hematology Meeting; December 5-8, 2005; New Orleans, Louisiana.
The authors thank Mr. David Jayabalan for his help in the production of the artwork.
- Issue online: 5 JAN 2011
- Version of Record online: 22 SEP 2010
- Manuscript Accepted: 29 JUN 2010
- Manuscript Revised: 18 MAY 2010
- Manuscript Received: 24 MAR 2010
- histone deacetylase;
- phase 2
Epigenetic dysregulation is a hallmark of cancer, including multiple myeloma. Inhibitors of histone deacetylases (HDACs) induce DNA hyperacetylation by inhibiting removal of acetyl groups from amino tails on histone proteins, thereby uncoiling condensed chromatin favoring transcription of silenced genes, including tumor suppressor genes. Romidepsin is an HDAC inhibitor that exhibits antiproliferative and apoptotic effects against multiple myeloma cell lines.
A phase 2 trial was performed of romidepsin in patients with multiple myeloma who were refractory to standard therapy. Treatment was comprised of romidepsin (13 mg/m2) given as a 4-hour intravenous infusion on Days 1, 8, and 15 every 28 days). Thirteen patients received a median of 2 cycles of therapy (range, 1-7 cycles).
Although no patients had an objective response, 4 of 12 patients with secretory myeloma exhibited evidence of M-protein stabilization, and several other patients experienced improvement in bone pain and resolution of hypercalcemia.
The results of the current study demonstrate that romidepsin, as a single agent, is unlikely to be associated with a response rate of ≥30% in patients with refractory myeloma, although there was some clinical evidence suggesting a biological effect associated with therapy. Cancer 2011. Published 2010 by the American Cancer Society.
Multiple myeloma (MM) is a clonal plasma cell neoplasm in which malignant cells are arrested at various stages of cell differentiation.1 The identification of novel oncogenes, chromosomal breakpoints, and immunoglobulin gene translocations has led to improved classification and understanding of the pathogenesis of the disease.2 Agents that can modify or regulate the expression of both established and newly discovered oncogenes involved in the clinical course and development of MM may be essential in defining new targets for treatment.3
Recent evidence suggests that the epigenome, which regulates gene expression, may be a promising therapeutic target in MM. Indeed, epigenomic dysregulation of DNA methylation and histone acetylation is a hallmark of cancer, including MM.4-6 Acetylation of histones allows the chromatin structure surrounding the protein to relax, thereby enabling gene transcription. In contrast, histone deacetylation results in tightly wound and compact chromatin, which impedes transcription. Histone deacetylase (HDAC) inhibitors induce DNA hyperacetylation by inhibiting removal of acetyl groups from amino tails on histone proteins, thereby de-repressing silenced genes, including tumor suppressor genes. HDAC is a validated therapeutic target, because the HDAC inhibitors vorinostat and romidepsin are approved for the treatment of cutaneous T-cell lymphoma.7 In addition, other HDAC inhibitors, including panobinostat, have also reported positive effects in this malignancy.8-10 The HDAC inhibitor vorinostat has been shown to induce differentiation and apoptosis of human MM cells,11 possibly by means of modulation of multiple targets including the insulin-like growth factor (IGF)/IGF-1 receptor and interleukin-6 receptor, antiapoptotic molecules, oncogenic kinases, DNA synthesis/repair enzymes, and transcription factors.12 HDAC inhibitors such as vorinostat also enhance the effectiveness of standard MM therapies, including bortezomib, dexamethasone, cytotoxic chemotherapy, and thalidomide analogs.11
Romidepsin (formerly known as despipeptide, FR901228, or FK228) is a cyclic peptide HDAC inhibitor that has been shown in vitro to induce apoptosis by down-regulation of the BCL-2 family of proteins (BCL-XL and MCL-1), and induce G1 cell cycle arrest (by enhancing expression of p21 and p53).13 Phase 1 to 2 trials have shown that romidepsin is effective for the treatment of cutaneous and peripheral T-cell lymphomas.9, 10, 14, 15 The dosage of romidepsin in its phase 1 trial was 1 to 24.9 mg/m2; dose-limiting toxicities included fatigue, nausea, vomiting, thrombocytopenia, and cardiac arrhythmia.15 At the recommended phase 2 dose of 17.8 mg/m2, romidepsin increased histone acetylation in patient-derived peripheral blood mononuclear cells, and also altered cell cycle kinetics of PC3 cells in culture.15 Although the recommended phase 2 dose was initially 17.8 mg/m2 given over 4-hour infusion on Days 1 and 5 of a 21-day cycle, a subsequent amendment to the phase 2 protocol recommended dose reduction to 13 to 14 mg/m2 on Days 1, 8, and 15 every 28 days due to better patient tolerability.16 Based on the aforementioned data, we designed a phase 2 trial to evaluate the efficacy, safety, and biologic effects of romidepsin monotherapy in patients with refractory or recurrent MM to provide a framework for integration of romidepsin with other standard therapies.
