Zusammenfassung
Das multiple Myelom (MM) ist charakterisiert durch eine Infiltration des Knochenmarks mit neoplastischen Plasmazellen. Eine beeinträchtigte Hämatopoese, die verminderte Produktion funktioneller Immunglobuline, sowie die Induktion der pathognomonischen osteolytischen Läsionen tragen wesentlich zur Morbidität dieser Patientengruppe bei. Die konventionelle Chemotherapie stellt die Behandlung der Wahl für ältere Patienten dar, während Patienten, die jünger als 60 Jahre sind, eher von einer Hochdosistherapie mit anschließender autologer Stammzelltransplantation profitieren. Die Weiterführung der Idee der Steigerung der Konditionierungsdosis erbrachte mit Entwicklung des Konzeptes der Tandem-Transplantation eine zusätzliche Überlebensverbesserung. Die Erhaltungstherapie mit Interferon-α und Glukokortikoiden wies ebenfalls einen günstigen Effekt auf, sie bleibt jedoch ein kontroversielles Thema aufgrund der damit verbundenen hohen Kosten und der beträchtlichen Toxizität. Die Wiedereinführung eines alten Arzneimittels, Thalidomid, für die Therapie des multiplen Myeloms und die Entwicklung hochpotenter immunmodulatorischer Derivate stellt ein vielversprechendes neues Behandlungskonzept dar, das auf Myelomzell-Stromazell Interaktionen, die biologische Umgebung im Knochenmark und die Myelomzelle selbst einwirkt. Die Bedeutung von Bisphosphonaten für die Prävention bzw. Verbesserung ossärer Komplikationen und Hyperkalzämie ist gut belegt. Es konnte auch gezeigt werden, dass eine neue Generation von Bisphosphonaten selbst Anti-Tumor-Aktivität besitzt, was wiederum die Wichtigkeit unterstreicht, dem Plasmazell-Klon günstige Bedingungen im biologischen Umfeld zu entziehen.
Summary
Multiple myeloma (MM) is characterized by infiltration of bone marrow with a clone of neoplastic plasma cells. Impaired hematopoiesis and reduced production of functional immunoglobulins, as well as the induction of pathognomonic osteolytic lesions primarily contribute to the morbidity of patients with MM. Conventional chemotherapy is the treatment of choice for older patients, whereas those under 60 years benefit significantly from high-dose therapy followed by stem-cell rescue. The use of tandem transplantation, developed to further escalate the conditioning dose, has achieved additional improvement in survival. Interferon-α and glucocorticoids are effective as maintenance measures in MM but remain controversial because of their associated high costs and considerable toxicity. The resurrection of an old drug, thalidomide, for the therapy of MM and the development of potent immunomodulatory derivatives are highly promising new treatments that target MM cell-host interactions and the bone-marrow microenvironment, as well as the myeloma cell itself. The importance of the use of bisphosphonates for the prevention or amelioration of skeletal complications and hypercalcemia is well established. New generations of bisphosphonates show potent antitumor activity, again emphasising the importance of targeting the microenvironment of the plasma-cell clone.
