Superiority of Bortezomib, Thalidomide and Dexamethasone in Frontline Therapy of Younger Patients with High-Risk Multiple Myeloma: A Single-Center Experience

Research Article

Ann Hematol Oncol. 2016; 3(4): 1086.

Superiority of Bortezomib, Thalidomide and Dexamethasone in Frontline Therapy of Younger Patients with High-Risk Multiple Myeloma: A Single-Center Experience

Tavares M¹*, Chacim S¹, Ramalheira S¹, Simas AM², Alves C³, Pereira D¹, Moreira C¹, Espírito- Santo A¹, Domingues N¹, Oliveira I¹, Moreira I¹, Martins A¹, Viterbo L¹, Campos A4 and Mariz JM¹

¹Department of Onco Hematology, Portuguese Institute of Oncology, Portugal

²Department of Medical Oncology, Portuguese Institute of Oncology, Portugal

³Department of Immunohaemotherapy, Portuguese Institute of Oncology, Portugal

4Department of Bone Marrow Transplant, Portuguese Institute of Oncology, Portugal

*Corresponding author: Márcio Tavares, Department of Onco Hematology, Portuguese Institute of Oncology, 4200-072 Porto, Portugal

Received: April 27, 2016; Accepted: June 27, 2016; Published: June 29, 2016

Abstract

Introduction: In July 2012, TD (thalidomide and dexamethasone) was substituted for vtD (low-dose bortezomib, thalidomide and dexamethasone) as our standard induction treatment of younger patients with high-risk multiple myeloma (MM). We aimed to evaluate in our clinical practice, outside clinical trials, whether vtD resulted in an improvement in high-quality responses.

Methods: We compared response post-induction, response post-transplant, progression-free survival (PFS) and overall survival (OS) at 3-year between vtD and TD.

Results: From a total of 235 consecutive patients newly diagnosed with symptomatic MM, 45 were considered high-risk and eligible to autologous stem cell transplant (ASCT). Twenty-nine and 16 patients received vtD and TD, respectively. After induction, the complete response (CR) rate (44.8% vs. 6.3%, p=0.008) and CR plus very-good partial response (VGPR) rate (65.5% vs. 12.5%, p=0.002) were significantly higher in the vtD vs. TD group. After ASCT, the CR plus VGPR rate was significantly higher in the vtD group (76.7% vs. 43.8%, p=0.023). The overall survival at 3-year was 74.4% vs. 68.8% in the vtD and TD groups, respectively.

Conclusion: Outside clinical trials, vtD remains a superior induction regimen compared with TD in transplant-eligible, newly diagnosed patients with high-risk MM.

Keywords: Multiple myeloma; Treatment outcome; Induction chemotherapy; Autologous transplantation

Abbreviations

ASCT: Autologous Stem Cell Transplant; CR: Complete Response; HDT: High-Dose Therapy; ISS: International Stage System; MM: Multiple Myeloma; ORR: Overall Response Rate; OS: Overall Survival; PFS: Progression-Free Survival; PR: Partial Response; TD: Thalidomide, Dexamethasone; VGPR: Very Good Partial Response; vtD: (Low-Dose) Bortezomib, Thalidomide, Dexamethasone

Introduction

Several new therapeutic interventions have been introduced for multiple myeloma (MM) during the past 50 years leading to a major increase in long-term survival of younger patients [1]. A combination of melphalan and prednisone remained the standard treatment during three decades but the median survival did not exceed three years [2]. The introduction of high-dose therapy with autologous stem-cell transplant (HDT/ASCT) was the first major cause of overall survival (OS) improvement observed in younger patients and extended median OS to 3-4 years [3,4]. However, approximately 40% of the patients achieved partial response (PR) only, long-term remissions remained rare and the vast majority of patients ultimately relapsed [3]. The inclusion of novel agents during induction (thalidomide, bortezomib, lenalidomide) dramatically increased post-induction and post-transplant response rates and substantially changed treatment strategies in the transplant setting [5,6].

