Description of the condition
Multiple myeloma (MM) is a malignant proliferative disease which is characterized by excessive proliferation of abnormal plasma cell originated from post-germinal-center B cells (Palumbo 2011a). The neoplastic plasma cells occupy the bone marrow and produce monoclonal immunoglobulins, which cause symptoms of bone pain or fracture, susceptibility to infection, anemia, hypercalcemia, renal failure and end-stage organ damage (Rajkumar 2012).
MM comprises 1% of all malignant diseases and accounts for about 15% of hematological malignancies (Blade 2010a). There are approximately 86,000 new cases and 63,000 deaths all over the world every year (Becker 2011). The morbidity of the disease increases with age. The age range with the high incidence is 60 to 70 years, while it is rare for people aged under 40 years (Blade 2010a). The incidence of MM in black populations is nearly twice as high as that in white populations, but it is the lowest in Asian populations (Brown 1999; Cartwright 1999). Prognostic factors of MM affect its survival rate. Previously, the β2-microglobulin and albumin levels were found to be the most significant prognostic factors and were used for defining the stage of the disease, as recommended by the International Staging System (Palumbo 2011a). Recently, increasing evidence has shown that several cytogenetic changes also play an important role in the prognosis of MM (Blade 2010a; Kyle 2009). Patients with risk factors such as hyperdiploidy or translocation t (11; 14) have a favorable prognosis; this is in contrast to those with hypodiploidy and translocation t (4; 14) or del (17p) who have a poor prognosis (Kyle 2009).
Up to now, MM remains an incurable disease. In the United States, the 5-year and 10-year relative survival rates were 34.7% and 17.4%, which were calculated by Brenner et al for 2002 to 2004 (Brenner 2008). The therapy options for MM include chemotherapy, autologous stem cell transplantation (ASCT) and allogeneic stem cell transplantation (alloSCT) (Bird 2011). However, the effectiveness of conventional chemotherapy is not satisfactory (Blade 2010b). In a randomized clinical trial, the 5-year overall survival (OS) rates and event-free survival (EFS) rates of the chemotherapy group were 12% and 10%, respectively (Attal 1996). In 2005, another trial comparing standard chemotherapy to ASCT showed short survival rates in the group with standard chemotherapy (Fermand 2005). The median OS and median EFS were 47.6 months and 18.7 months with standard chemotherapy, respectively. Despite the novel drugs such as bortezomib, thalidomide and lenalidomide having shown activity in MM (Richardson 2010), many studies have shown that hematopoietic stem cell transplantation (HSCT) has given much hope to patients for better clinical outcomes (Crawley 2007; Koreth 2007; Palumbo 2011b).
Description of the intervention
In brief, HSCT is a treatment involving a high-dose induction regimen followed by a stem cell transplant, which can be divided into ASCT and alloSCT. This classfication is based on the source of the transplant, from the patient's own or a donor's stem cells that suitably match the human leukocyte antigens of the patient. From the aspect of effectiveness, ASCT and alloSCT differ with respect to treatment related mortality and relapse. As ASCT usually leads to a high recurrence rate in MM, alloSCT has been investigated as an alternative option for treatment. Disappointingly, alloSCT has shown high transplant related mortality (TRM).
It has been 25 years since McElwain and Powles began to use ASCT for MM (Giralt 2012). Based on the incremental rates of EFS and prolonged OS compared with conventional combination chemotherapy (Attal 1996; Fermand 2005), ASCT is currently considered as the front-line standard treatment for eligible patients after induction therapy (Blade 2010b; Ludwig 2011). In ASCT, a high-intensity conditioning chemotherapy becomes possible with subsequent stem cell rescue using autologous stem cells collected after induction during remission. In this way, ASCT reduces bone marrow toxicity and improves survival rates. A randomized study including 401 patients with MM indicated that the median survival was 54 months in the ASCT group and approximately 44% of patients achieved complete remission (CR) (Child 2003). Unfortunately, the majority of patients who received ASCT eventually relapsed or suffered from progressive disease (Bensinger 2009).