References
Alexanian R, Haut A, Khan AU, Lane M, McKelvey EM, Migliore PJ, et al (1969) Treatment for multiple myeloma. Combination chemotherapy with different melphalan dose regimens. JAMA 208: 1680–1685
Wheatley K (1998) Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials. Myeloma Trialists’ Collaborative Group. J Clin Oncol 16: 3832–3842
Barlogie B, Smith L, Alexanian R (1984) Effective treatment of advanced multiple myeloma refractory to alkylating agents. N Engl J Med 310: 1353–1356
Segeren CM, Sonneveld P, van der Holt B, Baars JW, Biesma DH, Cornellissen JJ, et al (1999) Vincristine, doxorubicin and dexamethasone (VAD) administered as rapid intravenous infusion for first-line treatment in untreated multiple myeloma. Br J Haematol 105: 127–130
Cook G, Sharp RA, Tansey P and Franklin IM (1996) A phase I/II trial of Z-Dex (oral idarubicin and dexamethasone), an oral equivalent of VAD, as initial therapy at diagnosis or progression in multiple myeloma. Br J Haematol 93: 931–934
Glasmacher A, Haferlach T, Gorschluter M, Mezger J, Maintz C, Clemens MR, et al (1997) Oral idarubicin, dexamethasone and vincristine (VID) in the treatment of multiple myeloma. Leukemia 11 [Suppl 5]: 22–26
Selby PJ, McElwain TJ, Nandi AC, Perren TJ, Powles RL, Tillyer CR, et al (1987) Multiple myeloma treated with high dose intravenous melphalan. Br J Haematol 66: 55–62
Moreau P, Fiere D, Bezwoda WR, Facon T, Attal M, Laporte JP, et al (1997) Prospective randomized placebocontrolled study of granulocyte-macrophage colony-stimulating factor without stem-cell transplantation after high-dose melphalan in patients with multiple myeloma. J Clin Oncol 15: 660–666
Harousseau JL, Attal M (1997) The role of autologous hematopoietic stem cell transplantation in multiple myeloma. Semin Hematol 34 [Suppl 1]: 61–66
Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF (1996) A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myelome. N Engl J Med 335: 91–97
Atkins CD (1996) High-dose chemotherapy in multiple myeloma. N Engl J Med 335: 1844–1845
Segeren CM, Sonneveld P, Van Der Holt B, Vellenga E, Croockewit AJ, Verhoef GE, et al (2003) Overall and event-free survival are not improved by the use of myeloablative therapy following intensified chemotherapy in previously untreated patients with multiple myeloma: a prospective randomized phase 3 study. Blood 101: 2144–2151
Levy V, Katsahian S, Fermand J-P, Attal M, Mary J-Y, Chevret S (2002) High dose therapy followed by autologous stem cell transplantation or conventional chemotherapy as a first line treatment in multiple myeloma: A meta-analysis on individual patient data of randomized clinical trials with long-term follow-up. Blood 100: 401a Abstract 1556
Vescio RA, Han EJ, Schiller GJ, Lee JC, Wu CH, Cao J, et al (1996) Quantitative comparison of multiple myeloma tumor contamination in bone marrow harvest and leukapheresis autografts. Bone Marrow Transplant 18: 103–110
Henry JM, Sykes PJ, Brisco MJ, To LB, Juttner CA, Morley AA (1996) Comparison of myeloma cell contamination of bone marrow and peripheral blood stem cell harvests. Br J Haematol 92: 614–619
Harousseau JL, Attal M, Divine M, Milpied N, Marit G, Leblond V, et al (1995) Comparison of autologous bone marrow transplantation and peripheral blood stem cell transplantation after first remission induction treatment in multiple myeloma. Blood 92: 3131–3136
Schmitz N, Linch DC, Dreger P, Goldstone AH, Boogaerts MA, Ferrant A, et al (1996) Randomised trial of filgrastim-mobilised peripheral blood progenitor cell transplantation versus autologous bone-marrow transplantation in lymphoma patients. Lancet 347(8998): 353–357
Govindarajan R, Jagannath S, Flick JT, Vesole DH, Sawyer J, Barlogie B, Tricot G (1996) Preceding standard therapy is the likely cause of MDS after autotransplants for multiple myeloma. Br J Haematol 95: 349–353
Martinez E, Sureda A, Dalmases CD, Sanchez JA, Amill B, Tugues D, et al (1996) Mobilization of peripheral blood progenitor cells by cyclophosphamide and rhGM-CSF in multiple myeloma. Bone Marrow Transplant 18: 1–7
