Intermittent Low-Dose Thalidomide Plus Dexamethasone as Maintenance Therapy in Patients with Multiple Myeloma

Research Article

Ann Hematol Oncol. 2019; 6(2): 1235.

Intermittent Low-Dose Thalidomide Plus Dexamethasone as Maintenance Therapy in Patients with Multiple Myeloma

Galieni P¹*, Caraffa P¹, Bigazzi C¹, Falcioni S¹, Mazzotta S¹, Pezzoni V¹, Dalsass A¹, Mestichelli F¹, Camaioni E¹, Travaglini F¹, Vagnoni A², Angelini S¹ and Ruggieri M¹

¹Department of Hematology and Stem Cell Transplantation Unit, C. e G. Mazzoni Hospital, Italy

²Department of Pharmacy Services, C. e G. Mazzoni Hospital, Ascoli Piceno, Italy

*Corresponding author: Piero Galieni, Department of Hematology and Stem Cell Transplantation Unit, C. e G. Mazzoni Hospital, via degli Iris n. 1, 63100 Ascoli Piceno, Italy

Received: December 18, 2018; Accepted: February 08, 2019;Published: February 15, 2019


In patients with Multiple Myeloma (MM), maintenance therapy with thalidomide helps maintain the results achieved through first-line treatment, improving Progression-Free Survival (PFS) and even Overall Survival (OS). However, when given continuously thalidomide causes various adverse events and high toxicity, thus patients have an increased risk of developing neuropathies and thromboembolic complications. We evaluated the efficacy and safety of a treatment protocol combining intermittent low-dose thalidomide with a monthly fixed dose of dexamethasone, in order to reduce toxicity and adverse events without stopping the maintenance therapy. Between 2003 and 2014, at our centre 62 patients with MM received intermittent low-dose thalidomide (50mg/day for 2 weeks per month) in combination with a fixed dose of dexamethasone (20mg/day for 4 days per month) as maintenance treatment, plus low-dose salicylate (100mg/day) as antithrombotic prophylaxis. We observed positive effects on both OS and PFS, with a statistically significant advantage in patients with standard-risk cytogenetics compared to patients classified as high-risk (median OS of 70 months vs 34; median PFS of 41 months vs 22). Furthermore, our treatment protocol resulted in a remarkable reduction in toxicity and adverse events: peripheral neuropathy rate was 1.6% and no thromboembolic complications were recorded. Patients mainly experienced moderate fatigue (12.9%) and constipation (3.2%), which did not require dose reductions or discontinuation of therapy. Based on these data, intermittent lowdose thalidomide plus dexamethasone should be taken into consideration as maintenance regimen for MM, especially when treating elderly patients with favorable iFISH.

Keywords: Multiple myeloma; Intermittent low-dose thalidomide; Reduced incidence of adverse events; Low toxicity; Elderly patients; Standard-risk cytogenetics


Although with the use of novel agents it is possible to achieve a good response to first-line treatment, Multiple Myeloma (MM) is still incurable in almost all cases. Recurring periods of remission and relapse constitute a distinctive trait of MM, but remission times gradually become shorter while relapses progressively become less sensitive to therapies, and patients inevitably die because of diseaserelated and/or treatment-related complications [1]. Maintenance therapy in MM aims to maintain and, if possible, improve the results of an effective induction therapy, performed with or without autologous hematopoietic stem-cell transplantation [2]. Thalidomide was the first immunomodulatory drug to be used as maintenance therapy in MM: patients receiving maintenance therapy with thalidomide, administered at various doses as a single agent or in combination with steroids, showed significant improvements in Progression-Free Survival (PFS) and to a lesser extent in Overall Survival (OS) compared with both transplant-eligible and transplant-ineligible patients receiving no maintenance therapy [3]. However, the use and efficacy of this treatment are limited, because continuous administration of thalidomide, albeit at low doses, until disease progression is associated with neurological and thromboembolic toxicities. Furthermore, it was observed that thalidomide maintenance therapy should not be administered to patients with high-risk cytogenetics, because in such patients the positive results were inferior to those achieved by patients classified as standard-risk [4].

