Tandem Auto Stem Cell Transplant With Melphalan Followed by Melphalan and Bortezomib in Patients With Multiple Myeloma

Summary

High dose chemotherapy with stem cell transplantation is commonplace in the treatment of multiple myeloma. This treatment uses a chemotherapy drug called Melphalan that has been used in several thousand bone marrow transplant recipients worldwide for the same or similar disorders.

Timeline

Start

2010-04-08

Primary completion

2023-07-15

Completion

2023-07-15

Publications

• Background Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD, Maas J, Pien CS, Prakash S, Elliott PJ. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res. 1999 Jun 1;59(11):2615-22.
• Background Aghajanian C, Dizon DS, Sabbatini P, Raizer JJ, Dupont J, Spriggs DR. Phase I trial of bortezomib and carboplatin in recurrent ovarian or primary peritoneal cancer. J Clin Oncol. 2005 Sep 1;23(25):5943-9. doi: 10.1200/JCO.2005.16.006.
• Background Alexanian R, Dimopoulos M. The treatment of multiple myeloma. N Engl J Med. 1994 Feb 17;330(7):484-9. doi: 10.1056/NEJM199402173300709. No abstract available.
• Background Attal M, Huguet F, Schlaifer D, Payen C, Laroche M, Fournie B, Mazieres B, Pris J, Laurent G. Intensive combined therapy for previously untreated aggressive myeloma. Blood. 1992 Mar 1;79(5):1130-6.
• Background Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, Casassus P, Maisonneuve H, Facon T, Ifrah N, Payen C, Bataille R. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med. 1996 Jul 11;335(2):91-7. doi: 10.1056/NEJM199607113350204.
• Background Attal M, Harousseau JL, Facon T, Guilhot F, Doyen C, Fuzibet JG, Monconduit M, Hulin C, Caillot D, Bouabdallah R, Voillat L, Sotto JJ, Grosbois B, Bataille R; InterGroupe Francophone du Myelome. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med. 2003 Dec 25;349(26):2495-502. doi: 10.1056/NEJMoa032290.
• Background Badros A, Barlogie B, Siegel E, Roberts J, Langmaid C, Zangari M, Desikan R, Shaver MJ, Fassas A, McConnell S, Muwalla F, Barri Y, Anaissie E, Munshi N, Tricot G. Results of autologous stem cell transplant in multiple myeloma patients with renal failure. Br J Haematol. 2001 Sep;114(4):822-9. doi: 10.1046/j.1365-2141.2001.03033.x.
• Background Barlogie B, Jagannath S, Vesole DH, Naucke S, Cheson B, Mattox S, Bracy D, Salmon S, Jacobson J, Crowley J, Tricot G. Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Blood. 1997 Feb 1;89(3):789-93.
• Background Barlogie B, Kyle RA, Anderson KC, Greipp PR, Lazarus HM, Hurd DD, McCoy J, Moore DF Jr, Dakhil SR, Lanier KS, Chapman RA, Cromer JN, Salmon SE, Durie B, Crowley JC. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol. 2006 Feb 20;24(6):929-36. doi: 10.1200/JCO.2005.04.5807. Epub 2006 Jan 23.
• Background Berenson JR, Yang HH, Sadler K, Jarutirasarn SG, Vescio RA, Mapes R, Purner M, Lee SP, Wilson J, Morrison B, Adams J, Schenkein D, Swift R. Phase I/II trial assessing bortezomib and melphalan combination therapy for the treatment of patients with relapsed or refractory multiple myeloma. J Clin Oncol. 2006 Feb 20;24(6):937-44. doi: 10.1200/JCO.2005.03.2383. Epub 2006 Jan 17.
• Background Blade J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G, Gertz M, Giralt S, Jagannath S, Vesole D. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol. 1998 Sep;102(5):1115-23. doi: 10.1046/j.1365-2141.1998.00930.x. No abstract available.
