Combination Chemotherapy with Cyclophosphamide, Thalidomide and Dexamethasone Achieves a High Response Rate in Patients with Newly Diagnosed, VAD-Refractory and Relapsed Myeloma.
Authors: Williams Catherine D. , Byrne Jennifer L. , Sidra Gamal , Zaman Sonya , Russell Nigel H. 
Published: October 2019

Abstract
The established first-line treatment for younger myeloma patients includes regimens containing high-dose pulsed steroids and a combination of intravenous cytotoxic drugs such as vincristine and adriamycin (e.g.VAD). Response rates of 60% are reported but some patients are refractory. Patients may have complications relating to the need for central vascular access. Oral treatments, such as thalidomide, have shown response rates of about 36% in refractory patients.
In an attempt to improve on these results we have evaluated the efficiency and toxicity of a novel oral chemotherapy regimen containing pulsed cyclophosphamide, thalidomide and pulsed dexamethasone (CTD). This regimen consists of a four week cycle of oral cyclophosphamide 500mg, given on days 1, 8 and 15, daily oral thalidomide initiated at a dose of 100mg daily for the first two weeks, increasing to 200mg daily if tolerated, and oral dexamethasone 40mg daily on days 1–4 and 15–18. Patients were treated with 2–6 cycles depending on response. Response criteria were used according to the EBMT/IBMTR guidelines.
Results are reported on 62 myeloma patients: 15 with newly diagnosed (de novo) disease, 29 with VAD-refractory myeloma and 17 with relapsed disease.
Median age of the patients was 55 years (range 31–73). Isotype was IgG in 38 patients, IgA in 17, light chain in 6 and non-secretory (NS) in 1 patient.
Of the 15 patients with de novo disease, a median of 5 courses of CTD were given(range 4–6). All patients responded with 12 achieving a PR and 3 a CR. Of the 29 VAD-refractory patients, 14 had either no response or progressive disease after 2 cycles of VAD and 14 had only a minimal response to VAD with < 50% reduction in paraprotein after 3 cycles. One patient with NS myeloma had <50% reduction in bone marrow plasmacytosis after 3 cycles. PR or CR was achieved in 24 of the 29 patients (83%), with the remaining five achieving < 25% reduction in paraprotein.
Twenty nine of the 44 de novo and refractory patients were considered suitable to progress to high dose melphalan and underwent stem cell mobilisation with cyclophosphamide and G-CSF. The median CD34+ cell dose harvested was 5.22 x 106/kg (1.9–11.2). Only one patient failed to mobilise. Twenty eight of these patients have undergone high dose therapy of whom 10 (36%) have achieved a CR.
The relapsed disease group included 17 patients of whom 16 had received previous high-dose therapy. The overall response rate (PR/CR) was 71% (12/17). Ten patients went on to receive maintenance thalidomide and 2 a PSCT. Median follow-up is 19 months and 10 of the 17 are still alive.
Toxicity of the CTD regimen was minimal with most adverse affects being grade 1 or 2 by the WHO classification. One third of patients suffered constipation and, a quarter, somnolence due to the thalidomide. Dose reduction was rarely required. Peripheral neuropathy was reported by 9% of patients.Grade 3 toxicity was limited to 2 patients who had a DVT and 2 patients who developed febrile neutropenia.
Overall, CTD is a highly effective regimen for patients with newly diagnosed myeloma, VAD-refractory disease or relapsed disease. It is well tolerated and does not impair stem cell mobilisation. As it is oral, compliance is good and complications related to vascular access are minimised. This regimen has now gone on to be tested in new patients in a Phase III setting as one arm of the current MRC Myeloma IX trial.