Einsele_EU Haematology 04/03/2010 17:15 Page 70
Haematological Malignancies Lymphoproliferative Disorders
Progress in the Front-line Treatment of Multiple Myeloma
Stefan Knop,
1
Klaus Martin Kortüm
2
and Hermann Einsele
3
1. Consultant; 2. Staff Physician; 3. Full Professor of Internal Medicine, and Director, Department of Internal Medicine II,
Division of Haematology and Medical Oncology, University Hospital Würzburg
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 Kortüm 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: 12 October 2009 Accepted: 9 February 2010 Citation: European Haematology, 2010;4:70–4
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- for patients treated with MP compared with those receiving
germinal centre lymphocyte, the antibody-secreting plasma cell. It combination chemotherapy.
5
remains incurable despite the fact that numerous pre-clinical and
clinical investigations have been conducted. Therapeutic milestones High-dose Chemotherapy with
allowed for the extension of survival times in affected subjects Autologous Stem Cell Transplantation
during a 35-year period, as reported recently.
1
By nature, MM Substantially increasing the dose of melphalan provided the basis for
requires systemic therapy while local procedures (irradiation, the first major breakthrough in myeloma treatment: the introduction of
surgical interventions) remain supportive treatment. Currently, high-dose chemotherapy with subsequent retransfusion of autologous
presence of end-organ damage caused by the accumulation of peripheral blood progenitor cells (APBPCs). Initial reports of dose-
malignant plasma cells (hypercalcaemia, renal insufficiency, intensified melphalan (still without APBPC transplant) appeared in the
anaemia and bone disease [CRAB]) is considered to be symptomatic early 1980s. Response to therapy in the first small series on nine
myeloma and thus requires treatment.
2
The initial attempts to subjects was remarkable, especially in those few who had received
bring cytotoxic chemotherapy to myeloma patients in the late no prior treatment.
6
1960s consisted of drug combinations utilising the alkylator
melphalan and corticosteroids.
3,4
However, a major obstacle was the high rate of infectious
complications associated with a number of treatment-related
Melphalan and prednisone (MP) was considered the standard of deaths due to profound and long-lasting neutropenia. The
care for patients with MM in the following years. Attempts to administration of granulocyte-macrophage colony-stimulating factor
achieve disease control and survival rates beyond those seen with (GM-CSF) shortened the duration of neutropenia without affecting
the use of MP by intensive chemotherapy combinations were not the mortality rate.
7
Following reports of successful transplantation of
successful: an analysis of individual patient data combined with a APBPCs in two previously untreated subjects with myeloma, this
meta-analysis of 27 trials revealed no difference in mortality rate transplant modality replaced autologous bone marrow. Engraftment
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