Multiple Myeloma
2017-01-01 Kenneth C. Anderson , Giada Bianchi , Matthew Ho Zhi Guang Affiliation1.LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115. [email protected]; [email protected]; [email protected]
Abstract
Multiple Myeloma (MM) is a cancer of plasma cells resulting from the abnormal proliferation of malignant plasma cells within the bone marrow (BM) microenvironment. MM accounts for 1.3% of all malignancies and 12% of hematologic cancers, and is the second most commonly diagnosed blood cancer after non-Hodgkin lymphoma. The hallmark characteristics of MM include: high levels of intact monoclonal immunoglobulin or its fragment (free light chain) in serum or urine, and excess monotypic plasma cells in the bone marrow in conjunction with evidence of end organ damage related to MM: (1) hypercalcemia, (2) renal failure, (3) anemia, and (4) osteolytic bone lesions or severe osteopenia, known as CRAB criteria. Even though novel agents targeting MM cells in the context of the BM microenvironment such as proteasome inhibitors, immunomodulatory drugs (IMiDs), and monoclonal antibodies have significantly prolonged survival in MM patients, the disease remains incurable. A deeper understanding of the molecular mechanisms of MM growth, survival, and resistance to therapy, such as genomic instability, clonal heterogeneity and evolution, as well as MM-BM microenvironmental host immune and other factors, will provide the framework for development of novel therapies to further improve patient outcome.
Clinics and Pathology
Disease
MM is a plasma cell cancer which is preceded by an asymptomatic, premalignant condition called monoclonal gammopathy of undetermined significance (MGUS) which then progresses to MM or related malignancies with a rate of about 1% per year (Zingone and Kuehl 2011).
Phenotype stem cell origin
Antigen-selected, post-germinal center, terminally differentiated plasma cell (Anderson and Carrasco 2011)
Etiology
Etiology not known. No confirmed predisposing factors.
Possible (unconfirmed and controversial) risk factors include (Sundar Jagannath et al 2016):
Environmental factors such as radiation exposure, occupational exposure (agricultural, chemical, metallurgical, rubber plant, pulp, wood, paper), and chemical exposure (formaldehyde, epichlorohydrin, Agent orange, hair dyes, paint sprays, asbestos) Viral infection: Herpesvirus 8 infection noted in some patients with MM Genetic predisposition
The transformation of normal plasma cells into myeloma cells is thought to result from one of two primary genetic events: either (1) hyperdiploidy or (2) aberrant class switch recombination (CSR), likely occurring in the germinal center, leading to MGUS. Secondary cytogenetic abnormalities result in the progression of MGUS to SMM, MM, and plasma cell leukemia (PCL) (see below: Cytogenetics). MM cells are dependent upon the BM microenvironment for growth, survival, and drug resistance, due both to tumor cell adhesion to BM accessory cells and release of growth factors and cytokines including (1) interleukin-6 ( IL6), (2) vascular endothelial growth factor ( VEGFA), (3) insulin-like growth factor 1 ( IGF1), (4) members of the superfamily of tumor necrosis factor, (5) transforming growth factor beta1 (TGFB1), and (6) interleukin-10 ( IL10) (Palumbo and Anderson 2011). Coupled with various genetic changes, these abnormal microenvironmental interactions between MM cells and BM cells contribute to aberrant angiogenesis and MM disease progression (Palumbo and Anderson 2011).
Possible (unconfirmed and controversial) risk factors include (Sundar Jagannath et al 2016):
The transformation of normal plasma cells into myeloma cells is thought to result from one of two primary genetic events: either (1) hyperdiploidy or (2) aberrant class switch recombination (CSR), likely occurring in the germinal center, leading to MGUS. Secondary cytogenetic abnormalities result in the progression of MGUS to SMM, MM, and plasma cell leukemia (PCL) (see below: Cytogenetics). MM cells are dependent upon the BM microenvironment for growth, survival, and drug resistance, due both to tumor cell adhesion to BM accessory cells and release of growth factors and cytokines including (1) interleukin-6 ( IL6), (2) vascular endothelial growth factor ( VEGFA), (3) insulin-like growth factor 1 ( IGF1), (4) members of the superfamily of tumor necrosis factor, (5) transforming growth factor beta1 (TGFB1), and (6) interleukin-10 ( IL10) (Palumbo and Anderson 2011). Coupled with various genetic changes, these abnormal microenvironmental interactions between MM cells and BM cells contribute to aberrant angiogenesis and MM disease progression (Palumbo and Anderson 2011).
