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Molecular basis ofchronic lymphocytic leukemia 133
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interact with CLL cells and may either promote or inhibit the
growth and survival of the cancer cells. Stromal cells, such as
fibroblasts, provide structural support to the CLL cells, while
endothelial cells form the blood vessels that supply nutrients
to CLL cells. It also involves extracellular matrix components
and soluble factors such as cytokines, chemokines, and
growth factors. For instance, the cytokine interleukin- 6 (IL- 6)
promotes the survival of CLL cells, while the chemokine
(CXCL12) attracts CLL cells to the lymph nodes, where they
can grow and divide.
The interactions between CLL cells and the microenvironment are bidirectional. For example, CLL cells have the
potential to induce expression of adhesion molecules,
chemokines, and cytokines in stromal cells and promote
their recruitment and activation. This can create a supportive niche for the leukemia cells, allowing them to evade
immune surveillance, resist treatment modality (CIT or targeted therapies), and acquire drug resistance. In addition,
the microenvironment can also modulate the function of the
immune cells, such as T cells and NK cells, which are known
to have a role in recognizing and eliminating cancer cells.
Table9.1 A summary ofthe prognostic features inCLL
The impaired function of these cells in the CLL microenvironment can contribute to disease progression and immune
suppression.
Understanding the nuances of the CLL microenvironment
is critical for developing new therapies that not only target
the leukemia cells but also the supportive niche that sustains
them. One of the ongoing areas of research in the field is to
develop strategies to disrupt the interactions between CLL
cells and the microenvironment, such as targeting specific
signaling pathways or inhibiting the production of cytokines
and growth factors.
Impaired immunity in CLL
In CLL, the neoplastic lymphocytes do not function properly, and they will accumulate in the bone marrow, blood,
and lymphoid tissues resulting in a decrease in the number
of healthy white blood cells, including T lymphocytes, B lymphocytes and natural killer cells, which play critical roles in
the immune system. This will cause impaired immunity and
Prognostic marker Prognostic implication
IGHV mutation status IGHV •
Chromosome abnormalities Del(13q), trisomy 12, del(11q),
del(17p) and/or TP53mutation
Somatic mutations Genes that have a role in mRNA
processing (SF3B1 and XPO1), DNA
damage (TP53 and ATM), Notch
signaling (NOTCH1), B- cell signaling
(EGR2 or BRAF), chromatin
modification (HIST1H1E, CHD2 and
ZMYM3), Wnt signaling, and
inflammatory pathways (MYD88)
MicroRNA changes MicroRNAs can function as
oncogenes or tumor suppressors
Epigenetic factors Methylation profiling has identified 3
epigenetic CLL subtypes. These
subtypes correlate for the most part
with IGHV mutational status and
patient outcomes
Mutated IGHV– favorable
• Unmutated IGHV– unfavorable
• Del(13q)– favorable
• Trisomy 12– intermediate
• Del(11q)– unfavorable
• Del(17p)– unfavorable
• TP53, NOTCH1 and SF3B1– unfavorable prognosis
• Downregulation of miR- 15a/16- 1 results in increased
expression of BCL2– unfavorable
• Downregulation of miR- 34b/c will result in higher levels of
ZAP- 70,
mostly associated with unmutated IGHV status– unfavorable
• Downregulation of miR- 29 and miR- 181b is correlated with
TCL1 overexpression– unfavorable
• Memory- like CLL (m- CLL; mainly mutated IGHV, with good
prognosis)
• Intermediate CLL (i- CLL; mixed between mutated and
unmutated IGHV, with intermediate prognosis)
• Naïve- like CLL (n- CLL; mainly unmutated IGHV, with poor
prognosis)
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134 Molecular Hematology
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an increased risk of infection, which is one of the major
causes of morbidity and mortality in patients with CLL.
Additionally, people with CLL often struggle with a weakened immune system inherent to the disease itself. Treatments
used to manage CLL, particularly chemotherapy, CD20monoclonal antibodies, and radiation therapy in select cases will
result in further prolonged immunosuppression predisposing patients to a wide range of bacterial, fungal, and viral
infections.
The other contributing factor to impaired immunity is secondary hypogammaglobulinemia. Hypogammaglobulinemia
is present in one- quarter of patients with newly diagnosed
CLL. Roughly one- quarter of patients with normal levels of
IgG at diagnosis will subsequently develop hypogammaglobulinemia. Hypogammaglobulinemia is thought to occur due
to defective functioning of the non- clonal CD5- negative
B- cells and is more pronounced with prolonged disease duration and advanced disease stage. The relationship between
hypogammaglobulinemia, novel prognostic features such as
IGHV mutation status, genetic abnormalities detected by
FISH, expression of CD38, CD49d, and zeta- associated protein 70 [ZAP- 70], and clinical outcomes has not been systematically studied. At treating physician’s discretion, the majority
of patients with very low IgG levels (≤ 400mg/dl) or higher
but with frequent microbial infections throughout the year
will be considered for IgG replacement therapy, which is
administered either through an either intravenous or subcutaneous route on a regular basis.
