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and progresses to myeloma at a rate of 1% per year. SMM progresses to myeloma at a rate of approximately 10% per year over the first five years following diagnosis, 3% per year over the next five years, and 1.5% per year thereafter.10


According to the revised criteria published in late 2014 by the International Myeloma Working Group11 (see Figure 1), the diagnosis of MM requiring therapy or so called ‘symptomatic MM’ needs: (1) 10% or more clonal plasma cells on bone marrow examination or a biopsy proven plasmacytoma and

(2) any of the following: ● Myeloma-defining events: hypercalcaemia, renal insufficiency, anaemia, bone lesions

● Any one or more of the following markers of malignancy: Clonal bone marrow plasma cell percentage ≥60%, involved/uninvolved serum free light chain (FLCs) ratio ≥100, >one focal lesion on magnetic resonance imaging (MRI) studies.

Patients should be tested for the presence of monoclonal component using the combination of a serum and urine protein electrophoresis (S/U PEP), serum and urine immunofixation (S/U IFE), and the serum FLC assay. The M protein is considered to be measurable if it is 10g/l in the serum and/or 200mg/day in the urine. Minimal biological exams should include peripheral blood cells count, bone marrow (BM) aspirate, blood and BM smears, serum creatinine and calcium levels, serum albumin, beta 2 microglobulin and lactate dehydrogenase (LDH). Although standard X-rays of the skeleton are typically required to assess the extent of bone disease, MRI and positron emission tomography (PET)/ computed tomography (CT) scans are more sensitive and are indicated when symptomatic areas show no abnormality on routine radiographs, when there are neurological complications, and when solitary plasmacytoma is suspected.

Risk stratification

Prognosis in myeloma depends on host factors (age, performance status, co-morbidities), stage, disease aggressiveness (LDH levels, plasma cell labelling index, plasmablastic morphology, renal impairment), genetics abnormalities and response to therapy. Staging of myeloma using the

Definition of multiple myeloma

Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following myeloma defining events: Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically: • Hypercalcaemia: serum calcium >0.25mmol/l (>1mg/dl) higher than the upper limit of normal or >2.75mmol/l (>11mg/dl)

• Renal insufficiency: creatine clearance <40ml per min or serum creatinine >177 µmol/l(>mg/dl) • Anaemia: haemoglobin value of >20g/l below the lower limit of normal, or a haemoglobin value >100g/l

• Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT • Any one or more of the following biomarkers of malignancy: (1) Clonal bone marrow plasma cell percentage ≥60% (2) Involved/uninvolved serum free light chain ratio ≥100 (3) > one focal lesions on MRI studies

Definition of smouldering multiple myeloma

Both criteria must be met: • Serum monoclonal protein (IgG or IgA) >30g/L or urinary monoclonal protein ≥500mg per 24h and/or clonal bone marrow plasma cells 10–60% • Absence of myeloma-defining events or amyloidosis

Figure 1: Revised International Myeloma Working Group diagnostic criteria. International Staging System12 (ISS)

based on serum albumin and beta 2 microglobulin provides prognostic data and can be combined to ‘molecular’ analyses of the clonal cells to define risk categories.13

Bone marrow studies at the time of initial diagnosis should be performed to evaluate the prognosis of the disease and should include at least fluorescent in situ hybridisation (FISH) designed to detect gain of 1q, loss of 17p and the adverse translocation groups t(4;14), t(14;20) and t(14;16). Among the high-risk chromosomal abnormalities, the most powerful are del(17p), t(4;14), and del(1p32). These abnormalities impact significantly both progression-free survival (PFS), and overall survival (OS).14


In MM, the introduction of novel agents such as immunomodulatory drugs (IMiDs; thalidomide, lenalidomide and pomalidomide) and proteasome inhibitors (PI; bortezomib, carfilzomib, and, in future, ixazomib and oprozomib) into the treatment armamentarium has extended the OS of patients.15,16

A better

understanding of the clonal dynamics along with the incorporation, early in the course of the disease, of triplet combinations as induction and consolidation regimens, eventually followed by continuous therapy, may further improve outcomes. Currently, only symptomatic de novo MM patients should receive therapy with the aim to achieve a deep and long-lasting

response, to improve quality of life and ultimately to prolong survival. We are not yet ready to routinely propose a risk- adapted strategy unless some guidelines exist according to the mSMART classification of the Mayo Clinic,17

and the

high-risk signature of the Arkansas GEP model.18

Efforts to further improve response rates and survival in MM patients are still needed, mainly by increasing the depth of tumour reduction and the duration of response through more effective induction, consolidation and maintenance therapies. In Europe at least, high-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is the standard of care for eligible, newly diagnosed, MM patients. Several randomised studies demonstrated a survival advantage for patients undergoing transplantation, compared with conventional

chemotherapy. Introduction of new drugs in this setting has markedly increased survival rates in the last ten years. Nevertheless, this approach is currently challenged by the promising results of long-term treatment with novel agents without upfront HDT. Several European groups are conducting Phase III trials to compare upfront versus delayed ASCT in the era of modern strategies. New drug-based induction regimens decrease the tumour burden before HDT but also offer high response rate (RR) after HDT and further improve the depth of response within consolidation phase. Vincristine–doxorubicin– dexamethasone (VAD) is no longer


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