Despite marked therapeutic advances for most patients with MM, outcomes of a subgroup of patients with high-risk disease still remained poor at the end of the last decade. Three phase 3 large clinical trials randomized more than 1000 patients to compare double regimens with a triple regimen consisting of bortezomib, thalidomide and dexamethasone (VTD) [6-8]. All trials demonstrated a superiority of the triple regimen across patients with high-risk MM including poor-risk cytogenetics, ISS (International Staging System) 3 and extramedullary disease. Additionally, in the GIMEMA study, VTD managed to overcome the poor prognosis impact of poor-risk cytogenetics [6]. Besides the demonstrated efficacy, VTD avoided impairment of stem-cell collection and significant toxicity and has since then been considered the best induction treatment prior to HDT/ASCT.

The standard of care at our department includes triple regimen as the standard induction treatment for patients with high-risk myeloma since July 2012. The main purpose of this study was to evaluate in our clinical practice, outside clinical trials, whether vtD improved highquality responses compared with TD.

Materials and Methods

We searched retrospectively our myeloma report data base from January 2009 to December 2014 for patients newly diagnosed with symptomatic MM who had induction treatment at our department. Patients aged less or equal to 65 years with a suitable ECOG (Eastern Cooperative Oncology Group) performance status and normal organ function were considered eligible for HDT/ASCT after induction once they had achieved at least partial response (PR). Multiple myeloma patients are referred for transplant to the Bone Marrow Transplant Unit of our hospital. For this observational study, only patients with high-risk MM were included. High-risk MM was defined by the presence of at least one of the following criteria, as stated in the literature [9]: 1) ISS stage 3, 2) renal insufficiency (eGFR < 40 ml/min), 3) extramedullary disease, 4) translocation t(4;14) and/ or deletion del(17p), 5) advanced bone disease. From January 2009 to June 2012, our patients received a double regimen: TD and from July 2012 to December 2014, our patients received triple regimen: vtD. TD consisted of thalidomide 200mg daily (escalating doses in the first two cycles: 50 mg on days 1-14 and 100 mg on days 15-28 of the first cycle; 150 mg on days 1-14 of the second cycle and 200 mg afterwards) and dexamethasone 40 mg orally on days 1-4 (all cycles) and 9-12 (first four cycles) at 4-week intervals for four to eight cycles. vtD consisted of four to eight 3-week cycles of bortezomib 1mg/m2on days 1, 4, 8 and 11, thalidomide 100 mg daily (escalating doses in the first cycle: 50 mg on days 1-15 and 100 mg afterwards) and dexamethasone 40 mg orally on days 1-2, 4-5, 8-9 and 11-12. All patients with high-risk MM were assigned to tandem transplant. Response and progression were assessed according to the International Myeloma Working Group criteria at the end of induction therapy and around day 100 after transplant. Progression-free survival was calculated from the date of diagnosis to the date of progression/relapse or death. Overall survival was calculated from the date of diagnosis to the date of death from any cause or the last visit. Patient follow-up ended at March, 31, 2016. Primary endpoint was response post-induction. Other endpoints analyzed included response post-transplant, progressionfree survival (PFS) and overall survival (OS) at 3-year. Descriptive statistics and statistical analyses were performed in Statistical Package for the Social Sciences (SPSS) v.18.

Results

Population

From 2009 to 2014, a total of 235 consecutive patients were newly diagnosed with symptomatic myeloma, of which 102 were considered eligible for transplant. Fifty-two of these patients presented with high-risk MM. Seven patients were treated with different regimens and were excluded from this analysis. Of the 45 patients treated according to our standard of care, 16 and 29 patients received TD and vtD, respectively. The median duration of induction treatment for both groups was eight cycles. Data on cytogenetic abnormalities were available in a subset of 39 patients. Table 1 summarizes patients’ clinical characteristics. No significant differences were found between the two groups although the proportion of male patients was higher in the vtD group. A total of 32 patients underwent HDT/ASCT: 11 patients in TD (three underwent one ASCT and eight had a tandem transplant) and 21 in vtD (13 underwent one ASCT and eight had a tandem transplant). Sixteen patients who entered the transplant phase underwent a second transplant and two additional patients were awaiting a second transplant at the end of the study. Reasons for not undergoing the second transplant (n=14 patients) were: insufficient peripheral blood stem cells (n=6 patients), comorbidities (n=3 patients), early progression after transplant (n=2 patients), patient refusal (n=1 patient), enrollment in a clinical trial (n=1 patient) and missing follow-up (n=1 patient).