MATERIALS AND METHODS
Eligibility criteria included patients with recurrent and/or refractory stage IIa to IIIa MM who had received at least 2 prior lines of therapy. Other criteria included Karnofsky performance score of at least 70%; age ≥18 years; and adequate bone marrow (leukocyte count ≥3000/μL, neutrophil count ≥1500/μL, and platelet count ≥100,000/μL), hepatic (total bilirubin <2.0 mg/dL, and aspartate aminotransferase/alanine aminotransferase ≤2.5-fold the upper limits of normal), renal (serum creatinine ≤1.5 mg/dL or creatinine clearance ≥60 mL/min/1.73 m2), and cardiac (left ventricular ejection fraction ≥50% and normal electrocardiogram) function. Prior chemotherapy or radiotherapy was permitted if administered >4 weeks before enrollment (6 weeks for nitrosoureas or mitomycin C). Patients with a history of prior treatment with an HDAC inhibitor or an uncontrolled intercurrent illness (including cardiac arrhythmias) were excluded.
Patients received romidepsin at a dose of 13 mg/m2 as a 4-hour infusion on Days 1, 8, and 15 of a 28-day cycle. All patients were treated for at least 4 weeks, or equivalently, for at least 1 full cycle of treatment. After the first cycle, patients with progressive disease were discontinued from the study and all others proceeded to the next 4-week cycle. A maintenance regimen of romidepsin every other week (Days 1 and 15) was permitted for those reaching a stable plateau (±25% serum M-protein levels or urine protein excretion over 3 consecutive determinations, each at least 4 weeks apart). Treatment continued until the occurrence of disease progression, an adverse event requiring discontinuation, or withdrawal of patient consent. All patients received 8 mg of ondansetron for antiemetic prophylaxis at 1 hour before and every 8 hours thereafter for 24 to 48 hours after romidepsin infusion. Additional antiemetic treatment was administered based on patient symptoms. Thrombocytopenia was treated conservatively; in the absence of bleeding, platelet transfusions were administered only if the platelet count was <10,000/mm3. If the patient developed bleeding, platelet transfusions were administered in accordance with standard practice, to maintain a platelet count of ≥50,000/mm3. Potassium and magnesium were administered before romidepsin administration for patients who were either below normal or in the low to normal range of serum levels of these electrolytes.
Baseline and Follow-Up Evaluation
Evaluation before beginning protocol therapy included multiple gated acquisition scanning/radionuclear cardiac angiography, skeletal survey, chest x-ray, complete serum and urinary protein electrophoresis and immunofixation, quantitation of serum immunoglobulin and free light chains levels, and 24-hour urinary protein excretion. Laboratory values were obtained at screening, weekly during study participation, and at follow-up and included complete blood count/differential, full serum chemistries, troponin I levels (or creatine kinase isoenzymes, if available), and electrocardiography. Response to treatment was determined by standard criteria for complete response, near-complete response, partial response, stable disease, and progressive disease of MM.17 All patients who completed at least 1 cycle were assessed for response to treatment. Measurable disease was defined as ≥1.0 g/dL serum monoclonal protein, ≥0.1 g/dL serum-free light chains, ≥0.2 g/24-hour urinary M-protein excretion, and/or measurable plasmacytomas. Criteria for primary response were adopted from the European Group for Blood and Marrow Transplant/International Bone Marrow Transplant Registry/Autologous Blood and Marrow Transplant Registry of North America (EBMT/IBMTR/ABMTR)18 and international uniform response criteria for MM.17
The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) (version 3.0) was used to grade adverse events. Toxicity was defined as an adverse event possibly, probably, or definitely related to the study treatment. Data from all subjects who received any study drug were included in the safety analysis. The frequency of subjects experiencing a specific adverse event was tabulated.
