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The Oncologist, Vol. 12, No. 1, 99-106, January 2007; doi:10.1634/theoncologist.12-1-99
© 2007 AlphaMed Press

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Myelomas

Final Report of Toxicity and Efficacy of a Phase II Study of Oral Cyclophosphamide, Thalidomide, and Prednisone for Patients with Relapsed or Refractory Multiple Myeloma: A Hoosier Oncology Group Trial, HEM01-21

Attaya Suvannasankhaa, Christopher Fausela, Beth E. Juliarb, Constantin T. Yiannoutsosb, William B. Fisherc, Rafat H. Ansarid, Lisa L. Wooda, Gina G. Smitha, Larry D. Cripea, Rafat Abonoura

a Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA; b Biostatistics Core, Indiana University School of Medicine, Indianapolis, Indiana, USA; c Ball Memorial Hospital Cancer Center, Muncie, Indiana, USA; d Northern Indiana Cancer Research Consortiums, South Bend, Indiana, USA

Key Words. Antineoplastic-combined chemotherapy protocols • Multiple myeloma • Salvage therapy • Oral administration • Dexamethasone • Cyclophosphamide • Thalidomide

Correspondence: Rafat Abonour, M.D., Division of Hematology and Oncology, Department of Medicine, Indiana University School of Medicine, 1044 West Walnut Street, Indianapolis, Indiana 46202, USA. Telephone: 317-274-0843; Fax: 317-278-2262; e-mail: rabonour{at}iupui.edu

Received May 9, 2006; accepted for publication September 17, 2006.


   ABSTRACT
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Summary
 Disclosure of Potential...
 References
 
Thalidomide has direct antimyeloma and immunomodulatory effects. In addition, both thalidomide and metronomic chemotherapy inhibit angiogenesis. The synergy of such a combination may decrease toxicity while maintaining efficacy. The Hoosier Oncology Group conducted a phase II trial of oral cyclophosphamide (50 mg b.i.d. for 21 days), thalidomide (200 mg/day), and prednisone (50 mg q.o.d.) (CTP) per 28-day course in patients with relapsed multiple myeloma (MM). Of the 37 patients enrolled, 16 had prior stem cell transplantation. The median follow-up time was 25.3 months (95% confidence interval [CI] 23.2–27.7). Of 35 patients treated, 22 patients (62.9%) responded: 7 (20.0%) complete responses, 2 (5.7%) near-complete responses, and 13 (37.1%) partial responses. Eight patients (22.9%) had stable disease, and three (8.6%) had disease progression. Two patients withdrew from the study early due to reasons unrelated to progression or toxicity and were treated as nonresponders. The median time to best response and time to progression were 3.6 months (95% CI 2.8–10.9) and 13.2 months (95% CI 9.4–21.0), respectively. The median number of treatment cycles was seven (range 1–12 cycles). Grade III to IV toxicities included leukopenia (42.9%; febrile neutropenia, 11.4%), hyperglycemia (20%), sensory neuropathy (11.4%), thromboses (8%), and motor neuropathy (5.7%). No patient withdrew from the study due to toxicity. The efficacy and low toxicity of the CTP regimen support the future development of such an approach in MM.


   INTRODUCTION
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Summary
 Disclosure of Potential...
 References
 
