Behandlung des rezidivierten oder refraktären Multiplen Myeloms

Zusammenfassung

Das Multiple Myelom (MM) ist mit einer Inzidenz von 4–6/100000 Einwohnern die zweithäufigste maligne Erkrankung der B-Zellen. Die Inzidenz nimmt mit dem Alter zu. Dieser Übersichtsartikel wurde verfasst, um dem Leser die vielfachen Neuerungen bei der Therapie des rezidivierten/refraktären Myeloms zu vermitteln. Der Therapiestandard beim progredienten oder refraktären MM (RRMM) wurde vom Arbeitskreis „Refraktäres Multiples Myelom“ unter Einbezug einer Literaturrecherche mit den Suchworten „refractory multiple myeloma“ und „multiple myeloma relapse“ anhand von Studien erarbeitet, die zwischen 2003 und 2013 erschienen sind. Welche Rezidiv-, Hochdosis- oder Kombinationstherapien besonders wirksam und gleichzeitig wenig toxisch sind, wird derzeit intensiv in klinischen Studien untersucht. Daher wird – wenn möglich – der Einschluss von Patienten in Therapiestudien empfohlen. Außerhalb von Therapiestudien mit z. B. immunmodulatorischen Substanzen der 3. Generation (IMIDs; z. B. Pomalidomid), neuen Proteasominhibitoren, wie Carfilzomib, Ixazomib und Oprozomib, Antikörpern, wie Elotuzumab, Daratumumab oder SAR650984, Siltuximab, Tabalumab, Denosumab, Romosozumab, BTK-, HSP-Inhibitoren und anderen innovativen Phase-I/II-Substanzen, wird bei „fitten“ Patienten ohne wesentliche Komorbidität und einer Plateauphase von mindestens 12–24 Monaten nach initialer Hochdosistherapie, auch eine erneute Hochdosistherapie empfohlen.

Fazit: Die Therapieoptionen beim MM haben sich in den letzten Jahren entscheidend geändert. Die Kenntnisse über Pathogenese und Resistenzmechanismen haben zugenommen. Eine größere Therapievielfalt, d. h. mehr wirksame Substanzen und Kombinationen sind verfügbar. Auch im Rezidiv leben die Patienten mit der Erkrankung heute oft länger und komplikationsärmer.

Abstract

Multiple myeloma (MM) is with an incidence of 4–6/100 000 inhabitants a fairly frequent malignancy of B cells. The incidence increases markedly with age. In this review changes in the treatment of relapsed / refractory myeloma during the last decade have been analysed. The present standard of care in the progressive or refractory myeloma was elaborated by the working group “Refractory Multiple Myeloma” using an extensive literature search for studies published between 2003 and 2013. Outside of clinical trials, high-dose therapy with stem cell transplantation is recommended in fit patients up to 75 years without significant comorbidities. Ongoing studies address the question about the least toxic and the most effective treatment. Therefore, inclusion of patients in therapeutic trials and use of novel agent combinations is highly recommended, e. g. with 3^rd generation-IMIDs (pomalidomide), new proteasome inhibitors, such as carfilzomib, ixazomib or oprozomib, antibodies, such as elotuzumab, daratumumab or SAR650984, siltuximab, tabalumab, denosumab, romosozumab, BTK-, HSP-inhibitors and other innovative phase I/II agents.

Conclusion: Based on new insights in the pathogenesis of the disease, treatment options for MM have changed significantly in recent years. There is a significantly larger treatment diversity, i. e. more MM-active agents and combinations are available today. Even with relapsed MM, patients with the disease often live longer and have fewer complications.

