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Adobe Flash Player is required to view this feature. If you are using an operating system that does not support Flash, we are working to bring you alternative formats. Original Article High-Dose Chemotherapy with Hematopoietic Stem-Cell Rescue for Multiple Myeloma J. Anthony Child, M.D., Gareth J. Morgan, Ph.D., Faith E. Davies, M.D., Roger G.

Owen, M.D., Susan E. Bell, D.Phil., Kim Hawkins, M.Sc., Julia Brown, M.Sc., Mark T. Drayson, Ph.D., and Peter J. Selby, M.D., for the Medical Research Council Adult Leukaemia Working Party N Engl J Med 2003; 348:1875-1883 DOI: 10.1056/NEJMoa022340. Results Among the 401 patients who could be evaluated, the rates of complete response were higher in the intensive-therapy group than in the standard-therapy group (44 percent vs.

8 percent, P. In the controversial field of high-dose chemotherapy, multiple myeloma is one disease in which this approach may provide tangible benefits, but data from rigorous studies are limited. In randomized trials carried out by the Medical Research Council of the United Kingdom between 1964 and 1990, the most effective standard regimen of conventional-dose chemotherapy consisted of doxorubicin, carmustine, cyclophosphamide, and melphalan and resulted in a median survival of 32 months. Other conventional-dose regimens resulted in improved response rates, but not enduring remissions. Escalating the doses of melphalan to a level requiring autologous stem-cell rescue resulted in even higher rates of remission, with a complete response in approximately 50 percent of patients.

An approach involving conventional-dose chemotherapy followed by high-dose therapy offered the prospect of a better outcome, but the evidence of a survival benefit has been inconclusive in nonrandomized and randomized studies. To investigate this strategy further, we initiated a phase 3 trial in which patients received either a standard regimen of doxorubicin, carmustine, cyclophosphamide, and melphalan or a regimen consisting of infusional combination chemotherapy followed by high-dose melphalan with autologous stem-cell transplantation. Both regimens included interferon alfa as maintenance therapy. Patients The Medical Research Council Myeloma VII Trial (ISRCTN66518389) was conducted from October 1993 to October 2000.

All patients were previously untreated, fulfilled the Medical Research Council criteria for myeloma requiring treatment, were less than 65 years of age, and were suitable candidates for high-dose therapy. Written informed consent was obtained from all patients. Randomization was by telephone and used a minimization algorithm based on age (.

Standard Therapy Standard therapy consisted of a short infusion of 30 mg of doxorubicin per square meter of body-surface area intravenously and 30 mg of carmustine per square meter intravenously on day 1 followed by 100 mg of cyclophosphamide per square meter per day orally and 6 mg of melphalan per square meter per day orally on days 22, 23, 24, and 25. The cycle was repeated every six weeks until the maximal response was attained. A minimum of 4 cycles was given, and the maximum was 12 cycles. There were per-protocol dose reductions in the case of renal dysfunction, but patients who had treatment delays owing to myelosuppression received 300 mg of cyclophosphamide per square meter intravenously each week plus 40 mg of prednisolone per square meter orally every other day for the first six weeks. The planned maintenance therapy was 3 million U of interferon alfa-2a (Roferon-A) subcutaneously three times per week. Intensive Therapy Intensive therapy consisted of a continuous infusion of 9 mg of doxorubicin per square meter per day and 0.4 mg of vincristine per day on days 1 through 4, 1 g of methylprednisolone per square meter per day intravenously or orally (maximum, 1.5 g) on days 1 through 5, and 500 mg of cyclophosphamide per day intravenously on days 1, 8, and 15. The cycle was repeated every 21 days until a maximal response was attained.

Ichiban Kirei Na Watashi Wo / Mika Nakashima. 01 ichiban kirei na watashi o / 一番綺麗な私を. Always / Mika Nakashima. 01 ALWAYS 02 BABY BABY BABY 03 SPIRAL 2009.11.04 nagareboshi / 流れ星. Nagareboshi / Mika Nakashima. 01 nagareboshi / 流れ星 02 Memory(feat.DAISHI DANCE).