Epidemiology
| Incidence | 114,000 (global); 33,330; 6.5 per 100,000 persons (US) |
| Prevalence | 230,000 (global); 95,688 (US) |
| 5-year overall survival | 48.5% (US) |
| Median age at diagnosis | 70 years old (37% of patients younger than 65 years; 26% between ages 65-74; 37% are 75 years or older) (Palumbo and Anderson 2011) |
| Ethnicity | twice as common in African Americans as in Caucasian population US) (Waxman, Mink et al. 2010), low in ethnic Chinese (TW) (Huang, Yao et al. 2007) |
| Gender | Men affected more frequently than women (1.6:1 ratio) |
| Geographical | highest in industrialized regions of Australia/New Zealand, Europe, and North America (Becker 2011) |
Clinics
The most common presenting symptoms of MM are fatigue and bone or back pain. Multiple myeloma cells typically grow within the BM of the spine, skull, ribs, sternum, pelvis, humeri, and femora, causing pain, osteopenia, and frequently pathological fractures (Palumbo and Anderson 2011). Myeloma cells typically secrete an excess of a monoclonal immunoglobulin or its fragments (free light chain), which can then be detected in the patients serum and/or urine via protein electrophoresis and serum free light chain (sFLC) testing, respectively. Immunofixation shows the myeloma (M) protein to be monoclonal in nature and identifies heavy (IgG/IgA/IgM/IgD, in order of frequency) and light chain ( κ/λ) specific isotype. Rarely, MM may be non-secretory and neither a monoclonal Ig nor an excess sFLC can be identified. The diagnosis of MM is made based on the percentage of bone marrow involvement by clonal MM cells, size of M protein spike, and presence/absence of end-organ damage (CRAB) or myeloma-defining biomarkers (Rajkumar, Dimopoulos et al. 2014).
CRAB criteria:
Hypercalemia -> (C)
Up to 20% of newly diagnosed patients have hypercalcemia due to bone destruction. Hypercalcemia is associated with high tumor burden and requires prompt treatment with aggressive hydration and loop diuretic therapy, bisphosphonates, calcitonin, and anti-myeloma therapy for disease control.
Renal Failure -> (R)
Renal dysfunction (anuria or oliguria) resulting from direct tubular damage by free light chain tubular or glomerular deposition, hypercalcemia, dehydration, and nephrotoxic medications (NSAIDs for pain control, IV radiographic contrast, bisphosphonates) is present in 20 to 40% of newly diagnosed patients. Light-chain cast nephropathy is the most common cause of renal failure in MM. Other causes include amyloidosis and light-chain deposition disease.
Anemia-> (A)
At diagnosis, symptomatic normocytic, normochromic anemia (typically secondary to myelophthisis and hyporegenerative BM) is present in approximately 73% of patients. Mean corpuscular volume (MCV) may be macrocytic; an artifact related to rouleaux formation.
Bone Disease -> (B)
Up to 58% of patients report bone pain (especially from compression fractures of vertebrae or ribs), and up to 80% of newly diagnosed patients have bony lesions. The characteristic "punched-out" osteolytic lesions result from lytic bone destruction that is uncoupled from reactive bone formation. MM cells increase the activity of osteoclasts by upregulating osteoclast inducers (i.e. TNFSF11 (RANKL, TRANCE), CCL3 and CCL4 (MIP-1 alpha /beta), CXCL12 (SDF-1 alpha), IL1B (IL-1 beta), TNF (TNF-alpha), IL6,) and downregulating TNFRSF11B (OPG, decoy receptor for RANKL). Simultaneously, MM cells suppress osteoblast differentiation and function (by producing DKK1) resulting in an imbalance favouring bone resorption (osteoclast activation) over bone formation (osteoblast suppression) (Sezer 2009).
International Myeloma Working Group (IMWG) diagnostic criteria (Rajkumar, Dimopoulos et al. 2014):
Revised International Staging System (R-ISS) (Palumbo, Avet-Loiseau et al. 2015):
CRAB criteria:
Hypercalemia -> (C)
Up to 20% of newly diagnosed patients have hypercalcemia due to bone destruction. Hypercalcemia is associated with high tumor burden and requires prompt treatment with aggressive hydration and loop diuretic therapy, bisphosphonates, calcitonin, and anti-myeloma therapy for disease control.
