Multiple Myeloma and Other Plasma Cell Dyscrasias
Multiple Myeloma and Other Plasma Cell Dyscrasias
Multiple myeloma is a disseminated malignancy of monoclonal plasma cells that accounts for 1.3% of all malignancies and 15% of hematologic cancers. The incidence has been increasing by 0.7% each year for the last 10 years while mortality has come down by 1.7% each year over the same period. The incidence rate was 6.1 (7.4 in men and 4.7 in women) and the number of deaths was 3.4 per 100,000 persons per year (4.3 in men and 2.7 in women). Widespread use of the immunomodulatory drugs and proteasome inhibitors over the past decade has resulted in improved life expectancy, with a median survival just under 5 years. The prevalence of multiple myeloma has increased, and currently an estimated 83,367 people in the United States live with myeloma. In 2016, there will be an estimated 30,330 new cases of myeloma, and 12,650 estimated deaths.
Men are affected more frequently than women (1.6:1 ratio).
The median age of diagnosis is 69 years, with 75% of diagnosed patients between the ages of 55 and 84.
The annual incidence per 100,000 population, among white men and women, is 7.2 and 4.3, respectively, and among black men and women, 14.8 and 10.5, respectively. This racial difference is not explained by socioeconomic or environmental factors and is presumably due to unknown genetic factors.
There is no clear geographic distribution of multiple myeloma. In Europe, the highest rates are noted in the Nordic countries, the United Kingdom, Switzerland, Spain, Greece, Italy, Ireland, and Israel. France, Germany, Austria, and Slovenia have a lower incidence, and developing countries have the lowest incidence. This higher relative incidence in more developed countries probably results from the combination of a longer life expectancy and more frequent medical surveillance, although other factors may be involved.
Relative survival rate measures the survival of cancer patients in comparison to the general population, to estimate the effect of the cancer in question. There has been improvement in the 5-year relative survival rate for patients with multiple myeloma, from 29% in 1990 to 45% in 2009. There has been improvement in survival in all age groups, with medial survival estimates now between 5 and 7 years, and more recent data suggesting 7 to 10 years overall survival is achieved in patients receiving novel therapies both as part of initial therapy and at relapse.
No predisposing factors for the development of multiple myeloma have been confirmed, although possible contributing causes include certain toxic exposures and potential underlying genetic vulnerability.
Some causative factors that have been suggested include radiation exposure (radiologists and radium dial workers), occupational exposure (agricultural, chemical, metallurgical, rubber plant, pulp, wood and paper workers [including carpenters and furniture makers], and leather tanners), and chemical exposure to formaldehyde, epichlorohydrin, Agent Orange, hair dyes, paint sprays, and asbestos. None of these associations has proven to be highly statistically significant, and some have been contradicted by negative correlations. The initial report that survivors of the atomic bombings in Japan had an increased risk of developing myeloma has been refuted by longer follow-up, although the underlying rate of myeloma in the Japanese population is relatively low compared to other countries, and is now increasing.
A preliminary report in a limited number of patients noted the presence of herpesvirus 8 in the dendritic cells of patients with multiple myeloma. However, further evaluation by a number of investigators has failed to confirm this result.
One of the two primary genetic events, either hyperdiploidy or aberrant class switch recombination (CSR), occurring in antigen-selected post-germinal center B-cells ultimately leads to the development of multiple myeloma. The aberrant CSR results in a nonfunctional immunoglobulin heavy chain gene at 14q32 involved in translocation with partner chromosomes 4, 6, 8, 11, 16, and 20 (Table 1). Translocations involving chromosomes 4, 14, and 16 as well as secondary genetic events such as del17p13 or amplification of 1q21 are associated with poor prognosis. Hyperdiploidy generally consists of trisomies of chromosomes, 3, 5, 7, 9, 11, 15, 19, and 21. Multiple myeloma presents with multiple subclones at diagnosis, which have been shown to appear and disappear with treatment over the course of the disease and account for the ultimate failure to eradicate the disease. Better understanding of the biology of multiple myeloma is underway with the use of whole-genome sequencing, exon sequencing, RNA sequencing, studies of aberrant microRNA expression, and gene expression profiling. Such studies may ultimately help in tailoring therapy in the near future and so better characterize the phenomenon of clonal heterogeneity, as well as the challenging phenomenology of clonal tides, which likely represent the complex integrity of genotypic, phenotypic, and microenvironmental factors.
