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Originally published as JCO Early Release 10.1200/JCO.2005.04.5807 on January 23 2006 © 2006 American Society of Clinical Oncology. Standard Chemotherapy Compared With High-Dose Chemoradiotherapy for Multiple Myeloma: Final Results of Phase III US Intergroup Trial S9321
From the University of Arkansas for Medical Science, Little Rock, AR; Mayo Clinic, Rochester, MN; Dana-Farber Cancer Institute, Boston, MA; University Hospitals of Cleveland, Cleveland, OH; Wake Forest University School of Medicine, Winston-Salem, NC; Southwest Oncology Group Statistical Center, Seattle, WA; Wichita Community Clinical Oncology Program, Wichita, KS; Columbia River Community Clinical Oncology Program, Portland, OR; Henry Ford Hospital, Detroit, MI; St Jude Children's Research Hospital, Memphis, TN; University of Arizona Cancer Center, Tucson, AZ; and Cedars Sinai Cancer Center, Los Angeles, CA Address reprint requests to the Southwest Oncology Group (SWOG-9321), Operations Office, 14980 Omicron Dr, San Antonio, TX 78245-3217
PURPOSE: Results of a prospective randomized trial conducted by the Intergroupe Francais du Myélome (IFM 90) indicated that autologous hematopoietic cell–supported high-dose therapy (HDT) effected higher complete response rates and extended progression-free survial (PFS) and overall survival (OS) compared with standard-dose therapies (SDT) for patients with multiple myeloma (MM).
PATIENTS AND METHODS: In 1993, three North American cooperative groups launched a prospective randomized trial (S9321) comparing HDT (melphalan [MEL] 140 mg/m2 plus total-body irradiation 12 Gy) with SDT using the vincristine, carmustine, MEL, cyclophosphamide, and prednisone regimen. Responders on both arms ( RESULTS: With a median follow-up time of 76 months, no differences were observed in response rates between the two study arms (HDT, n = 261 patients; SDT, n = 255 patients). Similarly, PFS and OS durations did not differ between the HDT and SDT arms, with 7-year estimates of PFS of 17% and 16%, respectively, and OS of 37% and 42%, respectively. Of 242 patients achieving at least 75% tumor reduction, no difference was observed in PFS or OS among the 121 patients randomly assigned to IFN and the 121 patients randomly assigned to no maintenance therapy. Among 157 patients relapsing on SDT, 87 received a salvage autotransplantation; their median survival time of 30 months was only slightly better than the survival time of the remaining patients who were managed with further SDT (23 months; P = .13).
CONCLUSION: The HDT and SDT regimens used in S9321 yielded comparable response rates and PFS and OS durations. IFN maintenance therapy did not benefit patients who achieved
Two prospective randomized trials in newly diagnosed multiple myeloma (MM) patients indicated that autotransplantation-supported high-dose therapy (HDT) with melphalan (MEL) alone or in combination with total-body irradiation (TBI) significantly increased complete response (CR) rates and extended both progression-free survival (PFS) and overall survival (OS) markedly beyond results achieved with standard-dose therapy (SDT).1,2 Equivocal results were reported by Fermand et al3 and recently by the Spanish Programa para el Estudio de la Therapéutica en Hemopatía Maligna group.4 In 1993, three North American Cooperative Groups (Southwest Oncology Group [SWOG], Eastern Cooperative Oncology Group, and Cancer and Leukemia Group B) embarked on a randomized clinical trial comparing HDT with MEL 140 mg/m2 plus TBI (12 Gy) and SDT with vincristine, carmustine (BCNU), MEL, cyclophosphamide, and prednisone (VBMCP).5
Eligibility Criteria Eligibility criteria included untreated symptomatic MM, age  70 years, and Zubrod performance status of 0 to 2; a performance status of 3 to 4 as a result of myeloma-related bone disease was acceptable. Systolic ejection fraction and carbon dioxide diffusing capacity both had to be  50%. Prior malignancy, other than basal or squamous cell skin cancer or cervical cancer in situ, was an exclusion criterion, unless patients had been disease free for 5 years. The research protocol was approved by the review boards of the member institutions. All patients were required to provide written informed consent in accordance with US federal regulations.
