High‐dose chemotherapy and autologous stem cell transplantation for multiple myeloma
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
This review consists of two comparisons, which are to be analysed separately:
(I) To determine whether high‐dose chemotherapy and autologous stem cell transplantation is more effective than conventional chemotherapy for patients with multiple myeloma,
and
(II) to determine whether tandem high‐dose chemotherapy and autologous stem cell transplantation is more effective than single high‐dose chemotherapy and autologous stem cell transplantation for patients with multiple myeloma.
Background
Multiple myeloma (MM) is a haematological malignancy, which contributes to 10% of haematological malignancies and 1% of all malignancies (Jemal 2002). According to the World Health Organization (WHO) classification it belongs to peripheral B‐cell lymphoma. Myeloma cells derive from antibody‐producing B‐cells, therefore MM is characterized by presence of monoclonal protein in the serum and/or urine. Other important diagnostic and clinical features are osteolytic lesions and increased plasma cells in the bone marrow. MM was first described around 1850 by Bence‐Jones and Dalrymple in England. The term MM was introduced by Rustitzky in 1873. The incidence is approximately 4 per 100.000 per year (Kyle 1994) with regional differences ranging from 1‐4/100.00 and a male predominance (Durie 2001, Morgan 2002, Wingo 1998, Rajkumar 2002). The incidence increases steadily with age (Schwartz 1990). The median age of patients at diagnosis is about 65 years. Despite new approaches, especially regarding pathophysiology, the main cause of MM remains unknown (Durie 2001). Ionizing radiation, chemicals, family history and certain viruses such as human immunodeficiency virus (HIV), Epstein Barr Virus (EBV) and simian virus 40 (SV40) are considered to be risk factors for the development of MM (Durie 2001).
Patients are classified into 3 stages according to the Durie and Salmon staging system which is based on a combination of factors that correlates with the myeloma cell mass (Durie 1975). The localized form, called plasmacytoma, contributes only to 3% (Alexanian 1994) and must be regarded separately, because it differs from the disseminated form in terms of treatment and prognosis. Another subdivision, primarily of prognostic value, can be drawn by the immunoglobulin subtype which is detected in the serum or urine. Further prognostic factors are ß‐2‐microglobulin, albumin, anaemia, age, C‐reactive‐protein (CRP), plasma‐cell‐labelling‐index, and more recently demonstrated cytogenetic changes, such as chromosome 13 and chromosome 11 abnormalities, which are proposed to have strong correlation to a worse outcome (Desikan 2000).
Prognosis of symptomatic patients suffering from MM remains poor. The median survival is less than 3 years in patients treated with conventional chemotherapy consisting of melphalan and prednisone (MP) (Bergsagel 1998), established in 1969 by Alexanian (Alexanian 1969). The overall response rate is about 50‐60%, containing only 5‐15% of complete remissions (Alexanian 1994, Gregory 1992). Before the introduction of chemotherapy, patients had a median survival of 7 months. Several attempts introducing novel agents and drug combinations have been made to improve outcome, such as VBMCP, ABCM, VAD, high‐dose dexamethasone, and VMCP/VBAP. These more aggressive combination chemotherapy regimes resulted in superior response rates of 60‐70% (MTCG 1998 (Myeloma Trialists' Collaborative Group), Alexanian 1994). However, meta‐analyses consisting of randomized trials failed to show a survival benefit of these combination chemotherapies over standard MP regimen (Djulbegovic 1991, Gregory 1992, MTCG 1998).
Since McElwain demonstrated a dose‐response effect in the early 1980s (McElwain 1983), one approach was to intensify chemotherapy. Studies containing high‐dose chemotherapy (HDT) followed, but toxicity was high and myelosuppression were extensive, therefore survival was not substantially prolonged (Gore 1989, Harousseau 1992, Attal 1992, Reece 1993). Improvement to allow delivery of HDT has then been obtained by the use of peripheral blood progenitor cells, harvested after chemotherapy as well as growth factor priming. Treatment related mortality could be reduced to less than 5% (Vesole 1994, Jagannath 1997). Since the late 1980s the number of patients with MM who have received HDT has steadily increased. Attal et al were the first to compare high‐dose chemotherapy supported by autologous stem cell transplantation (ASCT) with conventional chemotherapy in a randomized trial which was published in 1996 (Attal 1996). They could demonstrate a significant higher response rate (CR: 21%) and a survival benefit (43% overall survival after 6 years) in patients younger than 65 years receiving HDT. More recently, non‐randomized studies also indicate that high‐dose procedures, single as well as tandem, can also be given to elderly patients and even in outpatient settings (Siegel 1999, Palumbo 1999, Dumontet 1998, Jagannath 1997). Only few other randomized studies on this topic have been published (Bladé 2002, Palumbo 2001, Lévy 2000, Morgan 2002). Results favored high‐dose therapy with ASCT according to response rate and survival, but were mostly not significant in contrast to those reported by Attal et al. In a recently published trial of the HOVON (Stichting Hemato‐Oncologie voor Volwassenen Nederland) group no survival benefit could be observed in patients receiving HDT and ASCT compared to patients receiving intensified conventional therapy without autologous stem cell support, although a significant higher rate of complete remissions was observed (Segeren 2003).