Multiple myeloma is not an inherited disease, but there have been numerous reports of multiple cases in the same family. However, a case-control study revealed no significant increase in its incidence among relatives of patients who had multiple myeloma, other hematologic malignancies, or other cancers. Nonetheless, this remains an area of active investigation, as case studies continue to describe associations both within families and with certain other cancers, such as renal cell carcinoma.
Interactions between multiple myeloma cells and their microenvironment (the extracellular matrix and the bone marrow stroma) allow multiple myeloma cells to survive, grow, migrate, and resist apoptosis induced by traditional chemotherapies. These effects are partially mediated through adhesion-mediated signalling and partly through various cytokines, including IL-6, vascular endothelial growth factor, insulin-like growth factor 1 (IGF-1), and tumor necrosis factor (TNF)-α. The molecular signals mediating the proliferative effects include the RAS/RAF/mitogen-activated protein kinase (MAPK) pathway, whereas the phosphoinositide 3-kinase (PI3K/AKT) pathway provides cell survival and drug resistance signals. Improved understanding of these interactions and the molecular mechanisms mediating them has allowed the evaluation of novel therapies that directly target multiple myeloma cells as well as act on the bone marrow microenvironment and other milieus, including cortical bone.
Monoclonal gammopathy of unknown significance (MGUS)
Patients with MGUS develop myeloma, lymphoma, or amyloidosis at a rate of 1% per year. Recent studies indicate that the diagnosis of symptomatic multiple myeloma is typically preceded by monoclonal gammopathy for 2 or more years.
The clinical features of multiple myeloma are variable. Findings that suggest the diagnosis include lytic bone lesions, anemia, azotemia, hypercalcemia, and recurrent infections. Approximately 30% of patients are free of symptoms and are diagnosed on routine physicals with abnormal laboratory studies, including elevation of serum protein.
Bone pain, especially from compression fractures of the vertebrae or ribs, is the most common symptom. At diagnosis, 70% of patients have lytic lesions, which are due to accelerated bone resorption. These changes are due to pathological imbalance between osteoblast (bone formation) and osteoclast (bone resorption) activity in the bone marrow microenvironment, induced by the presence of myeloma cells. Factors inducing osteoclastic activity include interleukin (IL)-1beta, TNF-α, and IL-6, as well as newly identified factors such as osteoprotogerin, TNF-related activation-induced cytokine (TRANCE), macrophage inflammatory protein (MIP)-1 α, and receptor activator of nuclear factor kappa B (RANK) ligand.
Osteoblastic activity is inhibited due to production of a soluble factor Dickkopf homolog 1 (DKK-1) by multiple myeloma cells, and overexpression of Activin-A by bone marrow stromal cells.
Normocytic, normochromic anemia is present in 60% of patients at diagnosis. It is due primarily to the decreased production of red blood cells by marrow, infiltration with plasma cells, and the suppressive effect of various cytokines. Patients with renal failure may also have decreased levels of erythropoietin, which can worsen the degree of anemia.
Among newly diagnosed patients, up to 20% have hypercalcemia (corrected serum calcium level > 11.5 mg/dL) secondary to progressive bone destruction, which may be exacerbated by prolonged immobility, especially in the context of fracture. Hypercalcemia should be suspected in patients with myeloma who have nausea, fatigue, confusion, polyuria, or constipation. It may also suggest high tumor burden. It should be considered an oncologic emergency and requires prompt treatment with aggressive hydration, use of bisphosphonates, calcitonin, and antimyeloma therapy, including steroids.
Approximately 20% of patients present with renal insufficiency and at least another 20% to 40% develop this complication in later phases of the disease. Light-chain cast nephropathy is the most common cause of renal failure. Additional causes include hypercalcemia, dehydration, and hyperuricemia. Less commonly, amyloidosis, light-chain deposition disease, nonsteroidal anti-inflammatory agents taken for pain control, intravenous radiographic contrast administration, and calcium stones may contribute to renal failure. More recently, bisphosphonate therapy has been associated with azotemia, which is usually reversible with treatment cessation.
