Allogeneic stem cell transplantation with matched sibling donor versus autologous stem cell transplantation for newly diagnosed Multiple Myeloma

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To compare the effects of the use of autologous stem cell transplantation (ASCT), which includes single ASCT and tandem ASCT, versus allogeneic stem cell transplantation (alloSCT) from a matched sibling donor, which includes single alloSCT, non-myeloablative alloSCT and ASCT-alloSCT, in patients with multiple myeloma (MM).

Background

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.

Objectives

To compare the effects of the use of autologous stem cell transplantation (ASCT), which includes single ASCT and tandem ASCT, versus allogeneic stem cell transplantation (alloSCT) from a matched sibling donor, which includes single alloSCT, non-myeloablative alloSCT and ASCT-alloSCT, in patients with multiple myeloma (MM).

Methods

Criteria for considering studies for this review

Types of studies

We will only consider prospective controlled clinical trials which assigned participants according to whether or not a participant had a matched sibling donor available. Because these trials essentially used a random process in deciding the presence or absence of a donor, this can be used as a surrogate for randomization, defined as Mendelian randomization by Gray and Wheatley (Wheatley 2004). Due to the potential bias or unreliable outcome, we will exclude trials in which participants were allocated with other methods such as using economic conditions or physical conditions. We will include both full-length articles and abstract publications.

Types of participants

We will include participants with newly diagnosed MM based on various diagnosis standards of MM (Bird 2011; Kyle 2009). These standards depend on the number of abnormal proliferous plasma cells in bone marrow, organ impairment and M-protein in serum or urine (such as the standards of the World Health Organization (WHO) and the International Myeloma Working Group (IMWG)). We will not set any restrictions on gender, age, ethnicity or stage.

We will exclude participants diagnosed with smoldering myeloma and other plasma cell disorders such as monoclonal gammopathy of undetermined significance, heavy chain diseases, primary systemic amyloidosis and plasmocytoma. This is because these diseases have different biological behavior and usually need different therapeutic methods. Finally, we will also exclude relapsed patients.

Types of interventions

We will include all trials which compare ASCT with alloSCT of matched sibling donor cells. We will accept any induction regimen, conditioning regimen, maintenance regimen and source of hemopoietic stem cells, either from peripheral blood or bone marrow. We will also allow all trials comparing tandem ASCT versus ASCT followed by alloSCT with matched sibling donor cells, irrespective of the timing of transplantations. Moreover, we will accept all types of regimens and any source of hemopoietic stem cells.

Types of outcome measures

Primary outcomes
  • Overall survival (OS)

  • Event-free survival (EFS)

The OS is defined as the time from assignment to death for any reasons. EFS is defined as the time from assignment to tumour progression, relapse or death without relapse. We have selected OS and EFS as the primary outcomes because they are clinically relevant outcomes which have attracted much attention from both researchers and patients. Besides, OS is related to death, which is not affected by bias. Similarly, EFS is an effective measure to express efficacy of treatments. In addition, EFS reduces the follow-up time compared with OS. Some of the trials have used similar endpoints like progression-free survival (PFS) or freedom from treatment failure (FFTF) and might not report EFS. We will also extract the data for PFS or FFTF and perform sensitivity analysis according to these endpoints.

Secondary outcomes
  • Complete remission (CR) rate

  • Relapse rate

  • Adverse effects (treatment-related mortality, incidence of grade III and IV graft-versus-host disease (GVHD), cumulative incidence of II, III and IV GVHD, incidence of fatal or life-threatening infectious complications)

  • Quality of life (using a standardized, validated questionnaire)

Search methods for identification of studies

We will adopt our search strategies from those suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Lefebvre 2011). We will not apply any language restriction in order to reduce language bias.

Electronic searches

We will search the following bibliographic databases:

  • Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, latest Issue), see Appendix 1 for search strategy;

  • MEDLINE (1966 to present), see Appendix 2 for search strategy;

  • EMBASE (1974 to present), see Appendix 3 for search strategy; and

  • Chinese BioMedical Literature Database (CBM) (1978 to present).

We will search conference proceedings of the following societies for the years they are not included in CENTRAL (1990 to present):

We will search the following database of ongoing trials:

Searching other resources

We will handsearch:

  • Conference Proceedings of the Chinese Society of Hematology (1980 to 2012); and

  • references of all identified trials, relevant review articles and current treatment guidelines.

We will contact experts in this area for extra unpublished and ongoing studies.