Renal Failure -> (R)
Renal dysfunction (anuria or oliguria) resulting from direct tubular damage by free light chain tubular or glomerular deposition, hypercalcemia, dehydration, and nephrotoxic medications (NSAIDs for pain control, IV radiographic contrast, bisphosphonates) is present in 20 to 40% of newly diagnosed patients. Light-chain cast nephropathy is the most common cause of renal failure in MM. Other causes include amyloidosis and light-chain deposition disease.
Anemia-> (A)
At diagnosis, symptomatic normocytic, normochromic anemia (typically secondary to myelophthisis and hyporegenerative BM) is present in approximately 73% of patients. Mean corpuscular volume (MCV) may be macrocytic; an artifact related to rouleaux formation.
Bone Disease -> (B)
Up to 58% of patients report bone pain (especially from compression fractures of vertebrae or ribs), and up to 80% of newly diagnosed patients have bony lesions. The characteristic "punched-out" osteolytic lesions result from lytic bone destruction that is uncoupled from reactive bone formation. MM cells increase the activity of osteoclasts by upregulating osteoclast inducers (i.e. TNFSF11 (RANKL, TRANCE), CCL3 and CCL4 (MIP-1 alpha /beta), CXCL12 (SDF-1 alpha), IL1B (IL-1 beta), TNF (TNF-alpha), IL6,) and downregulating TNFRSF11B (OPG, decoy receptor for RANKL). Simultaneously, MM cells suppress osteoblast differentiation and function (by producing DKK1) resulting in an imbalance favouring bone resorption (osteoclast activation) over bone formation (osteoblast suppression) (Sezer 2009).
International Myeloma Working Group (IMWG) diagnostic criteria (Rajkumar, Dimopoulos et al. 2014):
| Plasma Cell Disorder | Definition | Progression rate | Primary progression events |
| Multiple myeloma (MM) | (1) Clonal bone marrow plasma cells ≥ 10% or (2) Biopsy proven bony or extramedullary plasmacytoma and any one or more of the following myeloma-defining events: End organ damage (CRAB) Biomarkers of malignancy | NA | Some patients may develop plasma cell leukemia |
| Smoldering multiple myeloma (SMM) | Both criteria must be met: (1) Serum monoclonal protein (IgG or IgA) ≥30g/L or urinary monoclonal protein ≥500mg per 24h and/or clonal bone marrow plasma cells 10-60% (2) Absence of myeloma defining events or amyloidosis | NA | MM |
| Non-IgM monoclonal gammopathy of undetermined significance (non-IgM MGUS) | (1) Serum monoclonal protein (non-IgM type) <30 g/L (2) Clonal bone marrow plasma cells <10% (3) Absence of end-organ damage such as hypercalcaemia, renal insufficiency, anaemia, and bone lesions (CRAB) or amyloidosis that can be attributed to the plasma cell proliferative disorder | 1% per year | MM, solitary plasmacytoma, immunoglobulin-related amyloidosis (AL, AHL, AH) |
| IgM monoclonal gammopathy of undetermined significance (IgM MGUS) | (1) Serum IgM monoclonal protein <30 g/L (2) Bone marrow lymphoplasmacytic infiltration <10% (3) No evidence of anaemia, constitutional symptoms, hyperviscosity, lymphadenopathy, hepatosplenomegaly, or other end-organ damage that can be attributed to the underlying lymphoproliferative disorder | 1.5% per year | Waldenstrom macroglobulinemia (WM), immunoglobulin-related amyloidosis (AL, AHL, AH |
| Light-chain monoclonal gammopathy of undetermined significance (Light chain MGUS) | (1) Abnormal FLC ratio (<026 or >165) Increased level of the appropriate involved light chain (increased κ FLC in patients with ratio >165 and increased λ FLC in patients with ratio <026) (2) No immunoglobulin heavy chain expression on immunofixation Absence of end-organ damage such as hypercalcaemia, renal insufficiency, anaemia, and bone lesions (CRAB) or amyloidosis that can be attributed to the plasma cell proliferative disorder (3) Clonal bone marrow plasma cells <10% (4) Urinary monoclonal protein <500 mg/24 h | 0.3% per year | Light chain MM, immunoglobulin light-chain amyloidosis |
| Solitary plasmacytoma | (1) Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells (2) Normal bone marrow with no evidence of clonal plasma cells Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion) (3) Absence of end-organ damage such as hypercalcaemia, renal insufficiency, anaemia, or bone lesions (CRAB) that can be attributed to a lymphoplasma cell proliferative disorder | About 10% within 3 years | MM |