• Background Blade J, Rosinol L, Sureda A, Ribera JM, Diaz-Mediavilla J, Garcia-Larana J, Mateos MV, Palomera L, Fernandez-Calvo J, Marti JM, Giraldo P, Carbonell F, Callis M, Trujillo J, Gardella S, Moro MJ, Barez A, Soler A, Font L, Fontanillas M, San Miguel J; Programa para el Estudio de la Terapeutica en Hemopatia Maligna (PETHEMA). High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood. 2005 Dec 1;106(12):3755-9. doi: 10.1182/blood-2005-03-1301. Epub 2005 Aug 16.
• Background Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K, Brown J, Drayson MT, Selby PJ; Medical Research Council Adult Leukaemia Working Party. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003 May 8;348(19):1875-83. doi: 10.1056/NEJMoa022340.
• Background Cleveland, WS: Robust locally-weighted regression and smoothing scatterplots. J. Am Stat Assoc. 1979; 74: 829-836
• Background Cox, DR. Regression models and life tables (with discussion). J R Stat Soc B.1972; 34:187-220.
• Background Cusack JC Jr, Liu R, Houston M, Abendroth K, Elliott PJ, Adams J, Baldwin AS Jr. Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear factor-kappaB inhibition. Cancer Res. 2001 May 1;61(9):3535-40.
• Background Desikan R, Barlogie B, Sawyer J, Ayers D, Tricot G, Badros A, Zangari M, Munshi NC, Anaissie E, Spoon D, Siegel D, Jagannath S, Vesole D, Epstein J, Shaughnessy J, Fassas A, Lim S, Roberson P, Crowley J. Results of high-dose therapy for 1000 patients with multiple myeloma: durable complete remissions and superior survival in the absence of chromosome 13 abnormalities. Blood. 2000 Jun 15;95(12):4008-10.
• Background Dixon DO, Simon R. Sample size considerations for studies comparing survival curves using historical controls. J Clin Epidemiol. 1988;41(12):1209-13. doi: 10.1016/0895-4356(88)90025-x.
• Background Durie BG, Kyle RA, Belch A, Bensinger W, Blade J, Boccadoro M, Child JA, Comenzo R, Djulbegovic B, Fantl D, Gahrton G, Harousseau JL, Hungria V, Joshua D, Ludwig H, Mehta J, Morales AR, Morgan G, Nouel A, Oken M, Powles R, Roodman D, San Miguel J, Shimizu K, Singhal S, Sirohi B, Sonneveld P, Tricot G, Van Ness B; Scientific Advisors of the International Myeloma Foundation. Myeloma management guidelines: a consensus report from the Scientific Advisors of the International Myeloma Foundation. Hematol J. 2003;4(6):379-98.
• Background Fassas AB, Barlogie B, Ward S, Jagannath S, Vesole D, Mattox S, Siegel D, Muwalla F, Zangari M, Anaissie E, Rhee FV, Thertulien R, Lee CK, Desikan R, Arzumanian V, McCoy J, Tricot G. Survival after relapse following tandem autotransplants in multiple myeloma patients: the University of Arkansas total therapy I experience. Br J Haematol. 2003 Nov;123(3):484-9. doi: 10.1046/j.1365-2141.2003.04646.x.
• Background Fermand JP, Ravaud P, Chevret S, Divine M, Leblond V, Belanger C, Macro M, Pertuiset E, Dreyfus F, Mariette X, Boccacio C, Brouet JC. High-dose therapy and autologous peripheral blood stem cell transplantation in multiple myeloma: up-front or rescue treatment? Results of a multicenter sequential randomized clinical trial. Blood. 1998 Nov 1;92(9):3131-6.
• Background Fermand JP, Katsahian S, Divine M, Leblond V, Dreyfus F, Macro M, Arnulf B, Royer B, Mariette X, Pertuiset E, Belanger C, Janvier M, Chevret S, Brouet JC, Ravaud P; Group Myelome-Autogreffe. High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the Group Myelome-Autogreffe. J Clin Oncol. 2005 Dec 20;23(36):9227-33. doi: 10.1200/JCO.2005.03.0551. Epub 2005 Nov 7.
• Background Fonseca R, Barlogie B, Bataille R, Bastard C, Bergsagel PL, Chesi M, Davies FE, Drach J, Greipp PR, Kirsch IR, Kuehl WM, Hernandez JM, Minvielle S, Pilarski LM, Shaughnessy JD Jr, Stewart AK, Avet-Loiseau H. Genetics and cytogenetics of multiple myeloma: a workshop report. Cancer Res. 2004 Feb 15;64(4):1546-58. doi: 10.1158/0008-5472.can-03-2876.