Regardless of the effectiveness of HDT and ASCT, the timing of this intervention remains unclear. Stem cell transplantation is often performed early in the course of the disease. However, one randomized trial indicates that there is no significant difference in outcome, if transplantation is delayed until relapse, provided that stem cells are harvested and cryopreserved early after diagnosis (Fermand 1998).
On the assumption of favourable outcome, in the early 1990s some investigators concentrated on double, otherwise called tandem, HDT and ASCT to further intensify therapy in the (Björkstrand 1995, Harousseau 1992). Feasibility of tandem HDT could be demonstrated in large patient cohorts. In a series of approximately 500 patients, 95% of patients completed first and 73% second HDT and ASCT (Vesole 1996). These results were confirmed by an update consisting of 1,000 patients, which also observed a low treatment‐related mortality of 2,7% with the first and 4,8% with second HDT supported by ASCT and a high complete remission rate of 44% (Desikan 2000). Several other non‐randomized studies demonstrated tolerability as well as increased response rates of tandem HDT (Barlogie 1999, Vesole 1994, Weaver 1998, Björkstrand 1995). Recently a few randomized studies have been initiated to prove the survival benefit of double over single HDT and preliminary results have been published (Attal 2002, Cavo 2002, Fermand 2001).
As mentioned above several randomized trials on high‐dose therapy and stem cell transplantation in MM patients have been performed and completed recently. The value of a single and a tandem approach as well as the timing of these procedures remain to be determined. The aim of this review is to consider these trials.
Objectives
This review consists of two comparisons, which are to be analysed separately:
(I) To determine whether high‐dose chemotherapy and autologous stem cell transplantation is more effective than conventional chemotherapy for patients with multiple myeloma,
and
(II) to determine whether tandem high‐dose chemotherapy and autologous stem cell transplantation is more effective than single high‐dose chemotherapy and autologous stem cell transplantation for patients with multiple myeloma.
Methods
Criteria for considering studies for this review
Types of studies
(I) randomized controlled trials that compare the effectiveness of high‐dose chemotherapy and autologous stem cell transplantation with conventional chemotherapy for patients with multiple myeloma.
(II) randomized controlled trials that compare the effectiveness of tandem high‐dose chemotherapy and autologous stem cell transplantation with single high‐dose chemotherapy and autologous stem cell transplantation for patients with multiple myeloma.
Types of participants
Patients with histologically confirmed multiple myeloma at first diagnosis. No age restriction will be applied.
Types of interventions
(I) High‐dose chemotherapy and autologous bone marrow or stem cell transplantation with conventional chemotherapy. The varying conventional chemotherapy regimens between the different trials should be of equivalent effectiveness compared to the standard Alexanian Regimen with melphalan and prednisone (MP). The approximate effectiveness of other treatment regimens than MP must be clearly evident from the study literature. This rationale should be seen in the context of clinical practice which suggests that conventional therapy regimens in the control groups may include other agents.
(II) Tandem high‐dose chemotherapy and autologous stem cell transplantation with single high‐dose chemotherapy and autologous stem cell transplantation, regardless of the timing of transplantation. Some trials start induction therapy with 4 to 6 cycles of conventional chemotherapy and change to high dose therapy (early transplantation or substitution), other trials add the transplantation to a complete conventional chemotherapy (late transplantation or addition).
Types of outcome measures
Studies should include at least one of the following outcomes:
overall survival
event‐free survival
time to tumor progression
treatment related mortality
response rate
quality of life measures
Search methods for identification of studies
All searches start in the year 1990, as we do not anticipate data before that date. Same search strategies were used to identify both comparisons.
1.) Electronic searches (1990‐2003):
Cochrane Controlled Trial Register, MEDLINE, CancerLit, EMBASE
Databases of ongoing trials:
‐www.controlled‐trials.com
‐http://clinicaltrials.nci.nih.gov
‐http://clinicaltrials.gov/ct/gui
‐www.eortc.be/
‐www.ctc.usyd.edu.au/
‐www.trialscentral.org/index.html
Medline search:
#1 the Cochrane randomisation filter (Dickersin 1994, Robinson 2002)
#2 MULTIPLE MYELOMA:ME
#3 MYELOM*
#4 PLASMACYTOMA:ME
#5 PLASM?CYTOMA*
#6 MYELOMATOSIS
#7 LEUKEMIA, PLASMACYTIC:ME
#8 PLASMA* near NEOPLAS*
#9 HEMATOLOGIC NEOPLASMS:ME
#10 HEMATO* near MALIGN*
#11 HAEMATO* near MALIGN*
#12 HEMATO* near NEOPLAS*
#13 HAEMATO* near NEOPLAS*
#14 (#2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13)
#15 AUTOLOG*
#16 AUTOGRAFT*
#17 AUTO‐TRANSPLANT*
#18 AUTOTRANSPLANT*
#19 TRANSPLANTATION, AUTOLOGOUS:ME
#20 BONE MARROW TRANSPLANTATION:ME
#21 BONE‐MARROW
#22 BONE near MARROW
#23 STEMCELL*
#24 STEM‐CELL*
#24 STEM* near CELL*
#26 PBSCT
#27 BSCT
#28 ASCT
#29 ABMT
#30 HIGHDOSE
#31 HIGH‐DOSE
#32 HIGH near DOSE
#33 INTENSIVE near *THERAPY*
#33 TANDEM near TRANSPLANT*
#34 DOUBLE near TRANSPLANT*
#35 (#15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31 or #32 or #33 or #34)
#36 (#1 and #14 and #35)
2.) Hand searches (1990‐2003):
‐ Citations from identified trials and relevant review articles
‐ Hand searching of the conference proceedings of the American Society of Clinical Oncology, the American Society of Hematology, the European Society for Medical Oncology, the British Society of Haematology, the European Haematology Association, and the European Group for Blood and Marrow Transplantation.
