Plasma Cell Neoplasms: an overview

2017-11-01 Matthew Ho Zhi Guang , Giada Bianchi , Elijah Buon Affiliation

1.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. EB, MHZG: these authors contribute equally. elijah_buon@dfci.harvard.edu; matthew_ho@dfci.harvard.edu; giada_bianchi@dfci.harvard.edu

Abstract

Plasma Cell Neoplasms are a family of disorders characterized by clonal proliferation of a plasma cell. These include: Multiple Myeloma (MM) and its precursor states MGUS and SMM, solitary osseous or non-osseous plasmacytoma, POEMS syndrome, heavy chain disease, and systemic 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).

Clinics and Pathology

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 stem cell 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).

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

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 Raynauds 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):
CLINICS

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)
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 Castlemans 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

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

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

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

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

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

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

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

Genes Involved and Proteins

Gene name

Article Bibliography

Pubmed ID	Last Year	Title	Authors
21261519	2011	Pathogenesis of myeloma.	Anderson KC et al
24683718	2014	The heavy chain diseases: clinical and pathologic features.	Bianchi G et al
24396469	2014	Extramedullary plasmacytoma of the nasopharynx: A case report and review of the literature.	Chang YL et al
9482908	1998	Frequent occurrence of deletions and duplications during somatic hypermutation: implications for oncogene translocations and heavy chain disease.	Goossens T et al
25439696	2014	International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma.	Rajkumar SV et al
22931316	2012	MYD88 L265P somatic mutation in Waldenström's macroglobulinemia.	Treon SP et al
12861101	2003	Gamma-heavy chain disease: review of 23 cases.	Wahner-Roedler DL et al
25663904	2015	T-cell lymphoma with POEMS syndrome.	Zou F et al

Summary

Citation

Matthew Ho Zhi Guang ; Giada Bianchi ; Elijah Buon
Plasma Cell Neoplasms: an overview
Atlas Genet Cytogenet Oncol Haematol. 2017-11-01
Online version: http://atlasgeneticsoncology.org/haematological/1793/plasma-cell-neoplasms-an-overview

External Links

OMIM database
Cosmic database
Genecards database
Mitelman database