Data collection and analysis

Selection of studies

Two review authors will independently inspect all titles and abstracts of studies from the above literature search and identify potentially relevant studies to ensure that selection is reliable. Obviously ineligible studies will be removed. Where disagreement occurs, this will be resolved by discussion with a third review author. If necessary, the full article will be obtained for further evaluation (Higgins 2011a). We will endeavour to retrieve the full text of the potentially eligible studies, and we will also try to get sufficient information from unpublished trials. Two review authors will independently screen these studies to decide whether they meet all the review criteria in the methods section. The review authors will not be blinded to the authors' names, institutions and the journals of publication. Any disagreements will be discussed with a third review author. Duplicate studies will be identified and removed to avoid biases (Higgins 2011a). The detailed results of the inspection of the studies will be documented in a PRISMA chart (Moher 2009).

Data extraction and management

Two review authors will independently extract data from the included studies and record the information on paper forms. Similarly, any disagreement will be discussed with a third review author until consensus is reached. All data will be transferred into Review Manager 5 (RevMan 2011). The data will include the following information (Higgins 2011a).

  • General information about trials: title, author, country, contact address, publication year, publication type, publication status, language, center, sample size, reasons for exclusion and inclusion.

  • Study characteristics: design, objective, total study duration, allocation method (Mendelian randomization), blinding of outcome assessors, statistical methods, subgroup analysis, results, and key conclusions.

  • Participants: age, gender, ethnicity, stage, diagnostic criteria, setting of studies, prognostic factors, inclusion and exclusion criteria, total number recruited and allocated and analyzed, reasons for withdrawals, and losses to follow-up.

  • Interventions: in ASCT group, we will extract data including hemopoietic stem cell source (peripheral blood or bone marrow), types of induction and conditioning regimens (including the type and dosage of chemotherapy and radiation, number of cycles), number of transplants, and types of supportive treatment. In the alloSCT group, we will also extract data including hemopoietic stem cell source, types of conditioning regimens, numbers of transplants (if it is ASCT-alloSCT we will also include types of induction regimens), and types of supportive treatment.

  • Other therapies: transfusion requirements, addition of antibiotics, granulocyte-colony stimulating factor (G-CSF), and donor lymphocyte infusion.

  • Outcomes: as specified in the section on primary and secondary outcomes.

If the full text articles do not give sufficient information, we will contact the authors for further details.

Assessment of risk of bias in included studies

Two review authors will work independently to assess the risk of bias in the included studies. The review authors will judge the risk of bias of included studies in the following areas (Higgins 2011b):

  • sequence generation;

  • allocation concealment;

  • blinding of participants, personnel and outcome assessors;

  • incomplete outcome data;

  • selective outcome reporting; and

  • other sources of bias.

The risk of bias in each domain will be assessed and categorized into:

  • low risk of bias, plausible bias unlikely to seriously alter the results;

  • high risk of bias, plausible bias that seriously weakens confidence in the results; and

  • unclear risk of bias, plausible bias that raises some doubt about the results.

Any inadequate information will be resolved through direct contact with the authors of the study. Any disagreement will be discussed with a third review author to reach a consensus.

Measures of treatment effect

For time-to-event data, we intend to extract from the reported data hazard ratios (HRs) as measures of treatment effect with 95% confidence intervals (CI) as a measure of uncertainty. If HRs are not available, we will use the methods described by Parmar and Tierney to calculate HRs based on the data from published results (Parmar 1998; Tierney 2007). For dichotomous data, we will calculate the relative risk (RR) and its 95% CI (Deeks 2011). We will also calculate the number needed to treat (NNT) and number needed to harm (NNH) to re-express the results to facilitate interpretation. For continuous data, we will calculate the mean difference (MD) with 95% CI if the trials used the same scale or calculate the standardized mean difference (SMD) with 95% CI if the trials used different scales.

Unit of analysis issues

There are no relevant unit of analysis issues.

Dealing with missing data

We will deal with missing data as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011c). Firstly, we will categorize missing data into 'missing at random' and 'not missing at random'. If data are 'missing at random', we will only analyze the available data. Inversely, we will contact the authors to obtain missing data which are 'not missing at random'. If the missing data still cannot be obtained, we will make explicit the assumptions of any methods used to cope with the missing data. We will perform sensitivity analyses to assess how sensitive the results are to reasonable changes in the assumptions that are made. We will also assess the potential impact of missing data on the findings of the review in the discussion section. Besides, we will not reproduce or analyze the data in which more than 50% of participants were lost to follow-up, resulting in poor credibility of any results.