Overall Treatment Plan
All patients received HD-CTX and, except for allotransplantation candidates, proceeded with PBSC collection. Patients who were 55 years of age with an HLA-compatible sibling donor were offered the option of allogeneic transplantation with MEL 140 mg/m2 plus TBI. However, this arm was closed when an excessive first-year treatment-related mortality rate of 53% was observed after enrollment of 36 eligible patients. Patients randomly assigned to SDT received 1 year of VBMCP therapy administered in 5-week cycles. Patients randomly assigned to autotransplantation received MEL 140 mg/m2 intravenous plus TBI (12 Gy in 8 fractions with lung shielding).
Responding patients (
Treatment Modifications
Evaluations Before and After Start of Therapy
Definition of End Points OS was defined from the date of registration to the trial until death from any cause; survivors were censored at the time of last contact. PFS was defined from the date of registration onto the trial until death from any cause, disease progression, or relapse. Patients experiencing no event were censored at the time of last contact.
Statistical Considerations
Intent-to-treat analyses were carried out on all eligible randomly assigned patients. PFS and OS curves were estimated according to the product-limit method9 and compared using the log-rank test,10 which was stratified according to randomization factors as appropriate.11 Similarly, response rates were compared using the stratified
Progression of Patients Through Protocol Steps As shown in Table 2, 899 patients were enrolled onto induction therapy, of whom 813 were eligible for continuation on protocol. Reasons for ineligibility were as follows: required baseline laboratory studies had not been performed or had been performed outside of the required time frame (n = 54); patients did not have MM requiring therapy (n = 14); patients had an unacceptable amount of prior radiation therapy to be considered eligible for the TBI regimen of this study or protocol treatment started before registration (n = 16); and patients never started protocol treatment (n = 2).
Reasons for attrition of eligible patients before first random assignment included going off induction treatment because of adverse events (4%), progression or relapse (2%), patient or physician choice (9%), and death (3%). Twelve percent of the patients completed induction as planned but did not register to the randomization step because of reasons not known.
Clinical Outcome
A total of 516 eligible patients were randomly assigned, before HD-CTX, to HDT (n = 261) or SDT (n = 255). The cumulative CR, R, and PR rates of patients in either treatment arm were virtually identical and were as follows: 5%, 46%, and 21%, respectively, after VAD; 7%, 47%, and 20%, respectively, after HD-CTX; and 11%, 48%, and 17%, respectively after autotransplantation or VBMCP. The percentage of nonresponders was 28% after VAD, 26% after HD-CTX, and 24% after the autotransplantation/VBMCP regimen. Kaplan-Meier plots of PFS and OS showed no difference between the two arms; 7-year PFS and OS estimates were 17% and 38% after HDT and 14% and 38% after SDT, respectively (Fig 3). Whereas both study arms showed a continuous attrition of patients over time, eight of the 36 allotransplantation recipients remained progression free and 14 remained alive beyond 5 years (40% plateau at 7 to 10 years; Fig 3). The 242 eligible patients achieving at least R status after either HDT or SDT were further randomly assigned to observation (n = 121) or IFN (n = 121); no difference was noted in either PFS or OS between these two treatment arms (Fig 4).
On disease relapse on VBMCP, 87 of 157 patients with follow-up after relapse received a salvage autotransplantation, resulting in a median survival time of 30 months (Fig 5); this was slightly higher than the survival time of 23 months noted among the remaining patients receiving nontransplantation salvage therapies (P = .13). Information about the use of thalidomide as part of salvage regimens is not available.
Prognostic Factors The clinical implications of pretreatment standard parameters as well as plasma cell labeling index (PCLI) were examined (Table A1). On univariate analysis, elevated levels of B2M (> 3.5 mg/L), lactic dehydrogenase (LDH; > 190 U/L), calcium ( 10 mg/dL), creatinine (> 2 mg/dL), and PCLI (> 1%) as well as thrombocytopenia (< 130,000/µL) and age (> 60 years) adversely affected both PFS and OS. On multivariate analysis, high levels of PCLI, LDH, and calcium all affected PFS and OS adversely. Fluorescence in situ hybridization analysis, which was used to determine chromosome 13 deletion (del13), was available in only 171 enrolled patients (21%). Del13 was a strong adverse feature for both PFS and OS on multivariate analysis, along with PCLI and LDH (Table A1). Level of response and timing of onset of response did not translate into PFS or OS prolongation, regardless of study arm (data not shown).