Multiple myeloma (MM) is an incurable hematologic malignancy in which drug resistance and treatment-related toxicities are significant obstacles [1]. An effective and nontoxic therapy is greatly needed. Although the antiangiogenic effect of thalidomide led to its investigation in MM, thalidomide has multifaceted effects in MM that include the direct cytotoxicity to MM cells, the alteration of cytokines in the microenvironment, and immunomodulatory effects such as T- and natural killer cell activation [2–5]. Despite its benefit, significant toxicities of thalidomide occur, including neuropathy, sedation, and thrombosis [6, 7]. Efforts in overcoming thalidomide toxicity include the chemical modification of the compound [8] and the use of a lower dose of thalidomide in combination with other agents. We explored the use of a moderate dose of thalidomide with cyclophosphamide, which is administered in a prolonged, low-, and minimally toxic dosing (metronomic chemotherapy). The concept of metronomic chemotherapy was developed based on the understanding of the biology and importance of angiogenesis in tumor progression [9]. When given in this manner, multiple chemotherapeutics, including cyclophosphamide, selectively affect the activated endothelial cells compared with normal tissues. This method of chemotherapeutic administration therefore offers an antiangiogenic effect rather than a direct cytotoxicity to tumor cells, which is primarily observed with an acute dosing administration [10]. In animal models, the administration of metronomic cyclophosphamide causes the shrinkage of tumors that are resistant to an acute dosing of cyclophosphamide [11]. The selectivity against the endothelial cells also creates a therapeutic window whereby an antitumor effect can be achieved with only a limited adverse effect to normal cells. Whereas the acute dosing of cyclophosphamide causes significant myelosuppression, the metronomic dosing has been shown by multiple investigators to be well-tolerated both alone and in combination with other chemotherapeutics [12–14]. In addition, a metronomic dosing of cyclophosphamide has an immunomodulatory effect that leads to its use in various rheumatologic conditions and may also provide an additional mechanism for its antitumor effect [15–17]. Because of the heterogeneous nature of tumor endothelial cells, a synergy is often observed when different antiangiogenic agents are combined [18, 19]. A similar benefit is observed with the combination of thalidomide and a metronomic dose of cyclophosphamide as an extensive tumor necrosis was seen with this combination in a rat prostate cancer model [20].

The Hoosier Oncology Group (HOG) conducted a phase II trial of oral metronomic cyclophosphamide, thalidomide, and prednisone (CTP) in combination in patients with relapsed MM. Prednisone was added to the regimen based on its single-agent efficacy and synergy with thalidomide and chemotherapy. We report herein the efficacy and toxicity of the CTP regimen.


   MATERIALS AND METHODS
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Patients with relapsed MM were eligible for the study. There were no limitations on the type or number of prior therapies. Patients had to have an absolute neutrophil count ≥ 1,500 cells/mm3, hemoglobin ≥ 9 g/dl, platelet count ≥ 100,000/mm3, total bilirubin ≤ 1.5 x the upper limit of normal (ULN), and serum aspartate aminotransferase (AST; serum glutamic-oxaloacetic transaminase) ≤ 3 x ULN. Blood transfusions were allowed. Treatment was administered orally and consisted of 200 mg of thalidomide daily, 50 mg of cyclophosphamide twice daily for 21 days, and 50 mg of prednisone every other day per 28-day course. Adverse events were assessed at each visit and graded according to the National Cancer Institute Common Toxicity Criteria version 2.0. A dose modification was mandated for the hematologic toxicity of cyclophosphamide and the neurologic and dermatologic toxicity of thalidomide. In brief, for grade IV hematologic toxicity lasting more than 2 weeks or hospitalization for neutropenic fever, cyclophosphamide was held until the resolution of the event, followed by a 50% dose reduction in the subsequent cycle. If the event did not resolve within 4 weeks or reoccurred following the 50% dose reduction, the patient was taken off the study. For thalidomide, a 25% dose reduction was required for a neurotoxicity of grade ≥ III, with no dose interruption. If the neurotoxicity did not resolve, a 50% reduction of the original dose was required. The patient was taken off the study if the neurotoxicity continued following a 50% reduction. In the case of a depressed level of consciousness grade ≥ II (somnolence or sedation not interfering with activities of daily living), the dose of thalidomide was reduced by 25%. The thalidomide dose was further reduced to 50% of the original dose if the depressed level of consciousness did not resolve within 48 hours. Complete cessation of therapy was mandated in the case of continued side effects or if improvement did not occur within 48 hours after a 50% dose reduction. In a similar manner, a stepwise reduction of the thalidomide dose was also required for grade > III dermatologic toxicity. There was no dose adjustment for prednisone. Hyperglycemia was managed at the treating physician’s discretion. Hematopoietic growth factors, blood products, antibiotics, and bisphosphonates were allowed as clinically indicated. Patients underwent a clinical evaluation for deep venous thrombosis (DVT) and cardiovascular risk. All patients were encouraged to take low-dose aspirin, folic acid, and vitamin B12. Only patients with confirmed thrombosis were treated with anticoagulant. Both thalidomide and prednisone were held until adequate anticoagulation was achieved and the severity of the thrombotic adverse events decreased to grade ≤ II. Thalidomide and prednisone were resumed without dose reduction.

