Progress in the Front-line Treatment of Multiple Myeloma

Stefan Knop, Klaus Martin Kortüm, Hermann Einsele
European Haematology, 2010;4:70-4
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Abstract

Multiple myeloma (MM) is a clonal plasma cell tumour that requires systemic treatment once disease-related symptoms arise. Symptomatic MM is defined by at least one of the following: hypercalcaemia, renal failure, anaemia and/or bone lesions. Several therapeutic milestones have been achieved during the last few decades, resulting in improved prognosis for affected subjects. The alkylator melphalan has been a backbone of MM treatment since its introduction in the 1960s. The compound is currently used at high doses followed by autologous stem cell transplantation (ASCT) in patients ≤65–70 years of age in conventional doses in conjunction with prednisone and either thalidomide (MPT) or the proteasome inhibitor bortezomib (VMP). Both regimens have proved superior to MP alone in randomised clinical trials. In patients eligible for ASCT, initial cytoreduction should be performed using one of the ‘novel’ compounds (thalidomide, bortezomib, lenalidomide) in combination with dexamethasone because of enhanced response both before and after ASCT compared with standard anthracycline/dexamethasone. However, it has not yet been determined which combination should best be used in a given patient. Whether up-front allogeneic transplantation may contribute to improved outcomes in younger patients depends on results from clinical trials that have been fully recruited, but longer follow-up is awaited in the near future.
Keywords
Multiple myeloma, chemotherapy, autologous stem cell transplantation, allogeneic stem cell transplantation, melphalan, prednisone, thalidomide, bortezomib, lenalidomide, dexamethasone, maintenance therapy
Disclosure Stefan Knop receives honoraria from Celgene and Ortho Biotech and is a consultant for Celgene and Ortho Biotech. Klaus Martin Kortum has no conflicts of interest to declare. Hermann Einsele receives honoraria from Celgene and Ortho Biotech, is a consultant for Celgene and Ortho Biotech and receives research funding from Ortho Biotech.
Received: October 12, 2009 Accepted February 09, 2010
Correspondence: Stefan Knop, Department of Internal Medicine II, Division of Hematology and Medical Oncology, University Hospital of Würzburg, Oberduerrbacher Strasse 6, 97080 Würzburg, Germany. E: knop_s@medizin.uni-wuerzburg.de

Multiple myeloma (MM) is a malignancy originating from a post-germinal centre lymphocyte, the antibody-secreting plasma cell. It remains incurable despite the fact that numerous pre-clinical and clinical investigations have been conducted. Therapeutic milestones allowed for the extension of survival times in affected subjects during a 35-year period, as reported recently.1 By nature, MM requires systemic therapy while local procedures (irradiation, surgical interventions) remain supportive treatment. Currently, presence of end-organ damage caused by the accumulation of malignant plasma cells (hypercalcaemia, renal insufficiency, anaemia and bone disease [CRAB]) is considered to be symptomatic myeloma and thus requires treatment.2 The initial attempts to bring cytotoxic chemotherapy to myeloma patients in the late 1960s consisted of drug combinations utilising the alkylator melphalan and corticosteroids.3,4

Melphalan and prednisone (MP) was considered the standard of care for patients with MM in the following years. Attempts to achieve disease control and survival rates beyond those seen with the use of MP by intensive chemotherapy combinations were not successful: an analysis of individual patient data combined with a meta-analysis of 27 trials revealed no difference in mortality rate for patients treated with MP compared with those receiving combination chemotherapy.5

High-dose Chemotherapy with Autologous Stem Cell Transplantation

Substantially increasing the dose of melphalan provided the basis for the first major breakthrough in myeloma treatment: the introduction of high-dose chemotherapy with subsequent retransfusion of autologous peripheral blood progenitor cells (APBPCs). Initial reports of dose-intensified melphalan (still without APBPC transplant) appeared in the early 1980s. Response to therapy in the first small series on nine subjects was remarkable, especially in those few who had received no prior treatment.6

However, a major obstacle was the high rate of infectious complications associated with a number of treatment-related deaths due to profound and long-lasting neutropenia. The administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) shortened the duration of neutropenia without affecting the mortality rate.7 Following reports of successful transplantation of APBPCs in two previously untreated subjects with myeloma, this transplant modality replaced autologous bone marrow. Engraftment after APBPC transplantation was reliable, sustained and faster compared with bone marrow grafting, with APBPCs being more easily accessible.8–10

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