Moreau P, Facon T, Attal M, Hulin C, Michallet M, Maloisel F, et al (2002) Comparison of 200 mg/m(2) melphalan and 8 Gy total body irradiation plus 140 mg/m(2) melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myelome 9502 randomized trial. Blood 99: 731–735
Barlogie B, Jagannath S, Desikan KR, Mattox S, Vesole D, Siegel D, et al (1999) Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood 93: 55–65
Attal M, Harousseau JL, Facon T, Guilhot F, Doyen C, Fuzibet JG, et al (2002) Double autologous transplantation improves survival of multiple myeloma patients: final analysis of a prospective randomized study of the “Intergroupe Francophone du Myelome” (IFM 94). Blood 100: 5a Abstract 7
Fermand JP, Ravaud P, Chevret S, Divine M, Leblond V, Belanger C, et al (1998) 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 92: 3131–3136
Hahn T, Wingard JR, Anderson KC, Bensinger WI, Berenson JR, Brozeit G, et al (2003) The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of multiple myeloma: an evidence-based review. Biol Blood Marrow Transplant 9: 4–37
Gupta D, Bybee A, Cooke F, Giles C, Davis JG, McDonald C, et al (1999) CD34+-selected peripheral blood progenitor cell transplantation in patients with multiple myeloma: tumour cell contamination and outcome. Br J Haematol 104: 166–177
Vescio R, Schiller G, Stewart AK, Ballester O, Noga S, Rugo H, et al (1999) Multicenter phase III trial to evaluate CD34(+) selected versus unselected autologous peripheral blood progenitor cell transplantation in multiple myeloma. Blood 93: 1858–1868
Lemoli RM, Martinelli G, Olivieri A, Motta MR, Rizzi S, Terragna C, et al (1999) Selection and transplantation of autologous CD34+ B-lineage negative cells in advanced-phase multiple myeloma patients: a pilot study. Br J Haematol 107: 419–428
Barbui AM, Galli M, Dotti G, Belli N, Borleri G, Gritti G, et al (2002) Negative selection of peripheral blood stem cells to support a tandem autologous transplantation programme in multiple myeloma. Br J Haematol 116: 202–210
Alexanian R, Balzerzac S, Haut A, et al (1975) Remission maintenance therapy for multiple myeloma. Arch Intern Med 135: 147–152
Gisslinger H (1997) Interferon alpha in the therapy of multiple myeloma. Leukemia 11 [Suppl 5]: 52–56
Cooper MR, Dear K, McIntyre OR, Ozer H, Ellerton J, Canellos G, et al (1993) A randomized clinical trial comparing melphalan/prednisolone with or without interferon alfa-2b in newly diagnosed patients with multiple myeloma: a Cancer and Leukemia Group B study. J Clin Oncol 11: 155–160
Osterborg A, Bjorkholm M, Bjoreman M, Brenning G, Carlson K, Celsing F, et al (1993) Natural interferon-alpha in combination with melphalan/prednisone versus melphalan/prednisone in the treatment of multiple myeloma stages II and III: a randomized study from the Myeloma Group of Central Sweden. Blood 81: 1428–1434
Fritz E, Ludwig H (2000) Interferon-alpha treatment in multiple myeloma: meta-analysis of 30 randomised trials among 3948 patients. Ann Oncol Nov 11: 1427–1436
Salmon SE, Crowley JJ, Balcerzak SP, Roach RW, Taylor SA, Rivkin SE, et al (1998) Interferon versus interferon plus prednisone remission maintenance therapy for multiple myeloma: a Southwest Oncology Group Study. J Clin Oncol 16: 890–896
Berenson JR, Crowley JJ, Grogan TM, Zangmeister J, Briggs AD, Mills GM, et al (2002) Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients. Blood 99: 3163–3168
Lokhorst HM, Sonneveld P, Cornelissen JJ, Joosten P, van Marwijk Kooy M, Meinema J, et al (1999) Induction therapy with vincristine, adriamycin, dexamethasone (VAD) and intermediate-dose melphalan (IDM) followed by autologous or allogeneic stem cell transplantation in newly diagnosed multiple myeloma. Bone Marrow Transplant 23: 317–322
Seiden MV, Schlossman R, Andersen J, Freeman A, Robertson M, Soiffer R, et al (1995) Monoclonal antibodypurged bone marrow transplantation therapy for multiple myeloma. Leuk Lymphoma 17: 87–93