Treatment-Related Toxicity There were eight treatment-related deaths on the HDT arm; five patients died from ARDS/pneumonitis (probably as a result of high TBI dose), one died from cardiac failure (ventricular arrhythmia), and two died from infection. Hematopoietic recovery was prompt; the median number of days to engraftment, as determined by absolute neutrophil count to 500/µL and platelets to 25,000/µL, were 16 and 15 days, respectively. There was one treatment-related death on the SDT arm, which was attributed to pulmonary edema/ARDS. Treatment-related mortality rate for all patients was 5% at 12 months, whereas the mortality rate from other causes was 10% after the first year and 50% at 5 years. One death could be attributed to IFN therapy (ARDS); IFN was discontinued in 32% of patients after a median of 4 months because of intolerance. The 53% overall mortality rate among the first 36 patients receiving allotransplantation prompted early closure of this treatment option (on review by the Data Safety and Monitoring Board). Fourteen of these patients died as a result of treatment-related causes; seven patients died from pneumonia/sepsis, two patients died from acute graft-versus-host disease, and one patient each died from pneumonitis, renal failure, GI bleed, CNS hemorrhage, and pericarditis.
Results from this large multicenter trial are at variance with results published by the Intergroupe Francophone du Myelome (IFM)1 and the Medical Research Council (MRC).2 The IFM 90 trial effected higher CR rates and superior PFS and OS among patients randomly assigned to HDT with MEL 140 mg/m2 plus TBI 8 Gy versus patients assigned to SDT with vincristine, MEL, cyclophosphamide, and prednisone/vincristine, BCNU, doxorubicin, and prednisone. At 7 years, the OS rate was 44% in the HDT arm and 23% in the SDT arm.1 Similar data were reported for the MRC VII trial, with a 7-year OS estimate of 38% after HDT (mainly with MEL 200 mg/m2) compared with 26% with SDT with doxorubicin, BCNU, MEL, and cyclophosphamide.2 In both trials, patients were randomly assigned up front, whereas S9321 randomly assigned patients after VAD induction and before HD-CTX, which was administered to all patients. Several explanations can be advanced for the observed discrepancies between S9321 and IFM 90/MRC VII trial results. First, HD-CTX and VBMCP together may be more effective than the standard regimens used in the other trials. Second, TBI-containing HDT has been shown to be inferior to MEL 200 mg/m2 in both randomized and historical comparisons.13,14 Both the IFM 90 and MRC VII trials reported higher CR rates after HDT versus SDT (22% v 5% and 44% v 8%, respectively), whereas S9321 effected low CR rates that were similar after HDT (17%) and SDT (15%). According to most of the published literature, however, a clear link exists between survival extension and increased CR rate after HDT.15,16 The one exception is the Programa para el Estudio de la Therapéutica en Hemopatía Maligna trial (VBMCP, alternating with vincristine, BCNU, doxorubicin, and dexamethasone [VBAD] for up to 12 cycles v VBMCP/VBAD for four cycles followed by MEL-based autotransplantation); although effecting a higher CR rate of 30% v 11% (P < .002), MEL 200 mg/m2 did not prolong PFS or OS compared with the standard therapy arm.4 At a time when the benefit of HDT over SDT is generally accepted, the results of S9321 draw attention to several issues to be considered in future high-dose or standard-dose myeloma trial designs. First, TBI should be abandoned; in fact, detrimental effects of systemic irradiation were first reported with sequential hemi-body irradiation in the S8229/8230 trial.17 IFN, which was touted in its early days of use for investigating myeloma maintenance18 and up-front therapies19 as a major advance in patient management, has retained some value when examined in the context of meta-analyses.20 However, its lack of activity for maintenance of responders reported in this trial warrants abandoning use of this immunomodulatory agent because of its considerable toxicity and subsequent discontinuation in a high fraction of patients. This study confirmed the independent prognostic value of B2M (reflecting mainly tumor burden) but not of albumin levels (reflecting activity of cytokines, especially interleukin-6), both of which now form the basis of the International Staging System.21 Both PCLI (a measure of MM cell proliferation)22 and deletion 13q (Rb suppressor gene deletion)23,24 have been shown in several other large trials to be prognostically useful. Obviating the need for indwelling catheter placement with VAD therapy, the oral drug combination regimen of thalidomide plus