| Disease |
Plasma Cell Neoplasia is an umbrella term for diseases resulting from the excessive proliferation of plasma cells. These include: Multiple Myeloma (MM) and its precursor statesmonoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), solitary osseous or non-osseous plasmacytoma, POEMS syndrome, heavy chain disease, andsystemic AL amyloidosis. The hallmark characteristics of plasma cell neoplasms are: (1) histopathologic confirmation of excess clonal plasma cells; and (2) excessive production and secretion of an intact monoclonal protein (M spike) or free light chains (FLC; not in association with heavy chains) in the serum and/or urines. Plasma cell neoplasms can be premalignant (e.g. MGUS) or malignant (e.g. MM). |
| Phenotype / cell stem origin |
| MGUS, SMM, MM | Antigen-selected, post-germinal center, terminally differentiated plasma cell (Anderson and Carrasco 2011) | | Plasmacytoma | Well defined, monoclonal proliferation of plasma cells that occurs either (1) inside (solitary bone plasmacytoma) or (2) outside (extramedullary plasmacytoma) the bone (Chang et al, 2014). | | Heavy chain disease (HCD) | Group of three rare and clinically distinct B-cell neoplasms (alpha, gamma, mu HCD) that result in the excessive production of abnormal immunoglobulin heavy chain incapable of binding light chains (Bianchi et al 2014). Alpha HCD is associated with immunoproliferative small intestinal disease with features resembling MALT lymphoma. Gamma HCD has features resembling Waldenstrom macroglobulinemia (WM) while Mu HCD has features resembling CLL (Bianchi et al 2014). | | POEMS syndrome | Rare paraneoplastic syndrome caused by underlying plasma cell neoplasm. Characterized by polyradiculoneuropathy, the presence of clonal plasma cells, sclerotic bone lesions, elevated vascular endothelial growth factor, and Castleman disease. Other minor features include: organomegaly, endocrinopathy, characteristic skin changes, papilledema, extravascular volume overload, and thrombocytosis (Dispenzieri A, 2014). |
|
| Etiology | Etiology not known. Possible (unconfirmed and controversial) risk factors include:
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, but there are no data to substantiate a causative link; Genetic predisposition: Patients with a siblings or other first-degree relatives who have one of these diseases are more likely to develop it as well.
| MGUS, SMM, MM | Transformation of normal plasma cells into myeloma cells thought to result from one of two primary genetic events: either (1) hyperdiploidy or (2) aberrant class switch recombination (CSR). Secondary cytogenetic abnormalities result in progression of MGUS to SMM, MM, and plasma cell leukemia (Ho et al, 2017). | | Plasmacytoma | Similar to MM in that cell of origin is plasma cell; expresses antigens associated with myelomonocytes (CD33), megakaryocytes (GpIIb/IIIa), erythroid cells (glycophorin) (Nikhil Sangle, 2011). | | Heavy chain disease | Deletions, insertions or point mutations in the constant 1 (CH1) domain of the IgH are acquired during the process of somatic hypermutation. These mutations typically result in: (1) inability to bind and reach a stable quaternary structure with IgL chain; (2) inability to bind to the chaperone heat shock protein 78 (HSP 78), which mediates proteasomal degradation of free IgH (Goossens et al., 1998). As a result, free IgH can be detected in both serum and urine. Pathogenesis is unknown. Autoimmune disease is present in ~25% of patients and typically precedes by many years the onset of gamma HCD (Wahner-Roedler et al., 2003). | | POEMS syndrome | Etiology unknown. Major feature of POEMS syndrome is the chronic overproduction of pro-inflammatory cytokines (e.g. VEGF; IL6). Thought to be a paraneoplastic syndrome caused by an underlying plasma cell disorder (Zou et al 2015). |
