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Medical Progress

Multiple Myeloma
Antonio Palumbo, M.D., and Kenneth Anderson, M.D.
From the Myeloma Unit, Division of
Hematology, University of Turin, AOU
S. Giovanni Battista, Turin, Italy (A.P.);
and the Department of Medicine, Harvard Medical School, Division of Hematolgic Neoplasia, Dana–Farber CancerInstitute, Boston (K.A.). Address reprint
requests to Dr. Palumbo at the Myeloma
Unit, Division of Hematology, University
of Turin, Via Genova 3, 10126 Turin, Italy, or
at appalumbo@yahoo.com.
N Engl J Med 2011;364:1046-60.
Copyright © 2011 Massachusetts Medical Society.

M

ultiple myeloma is a neoplastic plasma-cell disorder that is
characterized by clonal proliferation of malignantplasma cells in the
bone marrow microenvironment, monoclonal protein in the blood or urine,
and associated organ dysfunction.1 It accounts for approximately 1% of neoplastic
diseases and 13% of hematologic cancers. In Western countries, the annual ageadjusted incidence is 5.6 cases per 100,000 persons.2 The median age at diagnosis
is approximately 70 years; 37% of patients are younger than 65years, 26% are between the ages of 65 and 74 years, and 37% are 75 years of age or older.2,3 In recent
years, the introduction of autologous stem-cell transplantation and the availability
of agents such as thalidomide, lenalidomide, and bortezomib have changed the
management of myeloma and extended overall survival.3-5 In patients presenting at
an age under 60 years, 10-year survival isapproximately 30%.4

The Biol o gy of Mult ipl e M y el om a
Myeloma arises from an asymptomatic premalignant proliferation of monoclonal
plasma cells that are derived from post–germinal-center B cells. Multistep genetic
and microenvironmental changes lead to the transformation of these cells into a
malignant neoplasm. Myeloma is thought to evolve most commonly from a monoclonal gammopathy ofundetermined clinical significance (usually known as
MGUS) that progresses to smoldering myeloma and, finally, to symptomatic myeloma (Fig. 1).6 Several genetic abnormalities that occur in tumor plasma cells play
major roles in the pathogenesis of myeloma.7
Primary early chromosomal translocations occur at the immunoglobulin switch
region on chromosome 14 (q32.33), which is most commonly juxtaposedto MAF
(t[14;16][q32.33;23]) and MMSET on chromosome 4p16.3. This process results in
the deregulation of two adjacent genes, MMSET in all cases and FGFR3 in 30% of
cases.6,8 Secondary late-onset translocations and gene mutations that are implicated in disease progression include complex karyotypic abnormalities in MYC, the
activation of NRAS and KRAS, mutations in FGFR3 and TP53, and theinactivation
of cyclin-dependent kinase inhibitors CDKN2A and CDKN2C.6,8 Other genetic
abnormalities involve epigenetic dysregulation, such as alteration in microRNA
expression and gene methylation modifications.9 Gene-expression profiling allows
classification of multiple myeloma into different subgroups on the basis of genetic abnormalities.10 (The full names of the genes used in the text areprovided
in the Glossary in the Supplementary Appendix, available with the full text of this
article at NEJM.org.)
Genetic abnormalities alter the expression of adhesion molecules on myeloma
cells, as well as responses to growth stimuli in the microenvironment (Fig. 2).
Interactions between myeloma cells and bone marrow cells or extracellular matrix

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n engl j med 364;11

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m edical progress

Figure 1. Multistep Pathogenesis of Multiple Myeloma.
Early chromosomal abnormalities (immunoglobulin heavy chain translocations or trisomies) are...