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

Clinics

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

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