Bjorkstrand BB, Ljungman P, Svensson H, Hermans J, Alegre A, Apperley J, et al (1996) Allogeneic bone marrow transplantation versus autologous stem cell transplantation in multiple myeloma: a retrospective casematched study from the European Group for Blood and Marrow Transplantation. Blood 88: 4711–4718
Mehta J, Tricot G, Jagannath S, Ayers D, Singhal S, Siegel D, et al (1998) Salvage autologous or allogeneic transplantation for multiple myeloma refractory to or relapsing after a first-line autograft? Bone Marrow Transplant 21: 887–892
Gahrton G, Tura S, Ljungman P, Blade J, Brandt L, Cavo M, et al (199) Prognostic factors in allogeneic bone marrow transplantation for multiple myeloma. J Clin Oncol 13: 1312–1322
Tricot G, Vesole DH, Jagannath S, Hilton J, Munshi N, Barlogie B (1996) Graft-versus-myeloma effect: proof of principle. Blood 87: 1196–1198
Lokhorst HM, Schattenberg A, Cornelissen JJ, Thomas LL, Verdonck LF (1997) Donor leukocyte infusions are effective in relapsed multiple myeloma after allogeneic bone marrow transplantation. Blood 90: 4206–4211
Badros A, Barlogie B, Siegel E, Cottler-Fox M, Zangari M, Fassas A, et al (2002) Improved outcome of allogeneic transplantation in high-risk multiple myeloma patients after nonmyeloablative conditioning. J Clin Oncol 20: 1295–1303
Anderson KC, Shaughnessy JD Jr, Barlogie B, Harousseau JL, Roodman GD (2002) Multiple myeloma. Hematology (Am Soc Hematol Educ Program): 214–240
Rajkumar SV, Fonseca R, Witzig TE, Gertz MA, Greipp PR (1999) Bone marrow angiogenesis in patients achieving complete response after stem cell transplantation for multiple myeloma. Leukemia 13: 469–472
Vacca A, Ribatti D, Presta M, Minischetti M, Iurlaro M, Ria R, et al (1999) Bone marrow neovascularization, plasma cell angiogenic potential, and matrix metalloproteinase-2 secretion parallel progression of human multiple myeloma. Blood 93: 3064–3073
D’Amato RJ, Loughnan MS, Flynn E, Folkman J (1994) Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA 91: 4082–4085
Kenyon BM, Browne F, D’Amato RJ (1997) Effects of thalidomide and related metabolites in a mouse corneal model of neovascularization. Exp Eye Res 64: 971–978
Gupta D, Treon SP, Shima Y, Hideshima T, Podar K, Tai YT, et al (2001) Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications. Leukemia 15: 1950–1961
Neben K, Moehler T, Kraemer A, Benner A, Egerer G, Ho A, Goldschmidt H (2001) Response to thalidomide in progressive multiple myeloma is not mediated by inhibition of angiogenic cytokine secretion. Br J Haematol 115: 605–608
Sezer O, Jakob C, Eucker J, Niemoller K, Gatz F, Wernecke K, Possinger K (2001) Serum levels of the angiogenic cytokines basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in multiple myeloma. Eur J Haematol 66: 83–88
Hideshima T, Chauhan D, Shima Y, Raje N, Davies FE, Tai YT, et al (2000) Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood 96: 2943–2950
Damiano JS, Cress AE, Hazlehurst LA, Shtil AA, Dalton WS (1999) Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines. Blood 93: 1658–1667
Klein B (1995) Cytokine, cytokine receptors, transduction signals, and oncogenes in human multiple myeloma. Semin Hematol 32: 4–19
Kaufmann H, Urbauer E, Ackermann J, Huber H, Drach J (2001) Advances in the biology and therapeutic management of multiple myeloma. Ann Hematol 80: 445–451
Raje N, Anderson KC (2002) Thalidomide and immunomodulatory drugs as cancer therapy. Curr Treat Options Oncol 14: 635–640
Davies FE, Raje N, Hideshima T, Lentzsch S, Young G, Tai YT, et al (2001) Thalidomide and immunomodulatory derivates augment natural killer cell cytotoxicity in multiple myeloma. Blood 98: 210–216
Singhal S, Metha J, Desikan R, Ayers D, Robertson P, Eddlemon P, et al (1999) Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 341: 1565–1571
Barlogie B, Desikan R, Eddlemon P, Spencer T, Zeldis J, Munishi N (2001) Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients. Blood 98: 492–494
Tosi P, Zamagni E, Cellini C, Ronconi S, Patriarca F, Ballerini F, et al (2002) Salvage therapy with thalidomide in patients with advanced relapsed/refractory multiple myeloma. Haematologica 87: 408–414