• Background Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, Kalman L, Miller V, Lee JS, Moore M, Gandara D, Karp D, Vokes E, Kris M, Kim Y, Gamza F, Hammershaimb L. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol. 2000 Jun;18(12):2354-62. doi: 10.1200/JCO.2000.18.12.2354.
• Background Fossella F. Docetaxel + Cisplatin (DC) and Docetaxel + Carboplatin (DCb) vs Vinorelbine + Cisplatin (VC) in chemotherapy-naïve patients with advanced and metastatic non-small cell lung cancer (NSCLC): Results of a multicenter, randomized phase III study. European Journal of Cancer, European Cancer Conference, ECCO 11, 2001; Lisbon, Portugal. 37(suppl 6):S154. Abstract 562
• Background Gahrton G, Svensson H, Bjorkstrand B, Apperley J, Carlson K, Cavo M, Ferrant A, Fouillard L, Gratecos N, Gratwohl A, Guilhot F, Lambertenghi Deliliers G, Ljungman P, Masszi T, Milligan DW, Powles RL, Reiffers J, Samson JD, Stoppa AM, Vernant JP, Volin L, Wallvik J. Syngeneic transplantation in multiple myeloma - a case-matched comparison with autologous and allogeneic transplantation. European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 1999 Oct;24(7):741-5. doi: 10.1038/sj.bmt.1701975.
• Background Goldberg SL, Klumpp TR, Magdalinski AJ, Mangan KF. Value of the pretransplant evaluation in predicting toxic day-100 mortality among blood stem-cell and bone marrow transplant recipients. J Clin Oncol. 1998 Dec;16(12):3796-802. doi: 10.1200/JCO.1998.16.12.3796.
• Background Gouyette A, Hartmann O, Pico JL. Pharmacokinetics of high-dose melphalan in children and adults. Cancer Chemother Pharmacol. 1986;16(2):184-9. doi: 10.1007/BF00256174.
• Background Hall AG, Tilby MJ. Mechanisms of action of, and modes of resistance to, alkylating agents used in the treatment of haematological malignancies. Blood Rev. 1992 Sep;6(3):163-73. doi: 10.1016/0268-960x(92)90028-o.
• Background Harousseau JL, Attal M, Divine M, Marit G, Leblond V, Stoppa AM, Bourhis JH, Caillot D, Boasson M, Abgrall JF, et al. Autologous stem cell transplantation after first remission induction treatment in multiple myeloma: a report of the French Registry on autologous transplantation in multiple myeloma. Blood. 1995 Jun 1;85(11):3077-85.
• Background Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J, Anderson KC. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res. 2001 Apr 1;61(7):3071-6.
• Background Hollmig K, Stover J, Talamo G, et al. Addition of bortezomib (Velcade™) to high dose melphalan (VelMel) as an effective conditioning regimen with autologous stem cell support in multiple myeloma (MM). Blood 2004;104:266a
• Background Jagannath S, Barlogie B, Berenson J, Siegel D, Irwin D, Richardson PG, Niesvizky R, Alexanian R, Limentani SA, Alsina M, Adams J, Kauffman M, Esseltine DL, Schenkein DP, Anderson KC. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol. 2004 Oct;127(2):165-72. doi: 10.1111/j.1365-2141.2004.05188.x.
• Background Kergueris MF, Milpied N, Moreau P, Harousseau JL, Larousse C. Pharmacokinetics of high-dose melphalan in adults: influence of renal function. Anticancer Res. 1994 Nov-Dec;14(6A):2379-82.
• Background LeBlanc R, Catley LP, Hideshima T, Lentzsch S, Mitsiades CS, Mitsiades N, Neuberg D, Goloubeva O, Pien CS, Adams J, Gupta D, Richardson PG, Munshi NC, Anderson KC. Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model. Cancer Res. 2002 Sep 1;62(17):4996-5000.
• Background Lee CK, Barlogie B, Zangari M, Fassas A, Anaissie E, Morris C, Van Rhee F, Cottler-Fox M, Thertulien R, Muwalla F, Mazher S, Badros A, Tricot G. Transplantation as salvage therapy for high-risk patients with myeloma in relapse. Bone Marrow Transplant. 2002 Dec;30(12):873-8. doi: 10.1038/sj.bmt.1703715.