The primary endpoint was response rate using the Eastern Cooperative Oncology Group (ECOG) response criteria. Secondary endpoints were safety, time to progression, and survival. Response was assessed at 3, 6, 9, and 12 months after treatment. Any patients receiving at least one dose of the study drug were included for response evaluation. Patients who discontinued treatment before a response could be assessed were considered to have had no response. A two-stage design was used with 17 patients mandated for the first stage. If 4 or more patients responded, 20 additional patients were entered into the second stage. If 12 or more of 37 total patients responded (32%), the regimen would warrant further investigations. This design had a 5% type I error probability for H0: a response rate of 20%, and 85% power for H1: a response rate of 40%. Confidence intervals (CIs) for the true response rate were obtained using the Jennison and Turnbull method. An early termination of the trial due to toxicity was considered if the lower limit of the 90% CI of the rate of any toxicity grade ≥ III exceeded 10%. The time to best response was defined as the time between the initiation of study drugs and the documented best response defined as the plateau of lowest monoclonal protein levels achieved in two separate measurements at least 2 weeks apart. The duration of a response was defined as the time from the achievement of a response to progression. Overall survival was defined from the beginning of therapy until the time of death or the last date on which the patient was known to be alive. Time-to-event analyses were estimated using the Kaplan-Meier method.

Because a protracted course of antiangiogenic therapy is needed for the best efficacy [21], we maintained our patients on thalidomide and metronomic cyclophosphamide. Prednisone, which was used as part of an "induction therapy," was tapered off over a period of 2–4 weeks. Patients with disease progression after prednisone cessation were taken off the study.

The written informed consent and protocol were approved by the local Institutional Review Boards and Indiana University Scientific Review Committee. All patients provided informed consent prior to enrollment. Data monitoring was maintained by the HOG central office.


   RESULTS
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Discussion
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From November 2001 to June 2003, 37 patients were enrolled through eight HOG sites. Their clinical features are described in Table 1Go. Two patients never received study drugs due to early progression and patient preference. Response evaluation among 35 treated patients using the ECOG criteria as originally proposed in our trial and the European Group for Blood and Marrow Transplant (Bladé) criteria [22] is described in Table 2Go. Types of responses observed were comparable between the two criteria. Two patients withdrew from the trial for nontoxicity-related reasons before their response could be evaluated and were considered nonresponders.


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  		Table 1. Patient characteristics (n = 37)

 

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  		Table 2. Response evaluation

 
Twenty-five patients (71.4%) responded by 3 months, 29 (82.9%) by 6 months, and 31 (88.6%) by 9 months. The median time to achieve the best response was 3.6 months (95% CI 2.8–10.9 months; Fig. 1Go). Sixteen patients achieved the best response at 3 months, two additional patients achieved the best response at 6 months, and four patients achieved the best response at 12 months. Among 22 responders, the median duration of the response was 14.5 months (95% lower CI limit = 8.1 months; upper CI limit has not been reached; Fig. 2Go). Among the nine patients with a complete response or noncomplete response, the median duration of the response was 18.4 months (95% lower CI limit = 7.7 months; upper CI limit has not been reached). The median time to the end of follow up with censoring at death was 25.3 months (95% CI 23.2–27.7 months). The median time to death or progression was 13.2 months (95% CI 9.4–21.0; Fig. 3Go). Ten patients have progressed to date. Twenty-three (65.7%) patients are alive (95% CI 47.8–80.9), and six are disease-free. The median disease-free survival was 13.2 months (95% CI 9.4–21.0), and the median overall survival has not been reached. The median number of cycles given was 7 (range 1–12). The most common adverse events were fatigue and myelosuppression, which were typically mild to moderate and were manageable with routine support. All events of grade ≥ III are reported in Table 3Go. The most common grade III and IV toxicities are neutropenia and leukopenia. There were no fatal infectious complications. Most patients had baseline neuropathy. Six patients (17%) reported worsening motor neuropathy (four grade II and two grade III), and 12 (34%) reported worsening sensory neuropathy (8 grade II and 4 grade III).