Many patients with myeloma develop bacterial infections that may be serious, and infectious complications remain the most common cause of death in myeloma patients. In the past, gram-positive organisms (eg, Streptococcus pneumoniae, Staphylococcus aureus) and Haemophilus influenzae were the most common pathogens. More recently, however, infections with gram-negative organisms, anaerobes, and fungi have become frequent. The increased susceptibility of patients with multiple myeloma to bacterial infections, specifically with encapsulated organisms, has been attributed to impairments of host-defense mechanisms (such as hypogammaglobulinemia, qualitative deficiency in immunoglobulin function, granulocytopenia, decreased cell-mediated immunity) and the prolonged use of steroids.
No screening measures for multiple myeloma have demonstrated any benefit to date.
The diagnosis usually requires the presence of bone marrow plasmacytosis and a monoclonal protein in the urine and/or serum (Table 2), along with end-organ damage. One immunoglobulin class is produced in excess, whereas the other classes are usually depressed, with all three heavy chains typically reduced in the presence of light chain disease.
The initial workup for patients suspected of having a plasma cell dyscrasia should include:
- CBC with differential count and platelet count
- Routine serum chemistry panel (to include calcium, blood urea nitrogen, creatinine)
- Bone marrow aspirate and biopsy to assess clonal plasmacytosis
- Serum protein electrophoresis and immunofixation to quantitate and define protein type
- Serum beta-2-microglobulin, serum albumin
- Serum free light chain
- 24-Hour urine protein, electrophoresis, and immunofixation
- Quantitative serum immunoglobulin levels
- Skeletal survey (bone scans contribute little since isotope uptake is often low in purely lytic bone disease)
- Cytogenetics, including FISH (fluorescence in situ hybridization) on bone marrow plasma cells.
The recently available serum free light chain assay is useful especially in patients with light-chain–only disease, oligo- or nonsecretory myeloma, renal failure, and amyloidosis.
MRI is an excellent tool for evaluation of spinal cord compression/impingement. In addition, MRI identifies generalized marrow signal abnormalities and focal lesions that can be monitored after therapy. Whole-body 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT scan provides details of axial and appendicular skeletal involvement but also identifies extramedullary soft-tissue plasmacytomas presenting as macrofocal lesions. Both MRI and PET/CT are especially useful in staging oligo- or nonsecretory disease.
Additional useful data may be obtained by analysis of such prognostic factors as plasma cell labeling index, ploidy, immunophenotyping, flow cytometry, C-reactive protein (CRP), and lactate dehydrogenase (LDH) levels.
The peripheral blood smear may reveal a normocytic, normochromic anemia with rouleaux formation. Less commonly, circulating plasma cells may also be seen.
Bone marrow examination usually reveals an increased number of plasma cells. These cells are strongly positive for CD38, CD138, MUM1, SLAMF7, and a single class of cytoplasmic immunoglobulin (cIg). The majority of myeloma cells also express CD40 and CD56. Myeloma cells are negative for CD5, CD19, and surface Ig (sIg) expression. CD20 may be expressed in a subset of myeloma patients presenting with the t(11;14) translocation. CD10 expression is generally negative but has sometimes been noted in advanced disease. Monoclonality is frequently demonstrated by immunoperoxidase staining with κ and λ antibodies.
The pattern of bone marrow involvement in plasma cell myeloma may be macrofocal. As a result, plasma cell count may be normal when an aspirate misses the focal aggregates of plasma cells that are better visualized radiographically or on direct needle biopsy, where the degree of plasmacytosis will be commensurably high.
The types of monoclonal protein produced are IgG (60%), IgA (20%), IgD (2%), IgE (< 0.1%), or light-chain κ or λ only (18%). IgM myeloma is rare, but distinct from its lymphoplasmacytic counterpart, Waldenström’s macroglobulinemia. Biclonal elevations of myeloma proteins occur in < 1% of patients, and < 5% of patients are considered to have nonsecretory disease, because their plasma cells do not secrete detectable levels of monoclonal Ig.