• Background Lightcap ES, McCormack TA, Pien CS, Chau V, Adams J, Elliott PJ. Proteasome inhibition measurements: clinical application. Clin Chem. 2000 May;46(5):673-83.
• Background McElwain TJ, Powles RL. High-dose intravenous melphalan for plasma-cell leukaemia and myeloma. Lancet. 1983 Oct 8;2(8354):822-4. doi: 10.1016/s0140-6736(83)90739-0.
• Background Mehta J, Tricot G, Jagannath S, Ayers D, Singhal S, Siegel D, Desikan K, Munshi N, Fassas A, Mattox S, Vesole D, Crowley J, Barlogie B. Salvage autologous or allogeneic transplantation for multiple myeloma refractory to or relapsing after a first-line autograft? Bone Marrow Transplant. 1998 May;21(9):887-92. doi: 10.1038/sj.bmt.1701208.
• Background Mitsiades N, Mitsiades CS, Richardson PG, Poulaki V, Tai YT, Chauhan D, Fanourakis G, Gu X, Bailey C, Joseph M, Libermann TA, Schlossman R, Munshi NC, Hideshima T, Anderson KC. The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood. 2003 Mar 15;101(6):2377-80. doi: 10.1182/blood-2002-06-1768. Epub 2002 Nov 7.
• Background NATHANS D, FAHEY JL, POTTER M. The formation of myeloma protein by a mouse plasma cell tumor. J Exp Med. 1958 Jul 1;108(1):121-30. doi: 10.1084/jem.108.1.121.
• Background Orlowski RZ, Stinchcombe TE, Mitchell BS, Shea TC, Baldwin AS, Stahl S, Adams J, Esseltine DL, Elliott PJ, Pien CS, Guerciolini R, Anderson JK, Depcik-Smith ND, Bhagat R, Lehman MJ, Novick SC, O'Connor OA, Soignet SL. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol. 2002 Nov 15;20(22):4420-7. doi: 10.1200/JCO.2002.01.133.
• Background Orlowski RZ, Voorhees PM, Garcia RA, Hall MD, Kudrik FJ, Allred T, Johri AR, Jones PE, Ivanova A, Van Deventer HW, Gabriel DA, Shea TC, Mitchell BS, Adams J, Esseltine DL, Trehu EG, Green M, Lehman MJ, Natoli S, Collins JM, Lindley CM, Dees EC. Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies. Blood. 2005 Apr 15;105(8):3058-65. doi: 10.1182/blood-2004-07-2911. Epub 2004 Dec 30.
• Background Paccagnella A, Chiarion-Sileni V, Soesan M, Baggio G, Bolzonella S, De Besi P, Casara D, Frizzarin M, Salvagno L, Favaretto A, et al. Second and third responses to the same induction regimen in relapsing patients with multiple myeloma. Cancer. 1991 Sep 1;68(5):975-80. doi: 10.1002/1097-0142(19910901)68:53.0.co;2-o.
• Background Palumbo A, Bringhen S, Petrucci MT, Musto P, Rossini F, Nunzi M, Lauta VM, Bergonzi C, Barbui A, Caravita T, Capaldi A, Pregno P, Guglielmelli T, Grasso M, Callea V, Bertola A, Cavallo F, Falco P, Rus C, Massaia M, Mandelli F, Carella AM, Pogliani E, Liberati AM, Dammacco F, Ciccone G, Boccadoro M. Intermediate-dose melphalan improves survival of myeloma patients aged 50 to 70: results of a randomized controlled trial. Blood. 2004 Nov 15;104(10):3052-7. doi: 10.1182/blood-2004-02-0408. Epub 2004 Jul 20.
• Background Pandit S, Vesole DH. Relapsed multiple myeloma. Curr Treat Options Oncol. 2001 Jun;2(3):261-9. doi: 10.1007/s11864-001-0040-6.
• Background Papandreou C, Daliani D, Millikan RE, Tu S, Pagliaro L, Adam J. Phase I Study of Intravenous (I.V.) Proteasome Inhibitor PS-341 in Patients (Pts) with Advanced Malignancies. Proc Am Soc Clin Oncol, 2001. Abstract 340
• Background Pineda-Roman M, Fox MH, Hollmig KA, et al. Retrospective analysis of fractionated high-dose melphalan (F-Mel) and bortezomib-thalidomide-dexamethasone (VTD) with autotransplant (AT) support for advanced and refractory multiple myeloma (AR-MM). Blood 2006;108:884a