dexamethasone has demonstrated remarkable efficacy in the primary management of MM.25-27 Therefore, SWOG study S0204 is investigating thalidomide plus dexamethasone as induction therapy before and as maintenance treatment after MEL 200 mg/m2–based tandem autotransplantations to determine whether the positive leads of the recently reported IFM 94 trial for tandem autotransplantations28 and of preliminary data on thalidomide plus dexamethasone maintenance29 can be confirmed. Standard allogeneic transplantations are fraught with a high treatment-related mortality,2,30,31 which, in this trial, was probably further accentuated by the high TBI dose (12 Gy) used in the context of added MEL at a dose of 140 mg/m2. As a result, more than 50% of patients had died by year 2; the subsequent survival (and event-free survival) curves were flat, consistent with a cured fraction of patients. Reduced-intensity regimen mini-allotransplantations have been applied with greater safety even to elderly patients.32-35 Crucial clinical trial questions in myeloma therapy in 2006 concern the following: (1) respective roles and timing of new agents in relationship to autotransplantations; (2) need of maximum cytoreduction before HDT; (3) durability of new agent-induced responses; (4) reversibility of bortezomib- and thalidomide-related polyneuropathy; (5) clinical trial end points, especially whether CR is a valid surrogate for survival; and (6) interpretation of clinical outcome data in the context of distinct molecular MM entities with distinctly different prognoses.36
Table A1. Proportional Hazards Regression of Prognostic Factors
NOTE. P value from Wald
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
Supported in part by the following Public Health Service Cooperative Agreement Grants No. awarded by the National Cancer Institute, Department of Health and Human Services: CA38926, CA32102, CA13650, CA14548, CA31946, CA32291, CA03927, CA37981, CA35431, CA45377, CA58416, CA22433, CA58686, CA46113, CA04919, CA46441, CA58861, CA46282, CA35261, CA27057, CA76132, CA35192, CA76447, CA76462, CA45450, CA76429, CA63845, CA12644, CA20319, CA63844, CA45560, CA58415, CA14028, CA58658, CA42777, CA35119, CA35090, CA35117, CA13612, CA16385, CA67575, CA68183, CA46368, CA04920, CA74647, and CA52654; also supported in part by Amgen and Schering. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Attal M, Harousseau JL, Stoppa AM, et al: A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med 335:91-97, 1996 2. Child JA, Morgan GJ, Davies FE, et al: High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 348:1875-1883, 2003 3. Fermand JP, Ravaud P, Katsahian S, et al: High-dose therapy (HDT) and autologous blood stem cell (ABSC) transplantation versus conventional treatment in multiple myeloma (MM): Results of a randomized trial in 190 patients aged 55 to 65 years of age. Blood 94:396a, 1999 (suppl 1, abstr 1754) 4. Blade J, Rosinol L, Sureda A, et al: High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to initial chemotherapy: Long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood 106:3755-3759, 2005 5. Oken MM, Harrington DP, Abramson N, et al: Comparison of melphalan and prednisone with vincristine, carmustine, melphalan, cyclophosphamide, and prednisone in the treatment of multiple myeloma: Results of Eastern Cooperative Oncology Group Study E2479. Cancer 79:1561-1567, 1997[CrossRef][Medline] 6. Barlogie B, Smith L, Alexanian R: Effective treatment of advanced multiple myeloma refractory to alkylating agents. N Engl J Med 310:1353-1356, 1984[Abstract] 7. Blade J, Samson D, Reece D, et al: Criteria for evaluating response in patients with multiple myeloma treated by high-dose therapy and hematopoietic stem cell transplantation. Br J Haematol 102:1115-1123, 1998[CrossRef][Medline] 8. Pocock SJ, Simon R: Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics 31:103-115, 1973 9. Kaplan EL, Meier R: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 10. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163-170, 1966[Medline] 11. Anderson GL, LeBlanc M, Liu PY, et al: On use of covariates in randomization and analysis of clinical trials, in Crowley J, Ankerst DP (eds): Handbook of Statistics in Clinical Oncology (ed 2). New York, NY, Taylor and Francis, 2005 12. Cox DR: Regression models and life tables. J R Stat Soc B 34:187-202, 1972 13. Moreau P, Facon T, Attal M, et al: Comparison of 200 mg/m2 melphalan and 8 Gy total body irradiation plus 140 mg/m2 melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: Final analysis of the Intergroupe Francophone du Myeloma 9502 randomized clinical trial. Blood 99:731-735, 2002 14. Desikan KR, Tricot G, Dhodapkar M, et al: Melphalan plus total body irradiation (MEL-TBI) or cyclophosphamide (MEL-CY) as a conditioning regimen with second autotransplant in responding patients with myeloma is inferior compared to historical controls receiving tandem transplants with melphalan alone. Bone Marrow Transplant 25:483-487, 2000[CrossRef][Medline] 15. Kyle RA, Rajkumar SV: Multiple myeloma. N Engl J Med 351:1860-1873, 2004 16. Fassas A, Shaughnessy J, Barlogie B: Cure of myeloma: Hype or reality? Bone Marrow Transplant 35:215-224, 2005[Medline] 17. Salmon SE, Tesh D, Crowley J, et al: Chemotherapy is superior to sequential hemibody irradiation for remission consolidation in multiple myeloma: A Southwest Oncology Group study. J Clin Oncol 9:705-707, 1991[Medline] 18. Mandelli F, Avvisati G, Amadori S, et al: Maintenance treatment with recombinant interferon alfa-2b in patients with multiple myeloma responding to conventional induction chemotherapy. N Engl J Med 322:1430-1434, 1990[Abstract] 19. The Myeloma Trialists' Collaborative Group: Interferon as therapy for multiple myeloma: An individual patient data overview of 24 randomized trials and 4012 patients. Br J Haematol 113:1020-1034, 2001[CrossRef][Medline] 20. Fritz E, Ludwig H: Interferon-alfa treatment in multiple myeloma: Meta-analysis of 30 randomized trials among 3948 patients. Ann Oncol 11:1427-1436, 2000 21. Greipp PR, San Miguel J, Durie BG, et al: An International Staging System (ISS) for multiple myeloma (MM). J Clin Oncol 23:3412-3429, 2005 22. Greipp PR, Lust JA, O'Fallon WM, et al: Plasma cell labeling index and beta 2-microglobulin predict survival independent of thymidine kinase and C-reactive protein in multiple myeloma. Blood 81:3382-3387, 1993 23. Shaughnessy J, Tian E, Sawyer J, et al: Prognostic impact of cytogenetic and interphase fluorescence in situ hybridization-defined chromosome 13 deletion in multiple myeloma: Early results of total therapy II. Br J Haematol 120:44-52, 2003[CrossRef][Medline] 24. Facon T, Avet-Loiseau H, Guillerm G, et al: Chromosome 13 abnormalities identified by FISH analysis and serum beta-2-microglobulin produce a powerful myeloma staging system for patients receiving high-dose therapy. Blood 97:1566-1571, 2001 25. Rajkumar SV, Hayman S, Gertz MA, et al: Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol 20:4319-4323, 2002 26. Weber D, Rankin K, Gavino M, et al: Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol 21:16-19, 2003 27. Cavo M, Zamagni E, Tosi P, et al: Superiority of thalidomide and dexamethasone over vincristine-doxorubicin-dexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Blood 106:35-39, 2005 28. Attal M, Harousseau JL, Facon T, et al: Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med 349:2495-2502, 2003 29. Attal M, Harousseau JL, Leyvraz S, et al: Maintenance treatment with thalidomide after autologous transplantation for myeloma: First analysis of a prospective randomized study of the Intergroupe Francophone du Myelome (IFM 99 02). Blood 104:155a, 2004 (abstr 535) 30. Bensinger W: Stem cell transplantation for multiple myeloma. Int J Hematol 77:232-238, 2003[Medline] 31. Gahrton G, Svensson H, Cavo M, et al: Progress in allogeneic bone marrow and peripheral stem cell transplantation for multiple myeloma: A comparison between transplants performed 1983-93 and 1994-98 at European Group for Blood and Marrow Transplantation centres. Br J Haematol 113:209-216, 2001[CrossRef][Medline] 32. Badros A Barlogie B, Siegel E, et al: Improved outcome of non-myeloablative allogeneic transplantation in multiple myeloma. J Clin Oncol 20:1295-1303, 2002 33. Maloney DG, Molina AJ, Sahebi F, et al: Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 102:3447-3454, 2003 34. Kroeger N, Sayer HG, Schwerdtfeger R, et al: Unrelated stem cell transplantation after a reduced-intensity conditioning with pretransplantation antithymocyte globulin is highly effective with low transplantation-related mortality. Blood 100:3919-3924, 2002 35. Lee CK, Badros A, Barlogie B, et al: Prognostic factors in allogeneic transplantation for patients with high-risk multiple myeloma after reduced intensity conditioning. Exp Hematol 31:73-80, 2003[CrossRef][Medline] 36. Shaughnessy J Jr, Zhan F, Barlogie B, et al: Gene expression profiling and multiple myeloma. Best Pract Res Clin Haematol 18:537-552, 2005[Medline] Submitted October 18, 2005; accepted December 9, 2005.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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Deceased.
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ABSTRACT
INTRODUCTION
2 test. Multivariate analyses of survival were performed using Cox regression.