In an effort to further increase the benefit of ASCT, tandem ASCT was investigated to further improve clinical outcomes of MM patients (Barlogie 1997). Several randomized clinical trials have been initiated to evaluate the impact of tandem ASCT on survival. Most of the studies revealed that tandem ASCT produced superior outcomes compared with single ASCT (Attal 2003; Naumann-Winter 2012).
In alloSCT, the donor's HSCT is infused into a patient's blood vessel after a range of conditioning regimens which can include total body irradiation (TBI), chemotherapy or TBI combined with chemotherapy. Due to the tumor-free graft, and its graft versus myeloma (GVM) effect, alloSCT showed a higher rate of CR and a lower risk of relapse compared with other treatments in patients from several studies (Bensinger 2009; Nishihori 2011). In addition, alloSCT provides the only curative potential for patients with MM (Arora 2005). However, alloSCT as a clinical treatment strategy for MM is still controversial. The high TRM, which exceeds 40%, and the deficiency of a match donor have posed the primary limits for wider application of this approach (Bjorkstrand 1996; Kuruvilla 2007). Since improvements in supplemental treatment and the development of a new therapy strategy, the data supported by the Center for International Blood and Marrow Transplantation Research (CIBMTR) have demonstrated that the risk of TRM with alloSCT has decreased almost 45% between 2001 and 2005 compared to the results during the previous period (Kumar 2011).
Since the turn of the century, a reduced intensity conditioning regimen before alloSCT was explored in order to reduce the high TRM while maintaining the GVM effect (Bensinger 2009; Nishihori 2011). This is so-called non-myeloablative alloSCT. Non-myeloablative alloSCT was proven to reduce the non-relapse mortality (NRM) rate but patients benefited little in OS due to the high recurrence (Crawley 2007). Subsequently another novel treatment strategy was designed for MM, namely prior ASCT followed by non-myeloablative alloSCT. Maloney and colleagues initially studied this and reported some promising results (Maloney 2003). The OS at a median follow-up of 552 days was 78%. The rate of CR and early TRM were 52% and 20%, respectively. Another long-term study including 102 patients with MM who received ASCT-alloSCT reported that the 5-year OS reached 69% and the 5-year progression-free survival (PFS) was 37% (Rotta 2009).
Recently, the results comparing ASCT-alloSCT with tandem ASCT have received more attention and several studies have focused on them. A study by Bruno et al reported that OS in patients who received an allograft was 80 months, compared with 54 months in patients who received double autografts (Krishnan 2011). On the other hand, the OS was not significantly different between ASCT-alloSCT and tandem ASCT in another trial (Bruno 2007).
How the intervention might work
High-intensity conditioning chemotherapy agents before ASCT not only eradicate neoplastic plasma cells but also suppress the hemopoietic system at the same time. The functional mechanism of ASCT treatment depends on hematopoietic reconstitution (Bensinger 2009; Blade 2010b). The hematopoietic stem cells possess the capacity for self-renewal and multilineage differentiation (Dykstra 2008). These cells migrate through the barrier between bone marrow (BM) and blood and return to the BM compartment. Thus the state of cytoreduction is rescued by infusing patients' own stem cells (Nishihori 2011; Servais 2011). Different from ASCT, alloSCT provides an additional immune reconstitution (Blade 2010b). The hematopoietic stem cells from donors have an advantage in that the GVM effect relies upon donor T lymphocytes. This effect was recognized in a series of clinical studies. In 2004, Lokhorst and colleagues included 54 patients with MM who relapsed after an alloSCT and received a donor lymphocyte infusion (DLI) (Lokhorst 2004). Twenty-eight patients responded to the DLI, nine patients had CR and 19 had a partial response. On the other hand, Rosinol et al indicated that patients with graft-versus-host disease (GVHD) had a lower rate of relapse during the trial (Rosinol 2008).
Why it is important to do this review
The choice between ASCT and alloSCT for treating MM is still controversial due to the advantages and disadvantages of each intervention. Therefore, a systematic review and meta-analysis that aims to compare the effect of ASCT and alloSCT in patients with newly diagnosed MM is needed in the hope of eliminating the controversy by providing evidence on the role of ASCT versus alloSCT in the treatment of MM.