A minimum of three cycles was given before stem cells were harvested. Patients with a serum creatinine level of more than 3.4 mg per deciliter (300 μmol per liter) did not receive cyclophosphamide; cyclophosphamide was omitted on day 8 or 15 (or both) in the event of undue myelosuppression.

Peripheral-blood stem cells were typically mobilized by the administration of 2 to 4 g of cyclophosphamide per square meter intravenously with hydration and granulocyte colony-stimulating factor on days 5 through 12. High-dose melphalan was given at a dose of 200 mg per square meter followed by the reinfusion of peripheral-blood stem cells 24 hours later. A bone marrow autograft and total-body irradiation plus melphalan (140 mg per square meter) were permissible options. Methylprednisolone (1.5 g per day) was given intravenously for four days after the administration of high-dose melphalan. The dose of melphalan was reduced according to the creatinine clearance. The planned maintenance therapy was 3 million U of interferon alfa-2a administered subcutaneously three times per week.

Assessment of Response The response to treatment was monitored by means of serum and urine protein studies carried out centrally at the University of Birmingham. In the intensive-therapy group, the studies were conducted every three weeks during the chemotherapy regimen and every three months thereafter. In the standard-therapy group, the studies were conducted every three months.

Bone marrow aspirates and trephine specimens were obtained as needed to determine the response to induction therapy, and also at three months and yearly after the completion of high-dose therapy and at relapse in the intensive-therapy group, and at the time of the maximal response and at progression in the standard-therapy group. The response criteria of the European Group for Blood and Marrow Transplantation – International Bone Marrow Transplant Registry were used. A complete response was defined by the absence of monoclonal immunoglobulin in serum (or light chains in urine) on immunofixation.

Causes of death were recorded by the participating centers as attributable to myeloma, infection, a variety of other secondary causes, unrelated causes, or combinations of these if the cause of death was considered to be multifactorial. Statistical Analysis Assuming the survival rate at four years to be 60 percent in the standard-therapy group, the study required 710 patients to have 80 percent power to detect an absolute improvement in survival of 10 percent in the intensive-therapy group. The recruitment target was 750 patients.

The steering committee agreed to stop the trial in October 2000 when there was a total of 407 patients, in view of declining enrollment. The primary end points were overall survival and progression-free survival. Overall survival was calculated from the date of randomization to the date of death from any cause.

Data on patients who were lost to follow-up or who were alive at the time of analysis were censored in the survival analysis on the last date they were known to be alive. Progression-free survival was calculated from the date of randomization to the date of progression or death. Patients recorded as having died from multiple myeloma and for whom no prior date for progression was available were considered to have had progressive disease on the day of death. Data on patients who had not had progression were censored on the last date they were known to be alive and progression-free. Survival curves were constructed with the use of Kaplan–Meier estimates, and treatment groups were compared with the use of the log-rank test at a significance level of 5 percent. Cox proportional-hazards models were used to adjust survival analyses for minimization factors (age, serum creatinine level, and hemoglobin level) and to investigate the correlation of the beta 2-microglobulin level with survival (which was specified in the statistical-analysis plan before any data were analyzed).

A cutoff date of October 20, 2001, was used for survival analysis. The maximal response was compared in the treatment groups with the use of chi-square tests. The proportions of deaths recorded as solely or partly attributable to myeloma and solely or partly attributable to infection are reported, with 95 percent confidence intervals. All analyses were two-sided and carried out on an intention-to-treat basis with the use of SAS software (SAS Institute). We used published data to conduct a meta-analysis of trials comparing conventional therapy with high-dose therapy in patients with myeloma.

The resulting Forrest plot yielded an estimate of the odds ratio of the combined treatment effect, with 95 percent confidence intervals, with use of a fixed-effects approach. Analyses were performed with Review Manager software (version 4.1).

Characteristics of the Patients and Treatments A total of 407 patients were enrolled from 83 centers in the United Kingdom and New Zealand over a seven-year period from 1993 to 2000. Six patients could not be included in any data summaries or analyses: five underwent randomization in error, and one patient withdrew consent ( Figure 1 Summary of Treatment Received. A total of 200 patients were randomly assigned to receive standard therapy and 201 to receive intensive therapy.

