No Aggressive Therapy in Multiple Myeloma-The Role of Thalidomide as Maintenance Therapy

Multiple myeloma is a hematological malignancy that is more frequent after 60 years, greater advances has been achieved in biology and molecular findings, but the best treatment has not been established. We performed a clinical trial to evaluate in older patients (>65 years), that were no candidates to stem cell transplant, because excessive toxicities are a risk. Initially dexamethasone, all-retinoic acid and thalidomide were administered by 6 monthly cycles, if the patients achieved complete response or very good partial response the y were allocated to received maintenance treatment in a 1:1 proportion, thalidomide 100m standard dose, days 1 to 21- or 28-days cycles for 3 years. Two hundred and thirty-eight patients were included, and 189 were included to received maintenance.   Progression-free survival and overall survival were statistically significant in patients that received low doses of thalidomide. Acute and late toxicities were minimal. We show, that a no-toxic induction regimen can achieve excellent response with minimal toxicity, and maintenance with low doses of thalidomide improve significantly outcome, without severe toxicities.

Multiple myeloma (MM), is a B-cell malignancy characterized by a monoclonal expansion and accumulation of abnormal plasma cells in the bone marrow; account of about 10% of hematological malignancies. Greater advances have been achieved about the biology of this neoplasm, and multiple treatment schemes has been reported, the most effectives have been an intensive chemotherapy regimen, and if complete response (CR) or very good partial response (VGPR) is achieved, autologous transplant stem cells is performed, although responses rates has been improvement, relapse remain the mayor problem. But, introduction of new drugs or combinations, have controversial dates. In the other hand, some patients are not candidates for stem cell transplant, because MM is common in > 60 years, and some patients did not tolerate aggressive treatments. [1-6] Some years ago, we performed some studies with less acute and late toxicities, and excellent results [7-9] Thus, we designed a clinical trial, to employ less aggressive induction, followed by maintenance regimen, in patients >65 years, and performance status (PS) ≤ 2.

Patients with diagnosed of MM, stages II and III, no previous treated, > 65 years with no upper limit, PS ≤ 2, that were ineligibles for stem cell transplant: were candidates to entry in the clinical trial and were allocated to an induction phase with: dexamethasone 40 mg, iv, days 1,8,15 of each cycle, all-trans retinoic 45 mg/m2, days 5-14 of each cycle and thalidomide 200 mg standard dose days 1 to 21 of each cycle; for a total of 6 cycles. All patients received zoledronic acid, 4 mg iv, standard doses, every 28 days. Patients with bone lesions received involved field according to the anatomic site, range doses were 2.5 Gy to 5.5 Gy. At 1 month after the 6th cycle patient was evaluated response; if CR or VGPR was achieved, the patients were allocated in a proportion 1:1 to received maintenance therapy with thalidomide 100 mg standard dose, days 1 to 21 at monthly interval, during 3 years. The study was approved by the Ethical and Scientific Committee, and all patients signed an informed consent to participate in the study. No attempts were performed to evaluate prognostic factor, because population was homogenous.

From June 2009 to December 2018, 245 patients were considered candidate, seven patients refuse the treatment and 238 were including in the study.

Table 1: Baselines

Table 1 show the baseline characteristics: as show advances stage (III), G monoclonal, and bone disease were the most frequent. CR and VGPR response were 70.4% of included patients, no statistical factors influence the response rate (data no shown). Acute toxicities were minimal and well controlled. The bone disease that received radiotherapy, response was well, and local toxicity were minimal. Only 23 patients show new presence of bone lesions, that was attributed to the use of zoledronic acid (12). The median follow-up was 7.2 (range 4.3 to 9.0) years. Actuarial curves at 5-years, show that progression-free survival was 75.4 % (95 % Confidence interval (CI): 65.3 %-78.1%) in patients that received maintenance with thalidomide and overall survival was 84.4% (95%CI: 76.4- 89.6%), that were statistical better that patient that did not received thalidomide: 61.5 % (95%CI: 54.2 % - 66.5%) and 70.2% (95%CI: 63.3- 76.3%), respectively. Acute toxicity was minimal, granulocytopenia > grade 2, were not found, infection related treatment was not observed. Durin thalidomide maintenance no toxicities were observed, 5 patients developed minimal neurological dates, the drug was reduced to 50 mg daily, and neurological problems were eliminated. Until now, late toxicities, including second neoplasms or acute leukemia, were not observed.

Although multiple studies have been performed to define the best treatment in MM, until now the most common treatment of an aggressive chemotherapy, followed by stem cell transplant. But relapse continue to be present; thus. he use of maintenance therapy has been included in those regimens, the first agent was thalidomide, an immunomodulator   that improve outcome; suddenly when another immunomodulator appear: lenalidomide, it was adding as maintenance therapy, even that severe toxicities: severe neutropenia and lymphopenia associated to, in some cases, lethal effect; and the need prophylactic antiviral agents, and second neoplasms with are lethal, moreover most of 5% of patients had to reduce or delay, thus the indicated dose-intensity is less [11] s. Some years ago, we continue with thalidomide as maintenance agent, and efficacy has been proven, without severe toxicities. In the present study, the low dose of thalidomide was maintained without excessive toxicity or reduction of dose [9]. In the other hand, a numerous group of patients are not eligible to aggressive chemotherapy and stem cell transplant, thus w explores the use of biological modifiers, and using thalidomide as maintenance, with excellent results. MM is considered as a single disease , it is really a collection of different cytogenetical distinct disease , thus , every year appear a new standard treatment, followed by another regimen , probably for these reasons the best treatment remain to be defined, Recently , Rajkumar , has been considered that MM will be considered as an incurable malignancy, thus, the treatment could be changed, employed  less toxic regimen, because accumulative toxicities in this older patients group will be considered an risks , that, eventually  limited the treatment options [13]. Although, in the present study we proposed a less aggressive, we show that in these group of patients is possible have excellent response rate, and the use of low doses of thalidomide showed that this drug is useful with limited toxicities, moreover is less expensive. Logically, we hope that treatment of MM, would be that some groups can performed more studies with less toxicity in patients with MM.