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Original ArticleFree Preview

Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma

List of authors.
  • Paul G. Richardson, M.D.,
  • Susanna J. Jacobus, M.Sc., M.B.A.,
  • Edie A. Weller, Ph.D.,
  • Hani Hassoun, M.D.,
  • Sagar Lonial, M.D.,
  • Noopur S. Raje, M.D.,
  • Eva Medvedova, M.D.,
  • Philip L. McCarthy, M.D.,
  • Edward N. Libby, M.D.,
  • Peter M. Voorhees, M.D.,
  • Robert Z. Orlowski, M.D., Ph.D.,
  • Larry D. Anderson, Jr., M.D., Ph.D.,
  • Jeffrey A. Zonder, M.D.,
  • Carter P. Milner, M.D.,
  • Cristina Gasparetto, M.D.,
  • Mounzer E. Agha, M.D.,
  • Abdullah M. Khan, M.B., B.S.,
  • David D. Hurd, M.D.,
  • Krisstina Gowin, D.O.,
  • Rammurti T. Kamble, M.D.,
  • Sundar Jagannath, M.D.,
  • Nitya Nathwani, M.D.,
  • Melissa Alsina, M.D.,
  • R. Frank Cornell, M.D.,
  • Hamza Hashmi, M.D.,
  • Erica L. Campagnaro, M.D.,
  • Astrid C. Andreescu, M.D.,
  • Teresa Gentile, M.D., Ph.D.,
  • Michaela Liedtke, M.D.,
  • Kelly N. Godby, M.D.,
  • Adam D. Cohen, M.D.,
  • Thomas H. Openshaw, M.D.,
  • Marcelo C. Pasquini, M.D.,
  • Sergio A. Giralt, M.D.,
  • Jonathan L. Kaufman, M.D.,
  • Andrew J. Yee, M.D.,
  • Emma Scott, M.D.,
  • Pallawi Torka, M.D.,
  • Amy Foley, M.A.,
  • Mariateresa Fulciniti, Ph.D.,
  • Kyle Hebert, M.S.,
  • Mehmet K. Samur, Ph.D.,
  • Kelly Masone, B.A.,
  • Michelle E. Maglio, M.B.A.,
  • Andrea A. Zeytoonjian, M.B.A.,
  • Omar Nadeem, M.D.,
  • Robert L. Schlossman, M.D.,
  • Jacob P. Laubach, M.D., M.P.P.,
  • Claudia Paba-Prada, M.D.,
  • Irene M. Ghobrial, M.D.,
  • Aurore Perrot, M.D., Ph.D.,
  • Philippe Moreau, M.D.,
  • Hervé Avet-Loiseau, M.D., Ph.D.,
  • Michel Attal, M.D., Ph.D.,
  • Kenneth C. Anderson, M.D.,
  • and Nikhil C. Munshi, M.D.
  • for the DETERMINATION Investigators*

Abstract

Background

In patients with newly diagnosed multiple myeloma, the effect of adding autologous stem-cell transplantation (ASCT) to triplet therapy (lenalidomide, bortezomib, and dexamethasone [RVD]), followed by lenalidomide maintenance therapy until disease progression, is unknown.

Methods

Download a PDF of the Research Summary.

In this phase 3 trial, adults (18 to 65 years of age) with symptomatic myeloma received one cycle of RVD. We randomly assigned these patients, in a 1:1 ratio, to receive two additional RVD cycles plus stem-cell mobilization, followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Both groups received lenalidomide until disease progression, unacceptable side effects, or both. The primary end point was progression-free survival.

Results

Among 357 patients in the RVD-alone group and 365 in the transplantation group, at a median follow-up of 76.0 months, 328 events of disease progression or death occurred; the risk was 53% higher in the RVD-alone group than in the transplantation group (hazard ratio, 1.53; 95% confidence interval [CI], 1.23 to 1.91; P<0.001); median progression-free survival was 46.2 months and 67.5 months. The percentage of patients with a partial response or better was 95.0% in the RVD-alone group and 97.5% in the transplantation group (P=0.55); 42.0% and 46.8%, respectively, had a complete response or better (P=0.99). Treatment-related adverse events of grade 3 or higher occurred in 78.2% and 94.2%, respectively; 5-year survival was 79.2% and 80.7% (hazard ratio for death, 1.10; 95% CI, 0.73 to 1.65).

Conclusions

Among adults with multiple myeloma, RVD plus ASCT was associated with longer progression-free survival than RVD alone. No overall survival benefit was observed. (Funded by the National Heart, Lung, and Blood Institute and others; DETERMINATION ClinicalTrials.gov number, NCT01208662.)

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Funding and Disclosures

Supported by grants from the National Heart, Lung, and Blood Institute and the National Cancer Institute (U10HL069294 and U24HL138660, to the Blood and Marrow Transplant Clinical Trials Network), grants from the National Institutes of Health (P01-155258 and 5P50 CA100707, to Drs. Richardson, Samur, Avet-Loiseau, K. Anderson, and Munshi, for sampling and analyses of genomic data), Celgene-Bristol Myers Squibb, Takeda Pharmaceuticals, the Dana-Farber Cancer Institute, and the R.J. Corman Multiple Myeloma Research Fund.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Drs. K. Anderson and Munshi contributed equally to this article.