Figure 1
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  		Figure 1. A Kaplan-Meier curve demonstrates time to response with 22 responders and 13 censored among 35 patients after initiating treatment with the cyclophosphamide, thalidomide, and prednisone regimen. The median time to achieve response was 3.6 months (95% exact confidence interval 2.8–10.9 months).

 

Figure 2
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  		Figure 2. A Kaplan-Meier curve demonstrates the duration of response, defined as the time from the achievement of a response to progression, among 22 responders. The median duration of the response was 14.5 months (95% exact lower confidence limit = 8.1 months; upper confidence limit has not been reached).

 

Figure 3
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  		Figure 3. A Kaplan-Meier curve demonstrates the time to progression or death, defined from the beginning of therapy until the time of progression, death, or the last date on which the patient was known to be alive. Median time to death or progression was 13.2 months (95% exact confidence interval 9.4–21.0).

 

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  		Table 3. All grade III or IV events regardless of relation to the study drugs

 
Four (11%) patients experienced grade III, and two (6%) had grade II, sensory neuropathy. Four patients (11%) experienced grade II motor neuropathy. Cyclophosphamide was held in nine (26%) patients due to myelosuppression. Thrombosis was observed in four patients: one grade II DVT, two grade III DVT, and one grade IV cardiovascular accident. Two of the three grade ≥ III thromboses occurred while patients were not on low-dose aspirin. No patients were removed from the study due to toxicity.


   DISCUSSION
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 Materials and Methods
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 Discussion
Summary
 Disclosure of Potential...
 References
 
Although metronomic chemotherapy has been explored in solid tumors and pediatric cancers, our study is one of a few to explore metronomic chemotherapy in MM [10, 13, 23]. Metronomic chemotherapy is a novel method of chemotherapeutic administration that targets angiogenesis in addition to the direct antitumor effects usually observed with traditional chemotherapy. The reasons why metronomic chemotherapy offers an antiangiogenic effect, whereas acute dosing does not, may include (a) the potential recovery of endothelial cells between acute dosing cycles, and (b) the possibility that tumor necrosis and hypoxia from acute dosing may increase vascular endothelial growth factor (VEGF) secretion and promote angiogenesis [21, 24]. Multiple tumor models and clinical observations have confirmed this concept. An example includes the Lewis lung carcinoma cells, which were selected for their resistance to the maximally tolerated dose of cyclophosphamide yet remain sensitive to metronomic cyclophosphamide. In addition, 40% of patients with non-small cell lung cancer who failed standard-dose etoposide responded to metronomic etoposide [25]. Similar findings were also reported in other tumors such as ovarian and breast cancers [26].

An oral metronomic cyclophosphamide, methotrexate, and thalidomide combination was explored in women with metastatic breast cancer [13]. A clinical benefit and decreased serum VEGF levels were observed. A recent pediatric cancer trial using oral thalidomide and celecoxib, with alternating metronomic oral etoposide and cyclophosphamide, showed efficacy and low toxicity [27].