Bone marrow aspirates (5-10 mL) and biopsy specimens were collected from 3 consenting patients at baseline, 24 hours after the first treatment, and 28 days after the first treatment for correlative studies. The samples underwent Ficoll separation, with CD138+ plasma cells selected by radiolabeled microbeads. Phenotype analysis was performed by immunohistochemistry for CD138/Ki-67 proliferation index, fibroblast growth factor receptor 3, CD31 (platelet endothelial cell adhesion molecule), and cleaved caspase 3.
Statistical Objectives and Statistical Plan
The primary objectives of the study were to evaluate the safety and efficacy of romidepsin as a therapy for patients with advanced refractory or recurrent MM. The study was designed to distinguish between a response rate of ≤10% versus ≥25%. The optimal 2-stage design of Simon was used, in which the probability of a type I error and the probability of a type II error were both set at 10%. If ≤3 responses occurred during the initial phase, accrual would be terminated. If there were ≥8 total responses reported among the patients, the study would be considered promising. The trial was halted after accrual of 13 patients when no objective responses were noted. A post hoc analysis indicated that it was unlikely that the response rate would exceed 30% (type I and II error rates of 10%).
Informed Consent and Regulatory Approval
The study was reviewed and approved by the Cancer Evaluation Therapy Program of the National Cancer Institute (P65996) and by the institutional review board at each participating institution (Clinical Trials.gov identifier NCT00066638). All patients provided written informed consent.
Thirteen patients were enrolled at 3 participating institutions between December 2003 and May 2006. The characteristics of the patient population are shown in Table 1. All patients had evidence of disease progression before enrollment. The median age was 57 years (range, 54-74 years), the median disease duration was 6 years (range, 2.3-11.3 years), and the median number of prior treatment regimens was 3 (range, 2-4), including 9 patients (69%) who had had a prior stem cell transplantation, 9 patients (69%) who had received thalidomide (N = 8) or lenalinomide (N = 1), and 6 patients (46%) who had received prior bortezomib. Pretreatment fluorescence in situ hybridization in 10 patients identified 2 patients with del 13q14 (including 1 with t(11;14)), 1 with tetrasomy 11, 1 with trisomy 11, and 6 with no abnormalities. Conventional cytogenetics identified 1 patient with inversion in chromosome 9.
|Median age (range), y||57 (45-73)|
|Median no. of y since initial diagnosis (range)||6 (2.3-11.3)|
|Median no. of prior therapies (range)||3 (2-4)|
|Prior therapy, no. of patients|
|Stem cell transplantation||9 (69%)|
|M-protein, no. of patients|
|IgG kappa||6 (46%)|
|IgG lambda||5 (38%)|
|Light chain lambda||1 (8%)|
Treatment Administration and Efficacy
Thirteen patients received an aggregate total of 27 treatment cycles; the median number of cycles given was 2 (range, 1-7 cycles). Reasons for discontinuation of therapy included disease progression in 6 patients (46%), an intercurrent bone fracture requiring surgery in 1 patient (8%), and patient withdrawal in 6 patients (46%) due to lack of response. Twelve of 13 patients were assessable for response by serum protein electrophoresis, urine protein electrophoresis, or free light chain measurement, which were obtained both at baseline as well as after each cycle of treatment; 1 patient had nonsecretory disease. No patients met the criteria for objective response. Four patients (31%; 95% confidence interval, 9%-61%) exhibited stabilization of M-protein levels during therapy (Fig. 1). There was no consistency in therapy preceding romidepsin indicative of a priming effect; the preceding treatment included bortezomib (Patient 1), thalidomide plus clarithromycin (Patient 2), melphalan (Patient 3), and LymphoRad-131 (Patient 11). Five patients demonstrated clinical benefit with improvement of hypercalcemia, and 2 patients reported improvement of pain. Nevertheless, the trial was halted after accrual of 13 patients because it was statistically unlikely that the objective response rate would exceed 30%.