Kumar S, Gertz MA, Dispenzieri A, Lacy MQ, Geyer SM, Iturria NL, et al (2003) Response rate, durability of response, and survival after thalidomide therapy for relapsed multiple myeloma. Mayo Clin Proc 78: 34–39
Hus M, Dmoszynska A, Soroka-Wöjtaszko M, Jawniak D, Legiec W, Ciepnuch H, et al (2001) Thalidomide treatment of resistant or relapsed multiple myeloma patients. Haematologica 86: 404–408
Kneller A, Raanani P, Hardan I, Avigdor A, Levi I, Berkowicz M, Ben-Bassat I (2000) Therapy with thalidomide in refractory multiple myeloma patients — the revival of an old drug. Br J Haematol 108: 391–393
Juliusson G, Celsing F, Turesson I, Lenhoff S, Adriansson M, Malm C (2000) Frequent good partial remissions from thalidomide including best response ever in patients with advanced refractory and relapsed myeloma. Br J Haematol 109: 89–96
Dimopoulos MA, Zervas K, Kouvatseas G, Galani E, Grigoraki V, Kiamouris C, et al (2001) Thalidomide and dexamethasone combination for refractory multiple myeloma. Ann Oncol 12: 991–995
Palumbo A, Giaccone L, Bertola A, Pregno P, Bringhen S, Rus C, et al (2001) Low-dose thalidomide plus dexamethasone is an effective salvage therapy for advanced myeloma. Haematologica 86: 399–403
Rajkumar SV, Hayman S, Gertz MA, Dispenzieri A, Lacy MQ, Greipp PR, et al (2002) Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol 20: 4319–4323
Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R (2003) Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol 21: 16–19
Barlogie B, Desikan R, Munshi N, et al (1998) Single course DTPACE anti-angiochemotherapy effects CR in plasma cell leukemia and fulminant multiple myeloma. Blood 92: 273b
Munshi N, Desikan R, Zangari M, et al (1999) Chemoangiotherapy with DT-PACE for previously treated multiple myeloma. Blood 94: 123a
Moehler TM, Neben K, Benner A, et al (2001) Salvage therapy for multiple myeloma with thalidomide and CED chemotherapy. Blood 98: 3846–3848
Garcia-Sanz R, Gonzalez-Fraile MI, Sierra M, Lopez C, Gonzalez M, San Miguel JF (2002) The combination of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) is feasible and can be an option for relapsed/ refractory multiple myeloma. Hematol J 3: 43–48
Ahmad I, Islam T, Chanan-Khan A, Hahn T, Wentling D, Becker JL, et al (2002) Thalidomide as salvage therapy for VAD-refractory multiple myeloma prior to autologous PBSCT. Bone Marrow Transplant 29: 577–580
Zangari M, Anaissie E, Barlogie B, Badros A, Desikan R, Gopal AV, et al (2001) Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy. Blood 98: 1614–1615
Osman K, Comenzo R, Rajkumar SV (2001) Deep venous thrombosis and thalidomide therapy for multiple myeloma. N Engl J Med 344: 1951–1952
Zangari M, Siegel E, Barlogie B, Anaissie E, Saghafifar F, Fassas A, et al (2002) Thrombogenic activity of doxorubicin in myeloma patients receiving thalidomide: implications for therapy. Blood 100: 1168–1171
Rajkumar SV, Gertz MA, Witzig TE (2000) Life-threatening toxic epidermal necrolysis with thalidomid therapy for myeloma. N Engl J Med 343: 972–973
Kees M, Dimou G, Sillaber C, Drach J, Ackermann J, Lechner K, Gisslinger H (2003) Low dose thalidomide in patients with relapsed or refractory multiple myeloma. Leuk Lymphoma (in press)
Richardson PG, Schlossman RL, Weller E, Hideshima T, Mitsiades C, Davies F, et al (2002) Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 100: 3063–3067
Adams J (2002) Development of the proteasome inhibitor PS-341. Oncologist 7: 9–16
Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J, Anderson KC (2001) The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 61: 3071–3076
Mitsiades N, Mitsiades CS, Richardson PG, Poulaki V, Tai YT, Chauhan D, et al (2003) The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood 101: 2377–2380
Orlowski RZ, Stinchcombe TE, Mitchell BS, Shea TC, Baldwin AS, Stahl S, et al (2002) Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol 20: 4420–4427
Aghajanian C, Soignet S, Dizon DS, Pien CS, Adams J, Elliott PJ (2002) A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies. Clin Cancer Res 8: 2505–2511