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| Epidemiology | | Disease | MGUS | SMM | MM | Plasmacytoma | POEMS syndrome | Heavy-chain disease | | Incidence | 3.76 per 100,000 persons; Progresses to MM at rate of ~1.4% per year | 0.9 per 100,000 persons | ~30,280 new cases/year; 6.6 per 100,000 persons (US) | ~1,543 new cases/year; 0.3 per 100,000 persons (US) | ~700 new cases/year (US) | A: Most common; G: Intermediate; M: Least common | | Prevalence | > 50y: 3.2%; M: 3.7%; F: 2.9% | Unknown | 118,539 (US) | N/A | N/A | A: >400; G: ~130; M: ~35 | | Overall survival | 5 yr: 78.3% | Median OS: 54.8 months (2003-2007); 67.1% (2008-2011) | 5 yr: 49.6% | SBP: 71.9% (5y); EMP: 88.2% (5y) | 5 yr: 60% | A: ~67% (5yr); G: 7.4yr (median); M: ~2yr (median) | | Median age at diagnosis | 70y (<2% younger than 40y) | 67y | 69y | 55-65y | 48y (men); 59y (women) | ?: 20-30y; G: 51-68y; M: 58y | | Ethnicity | Twice as common in African Americans as in the Caucasian population; low in Asian countries | Black > Asian/pacific islander> white | Twice as common in African Americans as in the Caucasian population; low in Asian countries | 30% higher incidence rate in African Americans; Also seen in Caucasians and low in Asian countries. | No known racial connection. | A: Mediterranean, North African, Middle Eastern; G: Worldwide distribution; M: Mostly Caucasian | | Gender | M > F | M> F | M > F (1.6:1) | M > F (2-3:1) | M > F (2.5:1) | A: M > F; G: F > M; M: M > F |
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| Clinics | Plasma Cell Neoplasm | Clinical Features | MGUS, SMM, MM | MGUS: Asymptomatic
SMM: Asymptomatic
MM: Hypercalcemia, renal failure, anemia, bone disease (CRAB criteria) | Plasmacytoma | As space occupying lesions, the symptoms of plasmacytoma vary based on the location of the tumor. Plasmacytomas located in the brain (e.g. solitary craniocerebral plasmacytoma or EMP of the brain) can cause headaches, seizures, and paralysis, while plasmacytomas in the rib may cause non-cardiac chest pain that is pleuritic in nature. Generally speaking, a common yet nonspecific clinical symptom of SBP is pain. Motor and sensory deficits can also occur, secondary to nerve impingement from compression fractures (Guo et al, 2013). Complications of SBP include pathological fractures due to lytic bone disease. EMP, on the other hand, usually manifests itself in the upper respiratory tract and oral cavity, symptoms often include epistaxis, sore throat, rhinorrhea, and hemoptysis (Chang et al, 2014)(Galieni et al, 2000) | HCD | A: Digestive, lymphomatous, or respiratory forms
G: Disseminated (generalized lymphadenopathy); localized (either isolated BM involvement or localized extra-nodal disease); minority with only autoimmune disease
M: Splenomegaly, hepatomegaly, lymphadenopathy | POEMS syndrome | Polyneuropathy: - Symmetric distal weakness and paraesthesia
- Impotence
- Raynaud's phenomenon
- Painful Diarrhea
Organomegaly: - Hepatomegaly
- Splenomegaly,
- Lymphadenopathy, castleman disease
Endocrinopathy: - Hypothyroidism##
- Gonadal axis abnormality (e.g. amenorrhea)
- Adrenal axis abnormality
- Gynecomastia/ galactorrhea
- Diabetes mellitus
- Peripheral edema
- Hyperhidrosis
M-protein (sign) Skin changes: - Hyperpigmentation
- Acrocyanosis and plethora
- Hemangioma/ telangiectasia
- Hypertrichosis
- Thickening
|
International Myeloma Working Group (IMWG) diagnostic criteria (Rajkumar, 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)
ï Hypercalcemia: Ca > 2.75 mmol/L (>11mg/dL)
ï Renal insufficiency: Cr > 177 mol/L (>2mg/dL)
ï Anemia: Hb < 100g/L or >20g/L below normal
ï Bone lesions: One or more osteolytic lesion on skeletal radiography, CT, or PET/CT (if BM <10% clonal plasma cells, more than one bone lesion required to distinguish from solitary plasmacytoma with minimal marrow involvement)
OR
Biomarkers of malignancy
ï ?60% clonal plasma cells on bone marrow examination
ï Serum involved/uninvolved free light chain ratio of 100 or greater, provided the absolute level of the involved light chain is at least 100mg/L
ï More than one focal lesion on MRI ?5mm in size | NA | At the terminal stage of disease, evolution to secondary plasma cell leukemia is common | 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%
AND
(2) Absence of myeloma defining events or amyloidosis | 10%/year in the first 5 years | MM | Non-IgM monoclonal gammopathy of undetermined significance
(non-IgM MGUS) | All criteria must be met:
(1) Serum monoclonal protein (non-IgM type) <30 g/L
AND
(2) Clonal bone marrow plasma cells <10%
AND
(3) Absence of end-organ damage such as hypercalcaemia, renal insu?ciency, anaemia, and bone lesions (CRAB) or amyloidosis that can be attributed to the plasma cell proliferative disorder | 1%/year | MM, solitary plasmacytoma, immunoglobulin-related amyloidosis (AL, AHL, AH) | IgM monoclonal gammopathy of undetermined significance
(IgM MGUS) | All criteria must be met:
(1) Serum IgM monoclonal protein <30 g/L
AND
(2) Bone marrow lymphoplasmacytic in?ltration <10%
AND
(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), IgM MM, immunoglobulin-related amyloidosis (AL, AHL, AH) | CLINICS Light-chain monoclonal gammopathy of undetermined significance
(Light chain MGUS) | All criteria must be met:
(1) Abnormal FLC ratio (<026 or >165) Increased level of the appropriate involved light chain (increased ? FLC in patients with ratio >165 and increased ? FLC in patients with ratio <026) and no immunoglobulin heavy chain expression on immuno?xation
AND
(2) Clonal bone marrow plasma cells <10%
AND
(3) Urinary monoclonal protein <500 mg/24 h
AND
(4) Absence of end-organ damage such as hypercalcaemia, renal insu?ciency, anaemia, and bone lesions (CRAB) or amyloidosis that can be attributed to the plasma cell proliferative disorder | 0.3% per year | Light chain MM, immunoglobulin light-chain amyloidosis | | Solitary plasmacytoma | All criteria must be met:
(1) Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells
AND
(2) Normal bone marrow with no evidence of clonal plasma cells
AND
(3) Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion)
AND
(4) Absence of end-organ damage such as hypercalcaemia, renal insu?ciency, 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 | All criteria must be met:
(1) Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells
AND
(2) Clonal bone marrow plasma cells <10%
AND
(3)Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion)
AND
(4) Absence of end-organ damage such as hypercalcaemia, renal insu?ciency, 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 | Both #1 and #2 must be present plus
(1) Polyneuropathy
AND
(2) Monoclonal plasma cell proliferative disorder (almost always ?)
AND
(3) Any one of the following three other major criteria:
ï Sclerotic bone lesions
ï Castleman's disease
ï Elevated levels of VEGFA
AND
(4)Any one of the following six minor criteria:
ï Organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy)
ï Extravascular volume overload (oedema, pleural e?usion, or ascites)
ï Endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, pancreatic)
ï Skin changes (hyperpigmentation, hypertrichosis, glomeruloid haemangiomata, plethora, acrocyanosis, ?ushing, white nails)
ï Papilloedema
ï Thrombocytosis/polycythaemia | NA | NA | | Systemic AL amyloidosis | All criteria must be met:
(1) Presence of an amyloid-related organ damage (eg, renal, liver, heart, gastrointestinal tract, soft tissue, lung or peripheral nerve involvement)
AND
(2) Positive amyloid staining by Congo red in any tissue (eg, fat aspirate, bone marrow, or organ biopsy)
AND
(3) Evidence that amyloid is light-chain-related established by direct examination of the amyloid using mass spectrometry-based proteomic analysis, or immunoelectronmicroscopy, and
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 |
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| Multiple myeloma: Left: Normal bone marrow; Right: Multiple Myeloma bone marrow (note: ? 10% clonal bone marrow plasma cells). Image taken from: http://www.keatslab.org/multiple-myeloma-info |
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| Plasmacytoma: Left: X-ray showing solitary bone plasmacytoma located in right shoulder complicated by pathological fracture of the head of humerus. Right: PET/CT showing extramedullary plasmacytoma located in the anterior clivus |
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| Waldenstrom macroglobulinemia: Bone marrow aspirate showing increased lymphoplasmacytoid lymphocytes. Image taken from: https://imagebank.hematology.org/image/1178/waldenstroumlmrsquos-macroglobulinemia-bone-marrow-aspirate--1?type=upload |