Different combinations of thalidomide and steroids, with acute-dosing cyclophosphamide, have been explored. The pilot work by Barlogie et al. showed the efficacy of the thalidomide, dexamethasone, cyclophosphamide, etoposide, and cisplatin regimen in relapsed MM [28]. Kropff et al. used hyperfractionated cyclophosphamide, pulsed dexamethasone, and thalidomide. This regimen was effective but associated with a high frequency of severe neutropenia [29]. Kyriakou et al. used a lower cyclophosphamide dose (300 mg/m2 orally weekly), pulsed dexamethasone, and thalidomide. A lower rate of neutropenia was observed [30]. Garcia-Sanz et al. used oral metronomic cyclophosphamide (50 mg/day), thalidomide (200–800 mg/day), and pulsed dexamethasone [31]. The response rate was 82%, but 12.6% of patients had protocol interruption due to toxicity. The lower infection rate and less leukopenia in our trial compared with previous reports may relate to the lower dose and shorter duration of cyclophosphamide or less myelosuppression due to a lower dose of thalidomide [32].

The CTP regimen is well-tolerated. Half the patients took 7 months or more of therapy. Neuropathy was manageable with a rapid-dose modification of thalidomide. Severe thrombosis occurred in 8% of patients, which is comparable to other reports [6, 33]. The pathophysiology of thrombosis in this setting is poorly understood. The benefit of aspirin in DVT prevention was reported with a liposomal doxorubicin, vincristine, dexamethasone, and thalidomide combination [34]. Because hyperhomocysteinemia is common in elderly populations and associated with thrombosis [35, 36], vitamin B12 and folate were recommended to our patients. The benefit of these agents must be further explored.

The role of maintenance therapy in MM, either after autologous stem cell transplantation or other therapy, continues to be controversial [37]. Over the past decade, the efficacy of interferon and prednisone in MM maintenance therapy yielded conflicting results [38]. The Southwest Oncology Group reported an improvement in progression and overall survival with the use of 50 mg of prednisone every other day after an induction chemotherapy with a vincristine, doxorubicin, and dexamethasone-like regimen [39], but its benefit in other settings, including post-transplant and postrelapsed therapy, is unknown. The use of thalidomide in maintenance therapy has recently received great interest. To date, most trials report an improvement in the quality and rate of response, but the impact of thalidomide on survival is not conclusive. Attal et al. reported an improvement in the 3-year event-free survival and the 4-year postdiagnosis probability of survival with the use of thalidomide after autologous stem cell transplantation [40, 41]. However, Barlogie et al. reported an extended event-free survival, at the expense of added adverse effects, without improving the overall survival [42].

In our trial, thalidomide and metronomic cyclophosphamide were continued past the induction phase to optimize the selective activity of protracted antiangiogenic agents on the activated endothelial cells [43]. The tapering of prednisone did not seem to increase the chance of progression, as our overall time to progression seems comparable to other salvage regimens. The regimen was relatively non-toxic, but the thalidomide-related neuropathy was not negligible. A clinical trial of maintenance therapy in MM using lenalidomide, which is less neurotoxic compared with thalidomide, is ongoing. The absolute benefit of maintenance therapy using any of these novel regimens can be reliably investigated only in a randomized manner.


   SUMMARY
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Summary
Disclosure of Potential...
 References
 
The efficacy, favorable toxicity profile, and convenience of administration make the oral CTP regimen an appealing treatment choice for patients with relapsed MM. We further believe that the future development of a combination of lenalidomide and metronomic chemotherapy in MM is warranted.


   DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
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The authors indicate no potential conflicts of interest.


   ACKNOWLEDGMENT
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This study was supported in part by The Center for Excellence in Molecular Hematology (NIH/National Institute of Diabetes and Digestive and Kidney Diseases P30 CD 49218-11), Walther Cancer Institute, and Celgene Corporation and was previously presented at The American Society of Hematology 46th Annual Meeting and Exposition, December 4–7, 2004, San Diego, USA.


   REFERENCES
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Journal of Pharmacy Practice, April 1, 2008; 21(2): 126 - 137.
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