The characteristics of the patients are summarized in Table 1 Base-Line Characteristics of the Randomized Patients.. The myeloma subtypes were as follows: IgG in 56 percent of patients, IgA in 22 percent, IgD in 2 percent, light chain in 13 percent, and nonsecretory in 4 percent; data on subtype were missing in 3 percent of cases. Summarizes the treatment received. In the intensive-therapy group, 197 patients received a median of five cycles (range, one to nine) of cyclophosphamide, vincristine, doxorubicin, and methylprednisolone.

In the standard-therapy group, 146 patients received a median of 6 cycles (range, 1 to 13) of doxorubicin, carmustine, cyclophosphamide, and melphalan; 47 received doxorubicin, carmustine, cyclophosphamide, and melphalan as well as cyclophosphamide weekly for a median of 4 cycles (range, 1 to 12); and 3 received cyclophosphamide weekly alone. In the intensive-therapy group, 50 of 201 patients (25 percent) did not receive high-dose melphalan, as a result of death, early disease progression (i.e., during induction chemotherapy), poor performance status, or low CD34 counts or by choice, and thus did not receive a stem-cell transplant. Therapy with high-dose melphalan was usually supported by the reinfusion of peripheral-blood stem cells (138 patients [92 percent]); only 8 patients received bone marrow (5 percent), and 3 received both bone marrow and stem cells (2 percent; this information was unavailable for 1 patient). The dose of melphalan was reduced in 17 patients (11 percent), as a result of poor stem-cell harvests, renal failure, or poor performance status. Eight patients received total-body irradiation plus melphalan (140 mg per square meter). Two patients received a second autograft at relapse.

Only 30 patients (15 percent) in the standard-therapy group went on to receive an autograft, and 4 (2 percent) an allograft, as part of off-protocol therapy. In the standard-therapy group, 84 patients (42 percent) received interferon alfa-2a for at least a month, as compared with 118 patients (59 percent) in the intensive-therapy group. Among these patients, the drug was stopped because of intolerance or adverse events in 14 (17 percent) and 39 (33 percent), respectively, and because of disease progression in 43 (51 percent) and 33 (28 percent), respectively. Overall Survival As of October 20, 2001, 206 of the 401 patients (51 percent) had died: 112 patients in the standard-therapy group and 94 in the intensive-therapy group. The median duration of follow-up among survivors was 42 months (range, 9 to 96), with an overall median survival of 48.5 months (95 percent confidence interval, 42.2 to 56.3). The median survival was 54.1 months (95 percent confidence interval, 44.9 to 65.2) in the intensive-therapy group and 42.3 months (95 percent confidence interval, 33.1 to 51.6) in the standard-therapy group (P=0.04 by the log-rank test and P=0.03 by the Wilcoxon test) ( Figure 2 Kaplan–Meier Estimates of Overall Survival in the Intention-to-Treat Population. Overall, there was an improvement in median survival of 11.8 months in the intensive-therapy group (median survival, 54.1 months; 95 percent confidence interval, 44.9 to 65.2) as compared with the standard-therapy group (42.3 months; 95 percent confidence interval, 33.1 to 51.6; P=0.04 by the log-rank test and P=0.03 by the Wilcoxon test).

A Cox model that adjusted for minimization factors showed that survival rates were higher among patients with a creatinine level of less than 1.7 mg per deciliter than among those with a level of 1.7 mg per deciliter or higher and among patients with a hemoglobin level of 9 g per deciliter or higher than among those with a level of less than 9 g per deciliter. A significant interaction between treatment group and the beta 2-microglobulin level was seen (P=0.003 in the Cox model), indicating that the treatment effect varied depending on the level of beta 2-microglobulin. Stratified log-rank analysis according to the serum levels of beta 2-microglobulin — low (less than 4 mg per liter), intermediate (4 to 8 mg per liter), or high (more than 8 mg per liter) — defined in previous Medical Research Council studies showed that within each stratum, the intensive-therapy group had a longer median survival than the standard-therapy group. This difference was greatest among those with base-line beta 2-microglobulin levels of more than 8 mg per liter. In these patients median survival was 41.9 months (95 percent confidence interval, 31.3 to 65.2) in the intensive-therapy group, as compared with 13.1 months (95 percent confidence interval, 9.2 to 23.9) in the standard-therapy group. Progression-Free Survival As of October 20, 2001, 288 of the 395 patients who could be evaluated for disease progression (73 percent) had evidence of progression; 36 in the standard-therapy group and 71 in the intensive-therapy group remained progression-free. Overall, the median duration of progression-free survival was 25.1 months (95 percent confidence interval, 21.4 to 27.8).

