4. Prognostication

United States [3]. The age-adjusted annual incidence in the United States has lingered similar for years at almost 4 per 100,000 [4]. Multiple myeloma is marginally more commonly reported in men than in women, and is twofold as common in African-Americans as compared with Caucasians [5]. At time of diagnosis of this disease, the median age is about 65 years [6].

The diagnosis of multiple myeloma requires the presence of one or more myeloma defining events (MDE) in addition to evidence of either 10% or more clonal plasma cells on bone marrow examination or a biopsy-proven plasmacytoma [7–12]. MDE consists of established CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) features as well as three specific biomarkers: clonal bone marrow plasma cells ≥60%, serum free light chain (FLC) ratio ≥100 (provided involved FLC level is ≥100 mg/L), and more than one focal lesion on magnetic resonance imaging (MRI). Each of the new biomarkers is associated with an approximately 80% risk of progression to symptomatic end-organ damage in two or more independent studies. The updated criteria represent a paradigm shift since they allow early diagnosis and initiation of therapy before end-organ damage [13–16]. The rate of progression is influenced by the underlying cytogenetic type of disease; patients with t(4;14) translocation, del(17p), and

gain(1q) are at a higher risk of progression from SMM to multiple myeloma [17–19].

available can provide additional prognostic value [22].

3. Molecular classification

When multiple myeloma is suspected clinically, patients should be tested for the presence of M proteins using a combination of tests that should include a serum protein electrophoresis (SPEP), serum immunofixation (SIFE), and the serum free light chain (FLC) assay [20]. Approximately 2% of patients with multiple myeloma have true non-secretory disease and have no evidence of an M protein on any of the above studies [6]. Bone marrow studies at the time of initial diagnosis should include fluorescent in situ hybridization (FISH) probes designed to detect t(11;14), t(4;14), t(14;16), t(6;14), t(14;20), trisomies, and del(17p) [21]. Conventional karyotyping to detect hypodiploidy and deletion 13 has value, but if FISH studies are done, additional value in initial risk-stratification is limited. Gene expression profiling (GEP) if

Although multiple myeloma is still thought to be a single disease, it is in reality comprises of collection of variable cytogenetically distinct plasma cell malignancies [23–30]. On fluorescent in situ hybridization (FISH) studies of the bone marrow, approximately 40% of multiple myeloma cells have trisomies (trisomic multiple myeloma), while remaining have translocation involving the immunoglobulin heavy chain (IgH) locus present on chromosome 14q32 (IgH translocated multiple myeloma) [31–34]. In small subset of patients both trisomies and IgH translocations are found simultaneously. Trisomies and IgH translocations are primary cytogenetic abnormalities and observed at the time of establishment of MGUS. In addition,

2. Approach for diagnosis

38 Update on Multiple Myeloma

The median survival of this disease is approximately 6–7 years; especially ASCT (Autologous stem cell transplant) eligible patients 4 year survival rates exceed 80%. However, behavior ofmalignancies is unpredictable, prognosis depends on patient characteristics such as age, co-morbids as well as disease characteristics such as disease stage, biology (cytogenetic abnormalities), and response to therapy [35, 36] Stage, i.e., tumor burden in multiple myeloma, is being evaluated by using the Durie-Salmon Staging (DSS) and the International Staging System (ISS) [37–39]. Disease biology best assessed by molecular abnormalities of multiple myeloma and the presence or absence of secondary cytogenetic abnormalities such as del(17p), gain(1q), or del(1p) [21, 29]. In literature, it is emphasized that the interpretation and impact of cytogenetic abnormalities are different according to the disease phase [30]. The recent staging system, Revised International Staging System (RISS) combines stage and disease biology (presence of high risk cytogenetic abnormalities or elevated lactate dehydrogenase level) to better define not only prognosis but guide treatment options [40].

It is important to note that in order to ensure constant availability, only three widely available cytogenetic markers are used in the RISS. Patients with standard risk multiple myeloma have a median overall survival (OS) of >7 years while those with high risk disease have a median OS of approximately 3 years despite tandem autologous stem cell transplantation (ASCT) [41, 42]. In addition to cytogenetic risk factors, two other markers that are related with rapid disease progression are elevated serum lactate dehydrogenase and plasma leukemic cells in circulation [43].