The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

This article was published on June 5, 2022, at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

We thank all the patients and their families for their participation in the trial; all the investigators, clinical research coordinators, nursing teams, and administrative staff at all the trial sites; the following persons for their contributions: Steve Hill, Ph.D., of Ashfield MedComms, an Ashfield Health company, for medical writing and editing assistance with an earlier version of the manuscript; the data and safety monitoring committee (Joan Bladé, M.D., Robert Kyle, M.D., Christian Straaker, M.D., Ralph D’Agostino, Ph.D., Joe Massarro, Ph.D., and Jean Pearlstein, B.A.); Jack Sparacino, B.S., and Ashley Ford, B.A., for administrative assistance to the response review committee; the steering committee (George Canellos, M.D., and the late Bertrand Coiffier, M.D., Ph.D.); the contract research organization CRA Solutions (especially Kellie Hill, Pharm.D.); Jean-Luc Harousseau, M.D., for assistance and mentorship; our pharmaceutical industry partners for their assistance, including Dixie-Lee Esseltine, M.D., formerly of Millennium Pharmaceuticals–Takeda Pharmaceuticals, Mark Williamson, B.S., Mei-Ling Smith, M.S.N., N.P., and Barbara Franklin, M.S., of Millennium Pharmaceuticals–Takeda Pharmaceuticals, Mark Alles, M.B.A., Mohammed Hussain, M.D., Thomas Cavanaugh, B.A., and Amit Agrawal, M.D., Ph.D., formerly of Celgene–Bristol Myers Squibb, and Michael Sturniolo, Ph.D., Bruno Costa, M.Sc., and Phenoia Browne, M.B.A., of Celgene–Bristol Myers Squibb; Anne T. Farrell, M.D., for guidance and assistance; the late Robert C. Kane, M.D., of the Food and Drug Administration, for the development of the protocol and conduct of the trial; the Blood and Marrow Transplant Clinical Trials Network for vital assistance; and the Alliance for Clinical Trials in Oncology for their endorsement.

Author Affiliations

From the Department of Medical Oncology, Dana–Farber Cancer Institute, Jerome Lipper Multiple Myeloma Center (P.G.R., M.F., M.K.S., K.M., M.E.M., A.A.Z., O.N., R.L.S., J.P.L., C.P.-P., I.M.G., K.C.A., N.C.M.), the Department of Data Science, Dana–Farber Cancer Institute (S.J.J., K.H.), the Division of Hematology and Oncology, Boston Children’s Hospital (E.A.W.), the Center for Multiple Myeloma, Massachusetts General Hospital (N.S.R., A.J.Y.), Harvard Medical School (P.G.R., S.J.J., E.A.W., N.S.R., A.J.Y.. M.F., K.H., M.K.S., K.M., M.E.M., A.A.Z., O.N., R.L.S., J.P.L., C.P.-P., I.M.G., K.C.A., N.C.M.), and the Veterans Affairs Boston Healthcare System (N.C.M.), Boston, and the Department of Medical Oncology, Davenport–Mugar Cancer Center, Cape Cod Hospital, Hyannis (T.H.O.) — all in Massachusetts; Myeloma Service, the Department of Medicine, Memorial Sloan Kettering Cancer Center (H. Hassoun, S.A.G.), and the Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai (S.J.), New York, the Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo (P.L.M., P.T.), and State University of New York Upstate Medical University, Syracuse (T.G.) — all in New York; the Winship Cancer Institute of Emory University, Atlanta (S.L., J.L.K.); Knight Cancer Institute, Oregon Health and Science University, Portland (E.M., E.S.); the Division of Medical Oncology and Fred Hutchinson Cancer Research Center, University of Washington, Seattle (E.N.L.); the Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Atrium Health, Charlotte (P.M.V.), Duke University Medical Center, Durham (C.G.), and the Hematology and Oncology–Cancer Center, Atrium Health Wake Forest Baptist Medical Center, Winston-Salem (D.D.H.) — all in North Carolina; the Department of Lymphoma and Myeloma, University of Texas M.D. Anderson Cancer Center (R.Z.O.), and Center for Cell and Gene Therapy, Baylor College of Medicine and Houston Methodist Hospital (R.T.K.), Houston, and Myeloma, Waldenstrom’s, and Amyloidosis Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas (L.D.A.) — all in Texas; the Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit (J.A.Z.), and the Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor (E.L.C.) — both in Michigan; the Division of Hematology and Oncology, University of Mississippi Medical Center, Jackson (C.P.M.); University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh (M.E.A.), and the Abramson Cancer Center, University of Pennsylvania, Philadelphia (A.D.C.) — both in Pennsylvania; the Division of Hematology, Ohio State University Comprehensive Cancer Center, Columbus (A.M.K.); the Department of Bone Marrow Transplant and Cellular Therapy, University of Arizona, Tucson (K.G.); Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope Comprehensive Cancer Center, Duarte (N.N.), and the Department of Medicine, Division of Hematology, Stanford University, Stanford (M.L.) — both in California; the Department of Blood and Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (M. Alsina); Vanderbilt University Medical Center, Nashville (R.F.C.); the Division of Hematology Oncology, Medical University of South Carolina, Charleston (H. Hashmi); Northern Light Eastern Maine Medical Center Cancer Care, Brewer (A.C.A.), and the Cancer Care Center of Maine, Bangor (T.H.O.); O’Neal Comprehensive Cancer Center, the University of Alabama at Birmingham, Birmingham (K.N.G.); the Center for International Blood and Marrow Transplant Research (CIBMTR), Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee (M.C.P.); the National Marrow Donor Program, CIBMTR, Minneapolis (A.F.); and the Department of Hematology (A.P., M. Attal) and Unit for Genomics in Myeloma (H.A.-L.), Institut Universitaire du Cancer de Toulouse–Oncopole, University Hospital, Toulouse, and the Department of Hematology, University Hospital Hôtel-Dieu, Nantes (P.M.) — both in France.

Dr. Richardson can be contacted at or at the Department of Medical Oncology, Dana–Farber Cancer Institute, 450 Brookline Ave., Dana 1B02, Boston, MA 02115.

A list of the DETERMINATION Investigators is provided in the Supplementary Appendix, available at NEJM.org.

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