3.) Contact:
‐ Groups or individuals who may have done randomized trials in autologous transplantation as therapy for multiple myeloma.
Data collection and analysis
Trials selection
Titles and abstracts of studies identified from the above sources will be undertaken independently by two reviewers. First screening will discard studies that are clearly ineligible. If this cannot be done satisfactory from title and abstract, a full text version will be obtained and eligibility discussed. The aim is to be overly inclusive rather than to risk losing relevant studies. Selected studies will be assessed with an eligibility form whether they meet the inclusion criteria, any disagreement is to be resolved by discussion. If necessary, further information will be sought from the authors where articles contain insufficient data to make a decision about eligibility. The eligibility form contains the following questions:
Q1. Is the study described as randomized?
Q2. Is the diagnosis of multiple myeloma histologically confirmed?
Q3. Were the participants previously untreated regarding specific myeloma therapy?
Q4. According to the first comparison (I): Were the participants in the experimental group treated by high‐dose chemotherapy and autologous stem cell transplantation?
According to the second comparison (II): Were the participants in the experimental group treated by double high‐dose chemotherapy and autologous stem cell transplantation?
Q5. According to the first comparison (I): Were the participants in the control group treated by a chemotherapy comparable to standard melphalan and prednisone regimen?
According to the second comparison (II): Were the participants in the control group treated by high‐dose chemotherapy and autologous stem cell transplantation?
Quality assessment
The quality of all studies which are deemed eligible for the review will be assessed independently by two reviewers, with discrepancies to be resolved by discussion. Quality will be assessed using an assessment form designed for the topic of this review (sources: Moher 2001, Verhagen 1998, Juni 2001). The following criteria will be considered:
1.) Was the method of randomisation satisfactory?
2.) Was the treatment allocation concealed?
3.) Was the number and reason of withdrawals, dropouts and loss to follow‐up in each group stated?
4.) Was an intention‐to‐treat analysis performed?
For any criterion that is unclear the first author of the study will be contacted.
Data Extraction
Data concerning details of study population, intervention and outcomes will be extracted independently by two reviewers using a standardised data extraction form. This form will include at least the following terms:
General information: Title, authors, source, publication year, country, language, duplicate publications, source of funding
Trial characteristics: design and methods of the study
Interventions: interventions with dose and timing, co‐treatment, source of stem cells, purging
Patients: sample size, exclusion criteria, baseline characteristics, diagnostic criteria for MM as well as for response to treatment, withdrawals, losses to follow‐up
Outcomes: as specified above and duration of follow‐up
Where possible, missing data will be sought from the authors.
Data analysis
The analyses will be of event data (dichotomous data). Weighted estimates of treatment effects across trials odds ratio (OR) and relative risks (RR) will be calculated using both the assumption free model (standard fixed, Mantel‐Haenszel) and the standard random effect model. To obtain numbers needed to treat (NNT) we will calculate risk differences (RD). Continuous data will be calculated as weighted mean differences (WMD) with 95% confidence intervals and summarized if appropriate. Time to event data will be calculated as Hazard Ratios (HR) according to Parmar (Parmar 1998). Publication bias will be assessed by using the Funnel plot. Heterogeneity of treatment effect between trials will be tested using a Chi‐squared statistic with significance being set at p < 0.05. Expected causes of heterogeneity will be assessed by sensitivity and subgroup analyses as described below. Unexpected causes of heterogeneity will be explored by meta‐regression before performing a subgroup analysis. All analyses will be conducted using appropriate software.
Sensitivity analysis and subgroup analysis
Sensitivity analysis:
‐ Study quality and study size.
Subgroup analysis:
‐ Varying chemotherapy regimen for conventional as well as for high‐dose and double high‐dose therapy.
‐ Intensity of the induction therapy in the control arm. This can be of intensity comparable to MP or escalated in dose and time.
‐ Different timing of transplantation: Some trials replace cycles of standard therapy by high‐dose therapy, other trials add the transplantation to a complete conventional induction therapy.
‐ Different prognostic factors (such as age, stage, myeloma subtype)