Richardson PG, Barlogie B, Berenson J, et al (2002) Phase II study of the proteasome inhibitor PS-341 in multiple myeloma (MM) patients (pts) with relapsed/ refractory disease [abstract]. Am Soc Clin Oncol Annu Meeting Proc 2002: 11a
Hayashi T, Hideshima T, Anderson KC (2003) Novel therapies for multiple myeloma. Br J Haematol 120: 1–10
www.multiplemyeloma.org/clinical_trials/4.04.asp
Soignet SL, Maslak P, Wang ZG, Jhanwar S, Calleja E, Dardashti LJ, et al (1998) Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med 339: 1341–1348
Zhu XH, Shen YL, Jing YK, Cai X, Jia PM, Huang Y, et al (1999) Apoptosis and growth inhibition in malignant lymphocytes after treatment with arsenic trioxide at clinically achievable concentrations. J Natl Cancer Inst 91: 772–778
Bachleitner-Hofmann T, Kees M, Gisslinger H (2002) Arsenic trioxide: acute promyelocytic leukemia and beyond. Leuk Lymphoma 43: 1535–1540
Munshi NC, Tricot G, Desikan R, Badros A, Zangari M, Toor A, et al (2002) Clinical activity of arsenic trioxide for the treatment of multiple myeloma. Leukemia 16: 1835–1837
Bachleitner-Hofmann T, Gisslinger B, Grumbeck E, Gisslinger H (2001) Arsenic trioxide and ascorbic acid: synergy with potential implications for the treatment of acute myeloid leukaemia? Br J Haematol 112: 783–786
Bahlis NJ, McCafferty-Grad J, Jordan-McMurry I, Neil J, Reis I, Kharfan-Dabaja M, et al (2002) Feasibility and correlates of arsenic trioxide combined with ascorbic acid-mediated depletion of intracellular glutathione for the treatment of relapsed/refractory multiple myeloma. Clin Cancer Res 8: 3658–3668
Clezardin P (2002) The antitumor potential of bisphosphonates. Semin Oncol 29 [Suppl 21]: 33–42
Lahtinen R, Laakso M, Palva I, Virkkunen P, Elomaa I (1992) Randomised, placebo-controlled multicentre trial of clodronate in multiple myeloma. Finnish Leukaemia Group. Lancet 340 (8827): 1049–1052
Berenson JR, Lichtenstein A, Porter L, Dimopoulos MA, Bordoni R, George S, et al (1996) Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group. N Engl J Med 334: 488–493
Djulbegovic B, Wheatley K, Ross J, Clark O, Bos G, Goldschmidt H, Cremer F, Alsina M, Glasmacher A (2002) Bisphosphonates in multiple myeloma. Cochrane Database Syst Rev 3: CD003188
Ludwig H, Fritz E, Kotzmann H, Hocker P, Gisslinger H, Barnas U (1990) Erythropoietin treatment of anemia associated with multiple myeloma. N Engl J Med 322: 1693–1699
Ludwig H, Fritz E (1998) Anemia of cancer patients: patient selection and patient stratification for epoetin treatment. Semin Oncol 25 [Suppl 7]: 35–38
Cazzola M, Messinger D, Battistel V, Bron D, Cimino R, Enller-Ziegler L, et al (1995) Recombinant human erythropoietin in the anemia associated with multiple myeloma or non-Hodgkin’s lymphoma: dose finding and identification of predictors of response. Blood 86: 4446–4453
Garton JP, Gertz MA, Witzig TE, Greipp PR, Lust JA, Schroeder G, Kyle RA (1995) Epoetin alfa for the treatment of the anemia of multiple myeloma. A prospective, randomized, placebo-controlled, double-blind trial. Arch Intern Med 155: 2069–2074
Osterborg A, Brandberg Y, Molostova V, Iosava G, Abdulkadyrov K, Hedenus M, et al (2002) Randomized, double-blind, placebo-controlled trial of recombinant human erythropoietin, epoetin beta, in hematologic malignancies. J Clin Oncol 20: 2486–2494
Dammacco F, Castoldi G, Rodjer S (2001) Efficacy of epoetin alfa in the treatment of anaemia of multiple myeloma. Br J Haematol 113: 172–179
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Gisslinger, H., Kees, M. Therapy strategies for multiple myeloma: current status. Wien Klin Wochenschr 115, 451–461 (2003). https://doi.org/10.1007/BF03041028
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DOI: https://doi.org/10.1007/BF03041028
Schlüsselwörter
- Behandlung des multiplen Myeloms
- autologe Stammzelltransplantation
- allogene Stammzelltransplantation
- konventionelle Chemotherapie
- Doppeltransplantationen
- Erhaltungstherapie
- Thalidomid
- Immunmodulierende Substanzen
- IMIDS
- Arsentrioxyd
- Bisphosphonate
- Erythropoetin