| Solitary plasmacytoma with minimal marrow involvement | (1) Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells (2) Clonal bone marrow plasma cells <10% Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion) (3) Absence of end-organ damage such as hypercalcaemia, renal insufficiency, anaemia, or bone lesions (CRAB) that can be attributed to a lymphoplasma cell proliferative disorder | 60% (bone) or 20% (soft tissue) within 3 years | MM |
| POEMS syndrome | (1) Polyneuropathy (2) Monoclonal plasma cell proliferative disorder (almost always λ) (3) Any one of the following three other major criteria: (4)Any one of the following six minor criteria: | NA | NA |
| Systemic AL amyloidosis | (1) Presence of an amyloid-related systemic syndrome (eg, renal, liver, heart, gastrointestinal tract, or peripheral nerve involvement) (2) Positive amyloid staining by Congo red in any tissue (eg, fat aspirate, bone marrow, or organ biopsy) (3) Evidence that amyloid is light-chain-related established by direct examination of the amyloid using mass spectrometry-based proteomic analysis, or immunoelectronmicroscopy, and (4) Evidence of a monoclonal plasma cell proliferative disorder (serum or urine monoclonal protein, abnormal free light-chain ratio, or clonal plasma cells in the bone marrow) | NA | Some patients might develop MM |
Revised International Staging System (R-ISS) (Palumbo, Avet-Loiseau et al. 2015):
| Stage I | Stage II | Stage III | |||||||||||||||||||||||||||||||||||||||||||||||
| Serum albumin | >3.5g/dL | <3.5 g/dL (and β2-MG<3.5mg/L) | N/A | ||||||||||||||||||||||||||||||||||||||||||||||
| Serum β2-MG | <3.5mg/L | 3.5-5.5mg/L | >5.5mg/L | ||||||||||||||||||||||||||||||||||||||||||||||
| Serum LDH |  M-protein Left: Serum protein electrophoresis showing characteristic "M-protein" spike. Image taken from: http://bestpractice.bmj.com/best-practice/images/bp/en-gb/179-5-iline_default.gif and http://www.aafp.org/afp/1999/0401/p1885.html; Right: Urine protein electrophoresis showing gamma-globulin peak corresponding to Bence-Jones proteinuria. Image taken from: https://ahdc.vet.cornell.edu/sects/clinpath/test/immun/electro.cfm  Osteolytic bone lesions (a-d) X-rays showing characteristic osteolytic bone lesions typical sites such as the (a) skull, (b) tibia, (c) femur, and (d) pelvis. Image taken from: http://orthoinfo.aaos.org/topic.cfm?topic=A00086 ; (e) Sagittal CT showing multiple osteolytic bone lesions of the vertebral column. Image taken from: https://radiopaedia.org/cases/multiple-myeloma-skeletal-survey PathologyMM is characterized by the presence of ≥10% malignant plasma cells in the bone marrow. MM can be divided into (1/>= secretory MM, (2) oligosecretory MM (aka light chain MM), and (3) non-secretory MM based on whether M-protein is secreted and detectable (Lonial and Kaufman 2013). Non-secretory MM accounts for  MM kidney disease Left: Normal kidney biopsy; Right: Monoclonal protein-containing casts surrounded by histiocytes and giant cells. Note the presence of acute tubular injury and interstitial nephritis which are commonly seen in MM kidney disease. Images taken from: https://ajkdblog.org/2012/06/14/test-your-knowledge-myeloma-and-the-kidney/#prettyPhoto (courtesy of Dr. Tibor Nadasdy)  Top: Normal Bone Marrow; Bottom: Multiple Myeloma Bone Marrow (note: ≥ 10% clonal bone marrow plasma cells). Image taken from: http://www.thrombocyte.com/causes-of-multiple-myeloma-cancer/  Natural History of MM Monoclonal Gammopathy of Undetermined Significance (MGUS; premalignant; asymptomatic) -> Smoldering Multiple Myeloma (SMM; pre-malignant; asymptomatic) -> Multiple Myeloma (MM; malignant; symptomatic) -> Plasma cell Leukemia (PCL), extramedullary disease. MM remains incurable in the long-term as most patients inevitably, yet unpredictably, develop refractory relapse disease (i.e. disease that fails to respond to induction or salvage therapy, or progresses within 60 days of last therapy). Images taken from: Kyle et al, NEJM, Volume 356:2582-2590 (Kyle, Remstein et al. 2007) and Roman Hajek, Intech open, DOI: 10.5772/55366 (Hajek 2013)  Treatment(NCCN guidelines version 3.2017) IMWG RESPONSE CRITERIA (Kumar, Paiva et al. 2016)
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