Schlüsselwörter

Multiples Myelom - Diagnostik - Rezidivtherapie - Supportivtherapie

Keywords

multiple myeloma - diagnostics - therapy - supportive treatment

• Literatur

• 1 Atanackovic D, Schilling G. Second autologous transplant as salvage therapy in multiple myeloma. Br J Haematol 2013; 163: 565-572
• 2 Auel B, Goldschmidt H, Geer T et al. German Refractory Myeloma Study Group. Treatment with thalidomide and cyclophosphamide (TCID) is superior to vincristine (VID) and to vinorelbine (VRID) regimens in patients with refractory or recurrent multiple myeloma. Indian J Hematol Blood Transfus 2012; 28: 67-76
• 3 Berger D, Engelhardt M, Mertelsmann R (Hrsg.). Chemotherapie-Manual Hämatologie und Internistische Onkologie. . 4. Auflage. Berlin, Heidelberg, New York: Springer; 2012: 693-702
• 4 Dadacaridou M, Papanicolaou X, Maltesas D et al. Dexamethasone, cyclophosphamide, etoposide and cisplatin (DCEP) for relapsed or refractory multiple myeloma patients. J BUON 2007; 12: 41-44
• 5 Deutsche Gesellschaft für Hämatologie und Medizinische Onkologie e. V.. Onkopedia, Multiples Myelom. http://www.dgho-onkopedia.de/de/onkopedia/leitlinien/multiples-myelom
• 6 Dimopoulos M, Siegel DS, Lonial S et al. Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088). Lancet Oncol 2013; 14: 1129-1140
• 7 Dimopoulos M, Spencer A, Attal M et al. Multiple Myeloma (010) Study Investigators. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 2007; 357: 2123-2132
• 8 Dimopoulos MA, Terpos E, Goldschmidt H et al. Treatment with lenalidomide and dexamethasone in patients with multiple myeloma and renal impairment. Cancer Treat Rev 2012; 38: 1012-1009
• 9 Durie BG, Harousseau JL, Miguel JS et al. International uniform response criteria for multiple myeloma. Leukemia 2006; 20: 1467-1473
• 10 Einsele H, Schäfer HJ, Hebart H et al. Follow-up of patients with progressive multiple myeloma undergoing allografts after reduced-intensity conditioning. Brit J Haematol 2003; 121: 411-418
• 11 Engelhardt M, Terpos E, Kleber M et al. European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma. Haematologica 2014; 99: 232-242
• 12 Garderet L, Iacobelli S, Moreau P et al. Superiority of the triple combination of bortezomib-thalidomide-dexamethasone over the dual combination of thalidomide-dexamethasone in patients with multiple myeloma progressing or relapsing after autologous transplantation. J Clin Oncol 2012; 30: 2475-2482
• 13 Hillengass J, Delorme S. Multiple myeloma: current recommendations for imaging. Radiologe 2012; 52: 360-365
• 14 Kropff M, Baylon HG, Hillengass J et al. Thalidomide versus dexamethasone for the treatment of relapsed and/or refractory multiple myeloma. Haematologica 2012; 97: 784-791
• 15 Kühnemund A, Liebisch P, Bauchmüller K et al. 'Light-chain escape-multiple myeloma'-an escape phenomenon from plateau phase. J Cancer Res Clin Oncol 2009; 135: 477-484
• 16 Lee CK, Barlogie B, Munshi N et al. DTPACE: an effective, novel combination chemotherapy with thalidomide for previously treated patients with myeloma. J Clin Oncol 2003; 21: 2732-2739
• 17 Lenhard Jr RE, Oken MM, Barnes JM et al. High-dose cyclophosphamide. An effective treatment for advanced refractory multiple myeloma. Cancer 1984; 53: 1456-1460
• 18 Lentzsch S, O'Sullivan A, Kennedy RC. Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective. Blood 2012; 119: 4608-4613
• 19 Lokhorst H, van der Holt B, Cornelissen JJ et al. Donor versus no-donor comparison of newly diagnosed myeloma patients included in the HOVON-50 multiple myeloma study. Blood 2012; 119: 6219-6215
• 20 Michael M, Bruns I, Bölke E et al. Bendamustine in patients with relapsed or refractory multiple myeloma. Eur J Med Res 2010; 15: 13-19
• 21 Mikhael JR, Belch AR, Prince HM et al. High response rate to bortezomib with or without dexamethasone in patients with relapsed or refractory multiple myeloma. Br J Haematol 2009; 144: 169-175
• 22 Morgan GJ, Davies FE, Gregory WM et al. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX). Lancet 2010; 376: 1989-1999
• 23 Oehrlein K, Langer C, Sturm I et al. Successful treatment of patients with multiple myeloma and impaired renal function with lenalidomide: results of 4 German centers. Clin Lymphoma Myeloma Leuk 2012; 12: 191-196
• 24 Orlowski RZ, Nagler A, Sonneveld P. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma. J Clin Oncol 2007; 25: 3892-3901
• 25 Palumbo A, Bertola A, Falco P et al. Efficacy of low-dose thalidomide and dexamethasone as first salvage regimen in multiple myeloma. Hematol J 2004; 5: 318-324
• 26 Richardson P. Management of the relapsed/refractory myeloma patient. Semin Hematol 2005; 42: 9-15
• 27 Richardson PG, Sonneveld P, Schuster M et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma. Blood 2007; 110: 3557-3560
• 28 San Miguel JF. Relapse/refractory myeloma patient: potential treatment guidelines. J Clin Oncol 2009; 27: 5676-5677
• 29 San Miguel JS, Weisel K, Moreau P et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003). Lancet Oncol 2013; 14: 1055-1066
• 30 Schmeel LC, Schmeel FC, Kim Y et al. Targeting the Wnt/beta-catenin pathway in multiple myeloma. Anticancer Res 2013; 33: 4719-4726
• 31 Sellner L, Heiss C, Benner A et al. Autologous retransplantation for patients with recurrent multiple myeloma. Cancer 2013; 119: 2438-2446
• 32 Siegel DS, Martin T, Wang M et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood 2012; 120: 2817-2825
• 33 Smith A, Wisloff F, Samson D. Guidelines on the diagnosis and management of multiple myeloma 2005. Brit J Haematol 2006; 132: 410-451
• 34 Terpos E, Moulopoulos LA, Dimopoulos MA. Advances in imaging and the management of myeloma bone disease. J Clin Oncol 2011; 29: 1907-1915
• 35 Tonia T, Mettler A, Robert N et al. Erythropoietin or darbepoetin for patients with cancer. . Cochrane Database Syst Rev 2012; 12 CD003407
• 36 Weber DM, Chen C, Niesvizky R. Multiple Myeloma (009) Study Investigators et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 2007; 357: 2133-2142
• 37 Yordanova A, Hose D, Neben K et al. Sorafenib in patients with refractory or recurrent multiple myeloma. Hematol Oncol 2013; 31: 197-200