Patients with symptomatic myeloma should be staged using either the Durie-Salmon system at diagnosis or the International Staging System (ISS), which is determined at the time systemic therapy is begun. These two systems are compared in Table 3. The Durie-Salmon staging system better provides information on tumor burden, whereas the ISS better serves as a prognostic indicator. The ISS is easier to use, and it classifies patients correctly regardless of their geographic origin (ie, North America, Europe, or Asia), age (ie, ≥ 65 years vs younger age), or type of treatment (ie, conventional chemotherapy vs high-dose therapy followed by autologous stem cell transplantation). More recent studies have provided evidence that the ISS is also reliable in patients treated with thalidomide (Thalomid), bortezomib, or lenalidomide, and has prognostic value at relapse.
Prognostic indicators may help guide treatment strategy, but the presence of poor prognostic features also should not result in initiation of therapy in patients with asymptomatic myeloma, although they should engender caution. Prognostic factors for risk stratification are well established for conventional chemotherapy. Use of bortezomib and, to some extent, lenalidomide may be able to overcome some features of poor risk, including adverse cytogenetics.
Cytogenetic abnormalities. Cytogenetic abnormalities detected by conventional karyotyping, such as hyperdiploidy, hypodiploidy or translocations, and deletions and presence of marker chromosomes are associated with adverse outcome. Primary translocations involving 14q32 and 4p16 (fibroblast growth factor receptor 3 [FGFR3]), 16q23 (c-maf proto-oncogene), and del17p13 (TP53) or amplification of 1q21 detected by FISH in multivariate analysis have been shown to be important predictors of poor survival. These cryptic translocations are best detected using FISH, which has been shown to be prognostically useful to evaluate patients both at diagnosis and at relapse.
Beta-2-microglobulin. Serum beta-2-microglobulin level is an important prognostic indicator, is integral to the ISS, and in combination with cytogenetics (including FISH) has strong predictive value. As beta-2-microglobulin is excreted by the kidneys, high levels are observed in patients with renal failure; even in this setting, elevated serum beta-2 microglobulin is associated with poor outcome.
LDH. High LDH levels also have been associated with plasmablastic disease, extramedullary tumor, plasma cell leukemia, plasma cell hypodiploidy, drug resistance, and shortened survival.
Other indicators. Other indicators of shortened survival include elevated CRP, DNA hypodiploidy, high plasma cell labeling indices, and plasmablastic histology. Patients with DNA hypodiploidy are also less likely to respond to conventional chemotherapy. Finally, extramedullary disease is associated with worse outcome, especially in the context of a large tumor burden such as bone involvement and bulk disease.
Because the criteria for treatment response in patients with multiple myeloma have varied among institutions and evolved over time, response rates have been difficult to compare in the past. In responders, the Bence-Jones protein level is reduced more rapidly than is serum myeloma protein, because of the rapid renal clearance of light chains.
The Center for International Bone Marrow Transplant Registry/European Bone Marrow Transplant Registry (CIBMTR/EBMTR) response criteria have been prospectively validated in numerous studies and are as follows:
Complete response (CR) requires all of the following:
- No serum/urine M protein by immunofixation electrophoresis for ≥ 6 weeks
- < 5% plasma cells in bone marrow aspirate
- No increase in the size or number of lytic bone lesions
- Disappearance of soft-tissue plasmacytomas.
Partial response requires all of the following:
- ≥ 50% reduction in serum M protein > 6 weeks
- ≥ 90% reduction in 24-hour urinary light-chain excretion
- ≥ 50% reduction in soft-tissue plasmacytomas.
Minimal response (but ≤ 49%) requires:
- ≥ 25% reduction in serum M protein for > 6 weeks
- ≥ 50%–89% reduction in 24-hour urinary light-chain excretion
- No increase in the size or number of lytic bone lesions.
The more recent Uniform Criteria for response proposed by the International Myeloma Working Group (IMWG) have sought to further refine these criteria by describing a stringent CR and a very good partial response (VGPR; > 90% reduction in the serum paraprotein level), as well as defining progressive disease in terms of minimum requirements of paraprotein increase, as opposed to changes in immunofixation alone. Near complete response is another modification of the criteria and has been applied to the EBMTR as part of a number of prospective studies.