Taking into account the findings of the first studies on thalidomide as maintenance regimen in patients with advanced MM [5] as well as the current studies on thalidomide maintenance therapy, and considering the well known side effects of thalidomide along with the ongoing clinical trials involving the use of thalidomide in both first-line treatment and maintenance protocol, at our centre patients diagnosed with MM (not enrolled in any other clinical trials) received maintenance therapy with intermittent low-dose thalidomide in combination with a monthly fixed dose of dexamethasone. Our primary aim was to evaluate whether a discontinuous administration of low-dose thalidomide, compared to the same regimen given continuously, would be equally effective in preventing disease progression but with less toxicity, in order for patients with MM to receive maintenance therapy until relapse without any interruptions due to treatment-related complications.

Patients and Methods

Study design and treatment protocol

At our centre, between January 2003 and December 2014, 62 patients diagnosed with symptomatic MM, not enrolled in any other clinical trials and with at least a partial response achieved after induction therapy, received maintenance treatment with intermittent low-dose thalidomide in combination with a monthly fixed dose of dexamethasone.

Diagnosis of MM was based on the clinical diagnostic criteria established by the International Myeloma Working Group [6]. Patients’ response to induction therapy and maintenance treatment was assessed according to the response criteria defined by the International Myeloma Working Group [7]. Toxicities were graded using the National Cancer Institute Common Toxicity Criteria.

This study was undertaken in conformity with the Declaration of Helsinki and written informed consent was provided by all patients before starting treatment.

Maintenance therapy consisted of thalidomide 50mg/day for 2 weeks per month (on days 1 through 14), and dexamethasone 20mg/ day for 4 days per month (on days 1 through 4).

Thalidomide was provided by the C. e G. Mazzoni Hospital Pharmacy as a galenic compound, prepared as size 2 hard gelatin capsules containing thalidomide 50mg plus excipient type B (composition: pregelatinized maize starch 97, 5% as diluentdisintegrant; magnesium stearate 1, 5% as lubricant; micronized silica 0, 5% as diluent; micronized talc 0, 5% as diluent-lubricant), free of lactose and hence suitable for all patients.

Antithrombotic prophylaxis with low-dose salicylate (100mg/ day) was given to all patients, and maintenance treatment was administered until disease progression and/or intolerance. Follow-up occurred every 3 months, with regular physical examinations preceded by laboratory tests (complete blood count, creatinine, calcium, total serum protein test and serum protein electrophoresis, serum free light chains assay, 24-hour urine total protein concentration plus Bence Jones protein test and, for patients in complete remission, serum/urine immunofixation). Bone marrow biopsy evaluation as well as X-ray, Computed Tomography (CT), Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) were performed in case of clinical or laboratory evidence of disease progression.

Statistical analysis

A descriptive analysis of all variables was performed including mean, median, standard deviation, range, minimum and maximum value for continuous variables, absolute and relative frequencies for categorical variables. Using parametric and multiparametric statistical procedures (chi-square test, Fisher’s exact test and Spearman’s rank correlation coefficient), the possible interdependence between two or more variables was evaluated and a p value of =0.05 was considered significant. OS and PFS were estimated using the Kaplan-Meier product limit method [8] and the curves of various subgroups were compared using the log-rank test [9]. OS was measured from the start of maintenance therapy to death from any cause, with censoring performed at the date of last contact. PFS was measured from the start of maintenance therapy to relapse, progression, or death from any cause, with censoring performed at the date of last contact. The analysis was conducted using two statistical software packages: SAS version 9.1.3 ( and R Version 2.15.3 (


Patients’ characteristics

Sixty-two patients (36 men and 26 women) with a median age at diagnosis of 74 years (range 44-86) were enrolled in this trial. Clinical features of patients are reported in Table 1. Twelve patients (19%) had previously been diagnosed with Monoclonal Gammopathy of Undetermined Significance (MGUS) and 5 patients (8%) with Smoldering Multiple Myeloma (SMM).