After a median follow-up of 31.5 months in the standard-therapy group and 40.0 months in the intensive-therapy group, 160 patients had evidence of progression in the standard-therapy group and 128 in the intensive-therapy group. The median duration of progression-free survival was 31.6 months (95 percent confidence interval, 27.4 to 38.0) in the intensive-therapy group, as compared with 19.6 months (95 percent confidence interval, 16.2 to 21.8) in the standard-therapy group (P. Response The maximal response to randomized treatment is summarized in Table 2 Maximal Response to Treatment.: the intensive-therapy group had a higher overall rate of response and a higher rate of complete remission than the standard-therapy group. Although no formal statistical tests were carried out, there was a trend toward improved survival in the intensive-therapy group as the extent of the response increased from minimal (25.6 months; 95 percent confidence interval, 7.0 to 31.3) to partial (39.8 months; 95 percent confidence interval, 33.8 to 61.4) to complete (88.6 months; lower 95 percent confidence limit, 61.4).

Causes of Death Of the 206 deaths, 183 (89 percent) were recorded as due to myeloma or related factors, including treatment. Multiple myeloma was cited as a causal factor in more patients in the standard-therapy group than in the intensive-therapy group (69 of 112 patients [62 percent; 95 percent confidence interval, 53 to 71] vs. 46 of 94 patients [49 percent; 95 percent confidence interval, 39 to 59]).

Infection, as at least a contributory factor, was reported in 68 patients (33 percent) who died and was more frequent in the intensive-therapy group than in the standard-therapy group (35 patients [37 percent; 95 percent confidence interval, 27 to 47] vs. 33 patients [29 percent; 95 percent confidence interval, 21 to 38]).

Six deaths occurred within 100 days after transplantation, five of which were due to sepsis. The rate of early death was not higher than expected in either group. Supported by unrestricted educational grants from Roche Products and Chugai Pharma United Kingdom, and by grants from the Leukaemia Research Fund United Kingdom (to Dr. Morgan), Cancer Research United Kingdom (to Dr. Selby), the Department of Health (to Dr.

Davies), and the Medical Research Council (to Dr. Drayson and the Clinical Trials Service Unit, Oxford). Child and Morgan contributed equally to the article.

We are indebted to the staff of the Clinical Trials Service Unit in Oxford for overseeing the randomizations; to Dr. Richards, Dr.

Wheatley, and other members of the Medical Research Council Adult Leukaemia Working Party for advice and help; and to Dr. Shevlin, and E. Sheldon for important contributions. Source Information From the Academic Unit of Haematology and Oncology, Cancer Research United Kingdom Clinical Centre and Leukaemia Research Fund Unit (J.A.C., G.J.M., F.E.D., R.G.O., P.J.S.), and the Northern and Yorkshire Clinical Trials and Research Unit, Academic Unit of Epidemiology and Health Services Research (S.E.B., K.H., J.B.), University of Leeds, Leeds, United Kingdom; and the Department of Immunology, University of Birmingham, Birmingham, United Kingdom (M.T.D.). Address reprint requests to Professor Child at the Department of Haematology, General Infirmary, Great George St., Leeds, West Yorkshire LS1 3EX, United Kingdom,. Appendix The following institutions and clinicians participated in the study (members of the Medical Research Council Adult Leukaemia Working Party are indicated by asterisks): New Zealand — Christchurch Hospital: N.

Spearings, S. Gibbons; Palmerston North Hospital, Palmerston North: B.

Baker; United Kingdom — Airedale General Hospital, Keighley: A. Cuthbert; Altnagelvin Area Hospital, Londonderry: M. Ryan; Arrowe Park Hospital, Wirral: D. Galvani; Ashford Hospital, Ashington: A. Laurie; Belfast City Hospital, Belfast: C. Desai; Birmingham Heartlands Hospital, Birmingham: C.