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| Heavy chain disease: In HCD, non-contiguous deletions in CH1 prevent binding of heavy chain to light chain and degradation in proteasome, and free heavy chains are secreted. Variably sized deletions also occur in the heavy chain diversity region, heavy chain joining region, and heavy chain variable region (Bianchi et al 2014). Image taken from: http://www.cancernetwork.com/oncology-journal/heavy-chain-diseases-clinical-and-pathologic-features |
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| Treatment | Types of Treatment Available (in Italic: FDA approved in MM; otherwise: clinical development):
Note: Specific treatment for each disease can be found in the various chapters in the Atlas
- Immunotherapy
- Immunomodulation
- Pembrolizumab
- Pidilizumab
- Nivolumab
- T cell-based therapies
- PVX-410
- MM-DC vaccine
- Anti-BCMA CAR-T cells
- Monoclonal antibodies
- Daratumumab
- Elotuzumab
- SAR
- BT062
- GSK2857916
- Chemotherapy
- Conventional chemotherapy (alkylating agents)
- Melphalan
- Carmustine
- Cyclophosphamide
- Doxorubicin
- Novel agents
- Proteasome inhibitors
- Bortezomib
- Carfilzomib
- Ixazomib
- Marizomib
- Oprozomib
- IMiDs
- Thalidomide
- Lenalidomide
- Pomalidomide
- Histone deacetylase inhibitors
- Panobinostat</li>
- Vorinostat
- Ricolinostat
- ACY-241
- Tyrosine kinase inhibitors
- Ibrutinib
- Supportive agents
- Zoledronic acid
- Bone marrow transplantation
- Autologous stem cell transplantation
- Allogeneic stem cell transplantation
- Stem cell Mobilization
- Plerixafor
- Cyclophosphamide
- Radiation therapy
- Indications
- Pre-transplantation
- Palliation of symptoms (i.e.: pain)
- Plasmacytoma
- Surgery
- Indications
- Plasmacytoma
- Pathological fractures
- Compression fractures
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| Prognosis | The prognosis varies substantially depending on:
Stage of disease Proliferation rates LDH levels Treatment availability: Conventional therapy / Targeted Therapy / High-dose chemotherapy M protein concentration Age Treatment response Plasmablastic histology
Poor prognosticators include:
High LDH levels Hypercalcemia Renal impairment Large tumor burden Bence-Jones proteinuria Low hemoglobin value |
| Pathogenesis of myeloma |
| Anderson KC, Carrasco RD |
| Annu Rev Pathol 2011;6:249-74 |
| PMID 21261519 |
| |
| The heavy chain diseases: clinical and pathologic features |
| Bianchi G, Anderson KC, Harris NL, Sohani AR |
| Oncology (Williston Park) 2014 Jan;28(1):45-53 |
| PMID 24683718 |
| |
| Extramedullary plasmacytoma of the nasopharynx: A case report and review of the literature |
| Chang YL, Chen PY, Hung SH |
| Oncol Lett 2014 Feb;7(2):458-460 |
| PMID 24396469 |
| |
| Frequent occurrence of deletions and duplications during somatic hypermutation: implications for oncogene translocations and heavy chain disease |
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| PMID 9482908 |
| |
| Multiple Myeloma in 2017 |
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| |
| TITLE Plasma Cell Neoplasms |
| Nikhil Sangle |
| Plasma cell myeloma (multiple myeloma). PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/lymphomamyeloma.html. Accessed August 1st, 2017. |
| |
| International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma |
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| Lancet Oncol 2014 Nov;15(12):e538-48 |
| PMID 25439696 |
| |
| MYD88 L265P somatic mutation in Waldenström's macroglobulinemia |
| Treon SP, Xu L, Yang G, Zhou Y, Liu X, Cao Y, Sheehy P, Manning RJ, Patterson CJ, Tripsas C, Arcaini L, Pinkus GS, Rodig SJ, Sohani AR, Harris NL, Laramie JM, Skifter DA, Lincoln SE, Hunter ZR |
| N Engl J Med 2012 Aug 30;367(9):826-33 |
| PMID 22931316 |
| |
| Gamma-heavy chain disease: review of 23 cases |
| Wahner-Roedler DL, Witzig TE, Loehrer LL, Kyle RA |
| Medicine (Baltimore) 2003 Jul;82(4):236-50 |
| PMID 12861101 |
| |
| T-cell lymphoma with POEMS syndrome |
| Zou F, Li Z, Ma JA, Qiu Z, Tang YF, Zheng JY |
| Oncol Lett 2015 Mar;9(3):1313-1316 |
| PMID 25663904 |
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