Original article
Continuous low-dose cyclophosphamide–prednisone is effective and well tolerated in patients with advanced multiple myeloma

https://doi.org/10.1016/S0300-2977(01)00140-1Get rights and content

Abstract

Background: Multiple myeloma is an incurable disease and after several lines of chemotherapy, patients enter a phase in which no standard treatment options are available. The poor outlook of these patients requires mild, palliative therapy with low toxicity. Previously used regimens either require frequent hospital attendance, lack efficacy or have significant toxicity.

Methods: In the current study, daily low dose, oral cyclophosphamide (100 mg) and prednisone (10–20 mg; CP) were administered to patients with advanced myeloma. Forty-two patients with progressive disease after melphalan-based and VAD treatment were enrolled.

Results: Objective responses were observed in 29 of 42 (69%) patients. In responding patients, median overall survival and progression-free survival were 22.2 months and 15.0 months, respectively. In non-responders, median OS was 3.5 months only. Side-effects were limited. Cytopenia was the most frequent event (8/29) prompting dose reduction. CP had to be stopped permanently in four patients (two cytopenia, two infections).

Conclusion: Orally administered, low dose continuous CP is a feasible, effective and well-tolerated regimen in the management of advanced multiple myeloma.

Introduction

Multiple myeloma is considered to be an incurable disease. Although intensified treatment regimens using high-dose chemotherapy followed by autologous stem cell transplantation may improve response, event free and overall survival, the relapse rate remains unaltered [1]. The treatment options in relapsed and refractory patients are limited due to primary and acquired multidrug resistance and the vulnerability of this category of patients [2]. The reinstatement of chemotherapeutic regimens to which patients responded in an earlier phase of the disease is successful in a limited number of patients, as is the use of pulsed dose dexamethasone [3]. Other strategies include the use of interferon [4] or thalidomide [5] as anti-myeloma therapies. Clearly, all these strategies have their specific drawbacks and even minor side-effects may be regarded as unacceptable toxicity in the perspective of a malignant disorder with only limited life expectancy.

Weekly intravenous cyclophosphamide and alternate day prednisone was introduced by Brandes and Israels [6]. This regimen induced an objective response in three of five patients with advanced myeloma. Using a higher dose of cyclophosphamide objective responses were observed in 7/28 (25%) primary refractory and 10/29 (35%) relapsing refractory myeloma patients with a mean duration of 10 months [7]. As objective responses were comparable to more aggressive regimens, but with considerable less toxicity this scheme has been widely adapted for advanced myeloma in Canada and Britain. To further reduce the need for hospital visits and avoid possible toxicity we adapted the treatment scheme of Wilson [7], using cyclophosphamide and prednisone orally on a daily basis. We report on the results of patient outcome using this regimen in advanced multiple myeloma.

Section snippets

Materials and methods

A total of 110 patients with MM that were seen at our institution between 1991 and 1998 for either treatment or second opinion of MM were studied. Forty-two patients fulfilled the criteria for advanced MM and were included in the study. These criteria were refractory or relapsed disease after at least two rounds of chemotherapy including anthracyclines or previous treatment with one round of chemotherapy and WHO performance 4. Patients pretreated with thalidomide were eligible as well.

Results

Twenty-nine (69%) patients responded to continuous CP, including 13 patients (31%) with a minor response and 16 patients (38%) with a partial response (Table 3). Thirteen patients did not respond to CP. Six of nine patients with primary refractory disease and 23 of 33 patients with relapsed refractory disease responded to CP. All six patients with primary refractory disease, who responded to CP, had received prior treatment with VAD and melphalan. Four of these patients were previously treated

Discussion

In this study we show that continuous low dose oral cyclophosphamide and prednisone had remarkable anti-myeloma activity in patients with advanced disease. Thirty three percent of patients had a 50% decrease in myeloma proteins including two patients with more than 90% reduction. An additional 38% of patients had reduction levels between 25 and 50% resulting in a total response of 69%. Besides objective tumour response, CP relieved myeloma-related symptoms such as bone pain, fatigue and

References (17)

There are more references available in the full text version of this article.

Cited by (39)

  • Phase 1/2 study of lenalidomide combined with low-dose cyclophosphamide and prednisone in lenalidomide-refractory multiple myeloma

    2016, Blood
    Citation Excerpt :

    These subgroups involve relatively small numbers of patients, and further analysis is needed to assess the impact of these variables on outcome with REP. We previously showed that the 2-drug combination of continuous low-dose cyclophosphamide and prednisone has also significant anti-MM activity in relapsed/refractory MM patients, who were not previously exposed to novel agents.37 However, another study showed that low-dose cyclophosphamide (50 mg daily) combined with steroids has markedly lower activity in lenalidomide- and bortezomib-exposed patients (63% of these patients were double-refractory to bortezomib and IMiDs), with at least PR in 11.4% of these patients and a median PFS and OS of only 3.3 months and 10.0 months, respectively.38

  • Anti-tumor and anti-osteolysis effects of the metronomic use of zoledronic acid in primary and metastatic breast cancer mouse models

    2013, Cancer Letters
    Citation Excerpt :

    Early in 2000, Klement and Browder published two pioneering articles showing that mice bearing subcutaneous tumors would respond to continuous repeated low doses of chemotherapy [23,24]. During the last decade, clinical studies have shown that the metronomic treatment represent an interesting alternative for either primary systemic therapy or maintenance therapy, e.g. positive results were reported with various metronomic chemotherapy regimens for patients with metastatic breast cancer, recurrent ovarian cancer, advanced multiple myeloma, recurrent malignant glioma, metastatic or locally advanced neuroendocrine carcinoma [25–27]. The effectiveness of metronomic regimen in patients with different cancer types, may account to the prolonged duration of clinical benefit obtained with metronomic way, and the chronic administration of chemotherapeutic agents at relatively low, minimally toxic doses [28].

  • Treatment of relapsed and refractory multiple myeloma in the era of novel agents

    2011, Cancer Treatment Reviews
    Citation Excerpt :

    Choice of relapse treatment must be tailored to the condition of the individual patient and depends not only on chronological age but also on psychological status, social support, performance status, and co-morbidity. Frail myeloma patients may benefit from dose-adjusted regimens with proven efficacy accompanied with mild toxicity such as lenalidomide combined with low-dose dexamethasone207, combinations with bortezomib administered once weekly86,214,215, oral cyclophosphamide with prednisone30–32, thalidomide plus low-dose dexamethasone, thalidomide with oral cyclophosphamide33, thalidomide with oral cyclophosphamide and a corticosteroid27,28, or lenalidomide–cyclophosphamide–prednisone.56 Careful monitoring of toxicity and prompt administration of supportive care is important in this group of patients.

  • Continuous administration of low-dose cyclophosphamide and prednisone as a salvage treatment for multiple myeloma

    2010, Clinical Lymphoma, Myeloma and Leukemia
    Citation Excerpt :

    Metronomic chemotherapy has also achieved some success for relapsing or refractory MM. de Weerdt and colleagues18 used a salvage treatment consisting of low-dose cyclophosphamide (100 mg) and prednisone (10-20 mg) without a rest period in 42 patients with advanced myeloma. Favorable response was observed in 29 patients (69%).

View all citing articles on Scopus
View full text