Multiple myeloma (MM) is a common malignant neoplasm of the hematological system, and Professor Bing Röllig Chen, Department of Hematology, Nanjing Gulou Hospital, Germany, recently reviewed the epidemiology, pathogenesis, and disease management of MM, which was published online in The Lancet on December 23, 2014.
MM is a neoplastic disease characterized by the proliferation of clonal plasma cells in the bone marrow and the detection of their secreted monoclonal immunoglobulins in serum and urine. With a better understanding of the relationship between tumorigenic plasma cells and bone marrow niches in the bone marrow microenvironment, and their role in disease progression and treatment resistance, new therapeutic agents can be better investigated to achieve a coordinated effect with cytostatic therapy.
With the improvement of autologous stem cell transplantation techniques and supportive therapies, the use of new drugs such as proteasome inhibitors and immunomodulators has greatly improved the response rate and survival of patients in the past few years. Much of the current clinical research is focused on the balance between treatment efficacy and quality of life, optimal treatment sequencing, achieving long-term remission or cure with multiple treatment modalities, preemptive treatment of high-risk smoldering myeloma, and the role of maintenance therapy.
As the results of ongoing clinical trials become available, and with a range of exciting new treatment modalities, sustained improvements in patient prognosis are possible in the future.
Epidemiology
MM is a malignant plasma cell disease that predisposes to invasion of bone and bone marrow, with an age-corrected annual incidence of 6/100,000 in Europe and the United States, and 2-3 times the incidence in African-Americans.
The median age at diagnosis of MM is 69 years, with three quarters of patients over 55 years of age at diagnosis and two thirds being male. With the advent of more effective treatments and improvements in supportive care, median survival has increased from 3 to 6 years over the past two decades. In the United States, the age-corrected mortality rate was 3.4 per 100,000 for the period 2006-2010.
Pathogenesis
MM has a strong bone marrow dependency, highly mutated somatic immunoglobulin gene, and no IgM expression. Unlike normal plasma cells, myeloma cells have the potential to return to a low proliferative state.
Role of the microenvironment
Current studies on the interaction of myeloma cells with the bone marrow microenvironment have focused on cell-cell and cell-matrix interactions, growth factors and cytokines. The cellular composition of the microenvironment includes bone marrow stromal cells, osteoblasts, endothelial cells, and cells of the innate and adaptive immune systems, the latter including regulatory T cells. Myeloma cells and the myeloid microenvironment can interact with each other.
Myeloma stem/progenitor cells
Since all current therapeutic measures, including stem cell transplantation, have failed to cure multiple myeloma, a therapeutic modality is being investigated that can target and eradicate a population of cells that can continuously replenish the tumor. Continuous transplantation models and in vitro cloning assays have revealed that MM stem cells are part of a CD38-CD19+CD27+ B precursor cell population that does not express the typical molecular markers of myeloma cells such as CD38 and CD138.
Clonal evolution of MM
Comprehensive high-resolution genomic studies have elucidated the clonal composition of myeloma at the time of diagnosis and disease progression. Contrary to what was previously thought, tumors including MM do not originate from a single tumor stem cell, but are composed of multiple different clonal subpopulations of tumor cells and are highly genetically distinct.
This theory is further supported by the frequent occurrence of biclonal disease in the clinic or the presence of monoclonal immunoglobulin conversion in patients with recurrent MM. The clonal evolution in the natural course of MM and the transformation of primary and secondary clones during disease treatment and relapse is currently an emerging field.
Symptoms, diagnosis and disease monitoring in MM
The most common clinical manifestations of symptomatic MM are anemia, infection, osteolytic or osteoporotic bone disease, and renal failure, with some patients occasionally being diagnosed in the asymptomatic phase. Overall, the diagnosis of MM is now being made earlier than in the past. Immediate screening for MM is needed for back pain (especially in older patients) and for unexplained anemia.
Standard screening tests for MM include total serum protein, blood and urine protein electrophoresis, blood and urine immunofixation electrophoresis, serum immunoglobulin free light chain (FLC) testing, and other markers including: complete blood count, creatinine level, electrolyte measurements, LDH
and β2-microglobulin levels. For patients with suspected MM, a bone marrow smear or bone marrow biopsy is required.
The diagnosis of MM can be made if monoclonal protein, pathological abnormal FLC ratio, and plasma cell ratio ≥ 10% are found in blood and urine protein electrophoresis, or if monoclonal protein ≥ 3 g/100 ml is found in patients who meet the above criteria but have a plasma cell ratio < 10%; for non-secretory MM, a bone marrow plasma cell ratio of more than 30% or a biopsy of plasmacytoma is required.
Isolated plasmacytoma is diagnosed in patients with a single site of bone or extraosseous plasma cell involvement, with a bone marrow plasma cell percentage <10% and a low monoclonal protein level, and is significantly different from symptomatic MM in terms of prognosis and treatment. In patients with MM, the presence of end-organ damage is an indication for treatment, and MM without end-organ damage is referred to as smoldering MM.
Patients with MM require whole-body radiological bone examination to detect osteolytic damage, severe osteoporosis, and pathologic fractures. MRI-level PET-CT may be indicated when the symptomatic area is not abnormal on conventional X-rays.
In patients with monoclonal gammoprotein, but with a bone marrow plasma cell ratio <10% or low M-protein levels, the diagnosis is monoclonal gammoproteinemia of undetermined significance (MGUS), which does not require treatment but requires regular follow-up because of the potential for progression to MM, which occurs in only about 1% of patients per year.
Patients with nephrotic syndrome, heart failure, neuropathy in non-diabetic patients, echocardiographic signs of left ventricular hypertrophy without corresponding electrocardiographic findings, limb lead hypovoltage, hepatomegaly with normal imaging and proteinuria need to be carefully evaluated for light chain amyloidosis due to light chain secretion.
Serum M protein is a good surrogate to detect response to therapy and to monitor disease activity. For light chain MM, 24h urine B-J protein can be used to monitor disease activity; for non-light chain MM, FLC is a useful indicator of disease activity; for the few non-secretory MM, only bone marrow plasma cell count and organ damage can be used to detect disease and assess disease outcome.
Detection techniques such as flow cytometry, fluorescence in situ hybridization, and polymerase chain reaction can be used to detect MM microscopic residual disease (MRD), which also updates the definition of complete disease remission and allows the classification of patients who respond to treatment into two categories, MRD positive and negative, with significant differences in progression-free survival (PFS) and overall survival (OS) between the two categories.