Assessment of heterogeneity

We will consider the included studies altogether to identify any factors that lead to clinical heterogeneity. For statistical heterogeneity, we will visually inspect the overlap in confidence intervals on the forest plot to investigate the possibility of heterogeneity. The heterogeneity of treatment effects across studies will be assessed using the Chi2 test with a significance level of P < 0.1. The quantity of heterogeneity will be detected using the I2 statistic (Deeks 2011). The rough guide to the interpretation of I2 is as follows:

  • 0% to 40%, might not be important;

  • 30% to 60%, may represent moderate heterogeneity;

  • 50% to 90%, may represent substantial heterogeneity; and

  • 75% to 100%, considerable heterogeneity.

If heterogeneity is identified, the potential causes of inconsistency among these studies will be explored. Firstly, we will check the data again to determine the accuracy of the data. Then we will conduct subgroup and sensitivity analyses as defined in the relevant sections.

Assessment of reporting biases

We will produce funnel plots and check their asymmetry to detect potential reporting bias if there are at least 10 studies available in meta-analysis. This method has low power to distinguish false (by chance) from true asymmetry when there are fewer studies.

Data synthesis

We will use the latest Cochrane statistical package Review Manager 5 (RevMan 2011) to perform meta-analysis using the methods recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2011). A fixed-effect model will be used for meta-analysis. For dichotomous data, we will pool RRs with their confidence intervals using the Mantel-Haenszel method. For continuous or time-to-event data, we will use the inverse variance approach. We will repeat the primary analysis using a random-effects model with the DerSimonian and Laird method in a sensitivity analysis.

We will use the software GRADEpro 3.6 to create 'Summary of findings' tables as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2011). We will summarize the evidence on OS, EFS, CR rate, relapse rate and adverse effects in these 'Summary of findings' tables.

Subgroup analysis and investigation of heterogeneity

We will consider the following subgroups:

  • age (adults < 65 years versus adults ≥ 65 years, or otherwise defined for elderly MM patients);

  • stage of myeloma (stage II versus stage III);

  • type of induction regimen (new drug such as bortezomib, thalidomde, lenalidomide based regimens versus conventional chemotherapy);

  • type of stem cell source (bone marrow transplantation or peripheral stem cell transplantation); and

  • single ASCT and tandem ASCT (single ASCT compared with single alloSCT versus tandem ASCT compared with ASCT-alloSCT).

Sensitivity analysis

We plan to examine the robustness of the review results using sensitivity analysis based on the following factors:

  • quality components, including or excluding studies with high risk of bias;

  • event-free survival (EFS), including or excluding studies with reporting progression-free survival (PFS) or freedom from treatment failure (FFTF); and

  • study size.

Acknowledgements

We are grateful to Ina Monsef (Trial Search Co-ordinator of the CHMG) for her assistance with the search strategy and Sabine Kluge (Managing Editor of the CHMG ) for her assistance with this protocol.

Appendices

Appendix 1. CENTRAL search strategy

IDSearch
#1MeSH descriptor Multiple Myeloma explode all trees
#2myelom*
#3MeSH descriptor Plasmacytoma explode all trees
#4plasm*cytom*
#5plasmozytom*
#6plasm* cell myelom*
#7myelomatosis
#8MeSH descriptor Leukemia, Plasma Cell explode all trees
#9(plasma* NEAR/3 neoplas*)
#10kahler
#11(#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10)
#12MeSH descriptor Stem Cell Transplantation explode all trees
#13MeSH descriptor Hematopoietic Stem Cell Transplantation explode all trees
#14MeSH descriptor Bone Marrow Transplantation explode all trees
#15MeSH descriptor Peripheral Blood Stem Cell Transplantation explode all trees
#16MeSH descriptor Cord Blood Stem Cell Transplantation explode all trees
#17MeSH descriptor Mesenchymal Stem Cell Transplantation explode all trees
#18(bone marrow NEAR/2 (transplant* or graft* or trasplant* or rescue*))
#19(stem cell* or stem-cell*)
#20"progenitor cell*"
#21(ASCT* or ABMT* or PBPC* or PBSCT* or PSCT* or BMT* or SCT* or HSCT*)
#22(#12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21)
#23MeSH descriptor Transplantation Conditioning explode all trees
#24myeloablat*
#25(nonmyeloablat* or non-myeloablat*)
#26reduced intens*
#27(mini-tra*splant* or minitra*splant*)
#28(#23 OR #24 OR #25 OR #26 OR #27)
#29MeSH descriptor Transplantation, Homologous explode all trees
#30(allograft* or allo-graft*)
#31(allotransplant* or allo-transplant*)
#32(allotrasplant* or allo-trasplant*)
#33(allogen* or allo-gen*)
#34((allogen* or allo-gen*) NEAR/5 (transplant* or trasplant* or graft* or rescue*))
#35(homograft* or homo-graft*)
#36homolog*
#37(homotransplant* or homo-transplant*)
#38(homotrasplant* or homo-trasplant*)
#39(#29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37 OR #38)
#40MeSH descriptor Transplantation, Autologous explode all trees
#41(autograft* or auto-graft*)
#42(autotransplant* or auto-transplant*)
#43(autotra*splant* or auto-tra*splant*)
#44(autolog* NEAR/5 (transplant* or graft* or trasplant* or rescue*))
#45(#40 OR #41 OR #42 OR #43 OR #44)
#46(#22 OR #28 OR #39 OR #45)
#47(#11 AND #46)
#48"accession number" near pubmed
#49(#47 AND NOT #48)