• Background Pinguet F, Martel P, Fabbro M, Petit I, Canal P, Culine S, Astre C, Bressolle F. Pharmacokinetics of high-dose intravenous melphalan in patients undergoing peripheral blood hematopoietic progenitor-cell transplantation. Anticancer Res. 1997 Jan-Feb;17(1B):605-11.
• Background Reece PA, Hill HS, Green RM, Morris RG, Dale BM, Kotasek D, Sage RE. Renal clearance and protein binding of melphalan in patients with cancer. Cancer Chemother Pharmacol. 1988;22(4):348-52. doi: 10.1007/BF00254244.
• Background Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Srkalovic G, Alsina M, Alexanian R, Siegel D, Orlowski RZ, Kuter D, Limentani SA, Lee S, Hideshima T, Esseltine DL, Kauffman M, Adams J, Schenkein DP, Anderson KC. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003 Jun 26;348(26):2609-17. doi: 10.1056/NEJMoa030288.
• Background Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, San-Miguel JF, Blade J, Boccadoro M, Cavenagh J, Dalton WS, Boral AL, Esseltine DL, Porter JB, Schenkein D, Anderson KC; Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005 Jun 16;352(24):2487-98. doi: 10.1056/NEJMoa043445.
• Background Richardson PG, Weller E, Jagannath S, Avigan DE, Alsina M, Schlossman RL, Mazumder A, Munshi NC, Ghobrial IM, Doss D, Warren DL, Lunde LE, McKenney M, Delaney C, Mitsiades CS, Hideshima T, Dalton W, Knight R, Esseltine DL, Anderson KC. Multicenter, phase I, dose-escalation trial of lenalidomide plus bortezomib for relapsed and relapsed/refractory multiple myeloma. J Clin Oncol. 2009 Dec 1;27(34):5713-9. doi: 10.1200/JCO.2009.22.2679. Epub 2009 Sep 28.
• Background Rowley SD, Siegel, D, Donato ML,et al. Combination melphalan and bortezomib conditioning with autologous hematopoeitic stem cell support in patients with advanced multiple myeloma. A phase I/II study. Blood 2009;114:499
• Background Samuels BL, Bitran JD. High-dose intravenous melphalan: a review. J Clin Oncol. 1995 Jul;13(7):1786-99. doi: 10.1200/JCO.1995.13.7.1786.
• Background Siegel DS, Desikan KR, Mehta J, Singhal S, Fassas A, Munshi N, Anaissie E, Naucke S, Ayers D, Spoon D, Vesole D, Tricot G, Barlogie B. Age is not a prognostic variable with autotransplants for multiple myeloma. Blood. 1999 Jan 1;93(1):51-4.
• Background Spanswick VJ, Craddock C, Sekhar M, Mahendra P, Shankaranarayana P, Hughes RG, Hochhauser D, Hartley JA. Repair of DNA interstrand crosslinks as a mechanism of clinical resistance to melphalan in multiple myeloma. Blood. 2002 Jul 1;100(1):224-9. doi: 10.1182/blood.v100.1.224.
• Background Teicher BA, Ara G, Herbst R, Palombella VJ, Adams J. The proteasome inhibitor PS-341 in cancer therapy. Clin Cancer Res. 1999 Sep;5(9):2638-45.
• Background Tricot G, Jagannath S, Vesole DH, Crowley J, Barlogie B. Relapse of multiple myeloma after autologous transplantation: survival after salvage therapy. Bone Marrow Transplant. 1995 Jul;16(1):7-11.
• Background Tricot G, Alberts DS, Johnson C, Roe DJ, Dorr RT, Bracy D, Vesole DH, Jagannath S, Meyers R, Barlogie B. Safety of autotransplants with high-dose melphalan in renal failure: a pharmacokinetic and toxicity study. Clin Cancer Res. 1996 Jun;2(6):947-52.
• Background Tricot G, Spencer T, Sawyer J, Spoon D, Desikan R, Fassas A, Badros A, Zangari M, Munshi N, Anaissie E, Toor A, Barlogie B. Predicting long-term (> or = 5 years) event-free survival in multiple myeloma patients following planned tandem autotransplants. Br J Haematol. 2002 Jan;116(1):211-7. doi: 10.1046/j.1365-2141.2002.03231.x.
• Background Vesole DH, Barlogie B, Jagannath S, Cheson B, Tricot G, Alexanian R, Crowley J. High-dose therapy for refractory multiple myeloma: improved prognosis with better supportive care and double transplants. Blood. 1994 Aug 1;84(3):950-6.

Drugs

Indications