In 3 patients who exhibited M-protein stabilization, we evaluated bone marrow samples before therapy, 24 hours after the first romidepsin treatment, and 28 days after the first treatment, at which point patients would have been exposed to a total of 3 romidepsin infusions. Cell cycle marker evaluation in CD138+ selected plasma cells revealed no detectable alteration in cell cycle kinetics in vivo (Fig. 2). In addition, evaluation of BCL-2, MCL-1, CD31, and cleaved caspase 3 revealed no detectable modulation in vivo (Fig. 3).
There were no grade 4 adverse events reported. Grade 3 thrombocytopenia occurred in 3 patients (23%). The most common adverse events included grade 1 to 2 nausea in 7 patients (54%), grade 2 fatigue in 4 patients (31%), and grade 2 taste alteration in 1 patient (8%). Of the 27 cycles administered, 22 were given at full dose, and 5 doses were given at a reduced dose in 5 patients. Electrocardiographic changes were common but clinically insignificant, including asymptomatic and reversible QT interval prolongation, ST segment depression, and T wave inversion. All these cardiac conduction abnormalities have been previously described with romidepsin therapy.19
We evaluated the HDAC inhibitor romidepsin in heavily pretreated patients with MM who were refractory to multiple therapies, often including stem cell transplantation, thalidomide, and bortezomib. Although no patients achieved an objective response, approximately 30% of patients exhibited stabilization of M-protein production, indicating a biologic effect. Several patients also exhibited resolution of hypercalcemia or improvement in bone pain, also potentially indicative of a biologic effect. Romidepsin did not appear to modulate apoptosis or cell cycle kinetics in vivo, even in those patients who exhibited serum M-protein stabilization. Even with this demonstrated clinical activity, it still appears that romidepsin monotherapy is unlikely to produce a significant objective response (in terms of M-protein reduction) in patients with refractory myeloma.
Numerous reports indicate that several HDAC inhibitors have significant antineoplastic effects in myeloma cell lines, including vorinostat,11 romidepsin,13 LAQ824,20 and R306465.21 However, to the best of our knowledge, our experience represents only the third report evaluating the clinical activity of an HDAC inhibitor as single agent in patients with MM. Richardson et al reported a phase 1 trial of vorinostat at various doses and schedules in 13 patients with refractory myeloma; 1 patient exhibited a minor response and 9 patients were reported to have stable disease.22 Gimsing et al reported disease stabilization in 1 patient with myeloma treated with the HDAC inhibitor belinostat (PXD101).23 The results of the current trial are consistent with these reports, indicating that HDAC inhibitors do not induce tumor regression, but do appear to induce some biological effects that may have clinical relevance.
Romidepsin and other HDAC inhibitors have been shown to enhance the effect of bortezomib in myeloma cell lines,24-27 and in some cases also inhibit osteoclasts. Recently, we reported the results of a phase 1 trial in recurrent and refractory MM, in which vorinostat administered at a dose of 400 mg daily for 8 days in conjunction with bortezomib at 1.3 mg/m2 proved to be safe and effective, with responses in patients who were previously proven bortezomib-unresponsive.28 Similar encouraging results have been reported on a phase 1 to 2 trial of romidepsin in combination with dexamethasone and bortezomib.29
Based on these results, several trials are currently in progress evaluating the combination of romidepsin and bortezomib in MM and vorinostat in combination with lenalidomide (NCT00642954, NCT00729118) or pegylated liposomal doxorubicin plus bortezomib (NCT00744353). Moreover, an ongoing phase 3 trial is currently evaluating bortezomib alone or in combination with vorinostat (NCT0077347). This and other trials will serve to define the future role of HDAC inhibitors in MM.
CONFLICT OF INTEREST DISCLOSURES
Supported by a contract from the National Institute of Health, National Cancer Institute (NCI) (N01-CM-62204 [Principal Investigator: Joseph A. Sparano]) and by the Leukemia and Lymphoma Society SCOR grant RFP S03-058 SAIC-Frederick, NCI K24 CA100287-02 (to J.G.), and NCI K23 CA109260-01.
- 18Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol. 1998; 102: 1115-1123., , , et al.
- 29High response rates with the combination of bortezomib, dexamethasone and the pan-histone deacetylase inhibitor romidepsin in patients with relapsed or refractory multiple myeloma in a phase I/II clinical trial. Blood. 2008; 112: 1267-1267., , , et al.