Appendix 2. MEDLINE search strategy

MEDLINE/Ovid

#Searches
1exp MULTIPLE MYELOMA/
2myelom$.tw,kf,ot.
3exp PLASMACYTOMA/
4plasm?cytom$.tw,kf,ot.
5plasmozytom$.tw,kf,ot.
6plasm$ cell myelom$.tw,kf,ot.
7myelomatosis.tw,kf,ot.
8LEUKEMIA, PLASMA CELL/
9(plasma$ adj3 neoplas$).tw,kf,ot.
10kahler.tw,kf,ot.
11or/1-10
12exp STEM CELL TRANSPLANTATION/
13HEMATOPOIETIC STEM CELL TRANSPLANTATION/
14BONE MARROW TRANSPLANTATION/
15PERIPHERAL BLOOD STEM CELL TRANSPLANTATION/
16CORD BLOOD STEM CELL TRANSPLANTATION/
17MESENCHYMAL STEM CELL TRANSPLANTATION/
18(bone marrow adj2 (transplant$ or graft$ or trasplant$ or rescue$)).tw,kf,ot.
19(stem cell$ or stem-cell$).tw,kf,ot.
20"progenitor cell$".tw,kf,ot.
21(ASCT or ABMT or PBPC or PBSCT or PSCT or BMT or SCT or HSCT).tw,kf,ot.
22or/12-21
23TRANSPLANTATION CONDITIONING/
24myeloablat$.tw,kf,ot.
25(nonmyeloablat$ or non-myeloablat$).tw,kf,ot.
26reduced intens$.tw,kf,ot.
27(mini-tra?splant$ or minitra?splant$).tw,kf,ot.
28or/23-27
29exp TRANSPLANTATION, HOMOLOGOUS/
30(allograft$ or allo-graft$).tw,kf,ot.
31(allotransplant$ or allo-transplant$).tw,kf,ot.
32(allotrasplant$ or allo-trasplant$).tw,kf,ot.
33(allogen$ or allo-gen$).tw,kf,ot.
34((allogen$ or allo-gen$) adj5 (transplant$ or trasplant$ or graft$ or rescue$)).tw,kf,ot.
35(homograft$ or homo-graft$).tw,kf,ot.
36homolog*.tw,kf,ot.
37(homotransplant$ or homo-transplant$).tw,kf,ot.
38(homotrasplant$ or homo-trasplant$).tw,kf,ot.
39or/29-38
40TRANSPLANTATION, AUTOLOGOUS/
41(autograft$ or auto-graft$).tw,kf,ot.
42(autotransplant$ or auto-transplant$).tw,kf,ot.
43(autotra?splant$ or auto-tra?splant$).tw,kf,ot.
44(autolog$ adj5 (transplant$ or graft$ or trasplant$ or rescue$)).tw,kf,ot.
45or/40-44
4622 or 28 or 39 or 45
4711 and 46
48randomized controlled trial.pt.
49controlled clinical trial.pt.
50randomi?ed.ab.
51placebo.ab.
52drug therapy.fs.
53randomly.ab.
54trial.ab.
55groups.ab.
56or/48-55
57humans.sh.
5856 and 57
5947 and 58

 