Milligan*; Bradford Royal Infirmary, Bradford: L. Williams; Bronglais General Hospital, Aberystwyth: H. Habboush; Cheltenham General Hospital, Cheltenham: R. Blundell; Chesterfield and North Derbyshire Royal Hospital, Chesterfield: R. Stewart; Countess of Chester Hospital, Chester: V. Rhodes; City Hospital, Birmingham: D. Bareford; Derbyshire Royal Infirmary, Derby: A.

Mitchell; Dewsbury District Hospital, Dewsbury: M. Chapple; Diana Princess of Wales Hospital, Grimsby: K.

Speed; Epsom General Hospital, Epsom: L. Jones; Freeman Hospital, Newcastle-upon-Tyne: P. Kesteven; George Eliot Hospital, Nuneaton: M. Narayanan; Gloucestershire Royal Hospital, Gloucester: S.

Ropner; Good Hope Hospital, Sutton Coldfield: M. Tucker; Grantham and District Hospital, Grantham: V. Tringham; Harrogate District Hospital, Harrogate: A. Bynoe; Hillingdon Hospital, Uxbridge: R. Janmohamed; Horton General Hospital, Oxford: J. Durant*; Huddersfield Royal Infirmary, Huddersfield: C.

Carter; John Radcliffe Infirmary, Oxford: P. Emerson; Kidderminster General Hospital, Kidderminster: M. Lewis; King's Mill Hospital, Sutton-in-Ashfield: E.

Logan; Kingston General Hospital, Hull: M. Patmore; Leeds General Infirmary, Leeds: G. Norfolk; Leicester Royal Infirmary, Leicester: A. Hutchinson, V. Mitchell; Lincoln County Hospital, Lincoln: M. Adelman; Middlesex Central Hospital, London: S.

Davies; Nevill Hall Hospital, Abergavenny: H. Habboush; North Tyneside General Hospital, North Shields: H. Tinegate; Northern General Hospital, Sheffield: M. Rayman Advance Rom Gba Fr.

Brown; Northwick Park Hospital, Harrow: C. Reid; Nottingham University Hospital, Nottingham: G. Dolan; Pembury Hospital, Pembury: D. Gillett; Pilgrim Hospital, Boston: S.

Sobolewski; Pinderfields General Hospital, Wakefield: P. Galvin; Pontefract Infirmary, Pontefract: R. Wright; Queen Elizabeth Hospital, Birmingham: J.

Holmes; Queen Elizabeth Hospital, King's Lynn: P. Keidan; Queen's Hospital, Burton-upon-Trent: A. Smith; Rotherham General Hospital, Rotherham: H. Taylor; Royal Free Hospital, London: A.

Mehta; Royal Liverpool Hospital, Liverpool: J. Clark*; Royal South Hampshire Hospital, Southampton: A. Smith*; Russells Hall Hospital, Dudley: P. Richardson; Sandwell District Hospital, West Bromwich: S. Stableforth; Scunthorpe General Hospital, Scunthorpe: S. Jalihal; Selly Oak Hospital, Birmingham: J. Murray; South Warwickshire Hospital, Warwick: P.

Rose; Southampton General Hospital, Southampton: A. Provan; Southmead Hospital, Bristol: J.

George's Hospital, London: J. Parker-Williams; St. Helier Hospital, Carshalton: J. Mercieca; St. James's University Hospital, Leeds: B. John's Hospital at Howden, Livingston: M.

Cook; Stafford District General Hospital, Stafford: P. Revell; Sunderland Royal Infirmary, Sunderland: D. Goff; Calderdale Royal Hospital, Halifax: A. Steed; Middlesex Hospital, London: R.

Tobias; Ulster Hospital, Belfast: M. El-Agnaf; University Hospital of Wales, Cardiff: A. Whitaker; Walton Hospital, Liverpool: W. Stevenson; West Hill Hospital, Dartford: V.

Andrews; Western General Hospital, Edinburgh: P. Mackie; Wolverhampton Hospital, Wolverhampton: A. Patel; Worcester Royal Infirmary, Worcester: A. Sawers; Wycombe General Hospital, High Wycombe: J. Pattinson; York District Hospital, York: L.

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