Appendix 3. EMBASE search strategy

#Searches
1‘MULTIPLE MYELOMA’/exp/de
2myelom*:ab,ti,tt
3‘PLASMACYTOMA’/exp/de
4plasm*cytom*:ab,ti,tt
5plasmozytom*:ab,ti,tt
6plasm* cell myelom*:ab,ti,tt
7‘myelomatosis’:ab,ti,tt
8‘PLASMA CELL LEUKEMIA’:de
9(plasma* NEAR/3 neoplas*):ab,ti,tt
10‘kahler’:ab,ti,tt
11#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10
12‘STEM CELL TRANSPLANTATION’/exp/de
13‘HEMATOPOIETIC STEM C ELL TRANSPLANTATION’:de
14‘BONE MARROW TRANSPLANTATION’:de
15‘PERIPHERAL BLOOD STEM CELL TRANSPLANTATION’:de
16‘CORD BLOOD STEM CELL TRANSPLANTATION’:de
17‘MESENCHYMAL STEM CEL L TRANSPLANTATION’:de
18(‘bone marrow’ NEAR/2 (transplant* OR graft* OR trasplant* OR rescue*)):ab,ti,tt
19(stem cell* OR stem-cell*):ab,ti,tt
20progenitor cell*:ab,ti,tt
21(‘ASCT’ OR ‘ABMT’ OR ‘PBPC’ OR ‘PBSCT’ OR ‘PSCT’ OR ‘BMT’ OR ‘SCT’ OR ‘HSCT’):ab,ti,tt
22#12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21
23‘ ‘MYELOABLATIVE CONDITIONING’:de
24‘NONMYELOABLATIVE CONDITIONING’:de
25‘REDUCED INTENSITY CONDITIONING’:de
26myeloablat*:ab,ti,tt
27(nonmyeloablat* OR non-myeloablat*):ab,ti,tt
28reduced intens*:ab,ti,tt
29(mini-tra*splant* OR minitra*splant*):ab,ti,tt
30#23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29
31‘ALLOTRANSPLANTATION’:de
32(allograft* OR allo-graft*):ab,ti,tt
33(allotransplant* OR allo-transplant*):ab,ti,tt
34(allotrasplant* OR allo-trasplant*):ab,ti,tt
35(allogen* OR allo-gen*):ab,ti,tt
36((allogen* OR allo-gen*) NEAR/5 (transplant* OR trasplant* OR graft* OR rescue*)):ab,ti,tt
37(homograft* OR homo-graft*):ab,ti,tt
38homolog*:ab,ti,tt
39(homotransplant* OR homo-transplant*):ab,ti,tt
40(homotrasplant* OR homo-trasplant*):ab,ti,tt
41#31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37OR #38 OR #39 OR #40
42‘AUTOTRANSPLANTATION’:de
43(autograft* OR auto-graft*):ab,ti,tt
44(autotransplant* OR auto-transplant*):ab,ti,tt
45(autotra*splant* OR auto-tra*splant*):ab,ti,tt
46(autolog* NEAR/5 (transplant* OR graft* OR trasplant* OR rescue*)):ab,ti,tt
47#42 OR #43 OR #44 OR #45 OR #46
48#22 or #30 or #41 or #47
47#11 and #48
48'randomized controlled trial'/exp OR 'single blind procedure'/exp OR  'double blind procedure'/exp OR 'crossover procedure'/exp
49random*:ab,ti OR placebo*:ab,ti OR allocat*:ab,ti OR crossover*:ab,ti  OR 'cross over':ab,ti OR trial:ti OR (doubl* NEXT/1 blind*):ab,ti
50#48 OR #49
51'animal'/de OR 'animal experiment'/de OR 'nonhuman'/de
52'human'/de
53#51 AND #52
54#51 NOT #53
55#50 NOT #54
56#47 AND #55

 

Contributions of authors

Ya Tan: developing protocol, identification of studies, screening studies, extracting data, conducting analysis, drafting report.

Shuangnian Xu: developing protocol, providing methodological and statistical perspectives, revising the protocol and the review.

Xi Li: screening studies, extracting data, conducting analysis.

Jieping Chen: developing protocol, identification of studies, screening studies, drafting report, revising the protocol and the review.

Declarations of interest

None known

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • National Natural Science Foud (81270605, 30971066), China.

  • Chongqing Natural Science Fund Project (CSTC, 2008BA5001), China.

  • Chongqing Postgraduate Education Reform Project (yjg123114), China.

Ancillary