3
Morphology andimmunophenotype
The presence of sheets of large neoplastic B lymphocytes
characterizes the morphology of the DLBCL- RT. It is important to note that an enlargement of proliferation centers in
lymph nodes is also reported in the accelerated CLL, which
is known to have a more aggressive course. Accelerated CLL
and DLBCL- RT need to be properly distinguished as the
treatments for the two entities differ and the outcomes of
patients with accelerated CLL are thought to be slightly inferior to patients with typical CLL.
DLBCL- RT cells express B- cell markers such as CD19,
CD20. Less frequently, they express CD5 (~30% of cases) or
CD23 (~15% of cases). In CLL/SLL, neoplastic B- cell PD- 1
expression is known to be weak and restricted to prolymphocytes/paraimmunoblasts within proliferation centers. While
in DLBCL- RT Neoplastic B- cell PD- 1 expression is highly
prevalent and demonstrates increased intensity– a differentiating feature from de novo DLBCL where PD- 1 expression
is extremely rare.
The cHL- RT subtype is morphologically depicted by the
presence of Reed–Sternberg cells either in a typical background of T cells, histiocytes, eosinophils– type I, which is
not considered true transformation, or scattered in a background of CLL cells – type II, which is considered true
transformation.
Reed–Sternberg cells show a characteristic CD15+, CD30+,
and CD20−. The Reed- Sternberg cells in cHL- RT are often
EBV positive.
Richter transformation
Definition
RT is defined as the development of an aggressive lymphoma
in patients with an underlying or synchronous diagnosis of
CLL/SLL. Different histopathologic variants of RT include
diffuse large B- cell lymphoma subtype (DLBCL- RT), which
accounts for up to 90–95% of RT cases, or classic Hodgkin
lymphoma subtype (cHLcases. A few cases of plasmablastic transformation have been
reported in the literature.
A higher incidence of RT has been reported in patients with
heavily pretreated relapsed/refractory CLL enrolled in the first
clinical trials with novel agents (2–15%). On the other hand, in
patients with no prior exposure to CIT who were started on
novel agents as the first line of therapy, the incidence has been
reported to be 0–4%. It is important to note that the follow- up
data in treatment- naïve patients who got started on novel
agents as the first line of therapy is still young and longer follow- up is required to accurately evaluate the impact of chemofree treatments on second malignancies/transformation.
Despite a presumed difference in incidence, similar clonal
evolution patterns are described for patients experiencing
transformation under novel agents or CIT.
RT) accounting for up to 5–10% of
Clonal relatedness between CLL and lymphoma
The definition of clonal relationship between RT and the
underlying CLL is based on the analysis of the IGHV- D- J
genes rearrangement, which can be done either by PCR or
next- generation sequencing modalities. The majority of
DLBCL- RT cases (~80%) are clonally related to the underlying CLL, suggesting a true transformation. Clonally unrelated cases are termed de novo DLBCL, occurring in a patient
with a synchronous diagnosis of CLL. Determination of
clonal relatedness in cases of CLL and DLBCL is critical as
the prognosis of the two entities (DLBCL-
RT and de novo
DLBCL) is drastically different with the de novo DLBCL
associated with superior prognosis as compared to
DLBCL- RT. In addition to prognosis, the treatment strategies are different between the two entities. De novo DLBCL
is treated with upfront CIT, whereas RT- DLBCL is mostly
refractory to CIT alone and if these patients are chemosensitive or achieve better than partial response to other treatment modalities, they will be considered for consolidation
with allogeneic hematopoietic cell transplantation. In the
recent years, multiple clinical trials have investigated treatment options in RT- DLBCL, including using checkpoint
inhibitors, BTK inhibitors, BCL2inhibitors as single agents
or combined with conventional CIT options.
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Clonal relationship between cHL- RT and the underlying
CLL has been reported in only 30% of cases. As in DLBCL- RT,
the outcomes of clonally related cHL- RT and CLL are
thought to be inferior as compared with cases of cHL not
clonally related to underlying CLL.
Biology of Richter’s DLBCL
The whole genome sequencing and epigenomic studies of
CLL and DLBCL- RT have shown an increasing complexity
from initial CLL diagnosis to relapse and transformation–
mainly gained at the level of subclones. As a comparison to
typical CLL, the DLBCL- RT genomes carry a higher number of mutations, copy number alterations structural variants. Different DLBCL- RT- directed lines of therapy do not
seem to affect the mutational landscape of the disease.
There are seemingly no major differences seen among
DLBCL- RT patients at diagnosis or after receiving multiple
lines of therapy.
The main alterations involve cell- cycle regulators and
proliferation pathways, chromatin modifiers, MYC,
NFκB, and NOTCH pathways. Aberrations in genes such
as TP53, NOTCH1, BIRC3, EGR2, and NFKBIE are usually detected and after the first CLL sample, suggesting
acquisition at the clonal level. Whereas others such as
CDKN2A/B, CDKN1A/B, ARID1A, CREBBP, TRAF3, and
TNFAIP3 are only detected at the time of transformation
or during the disease course, suggesting acquisition at the
subclonal level.
TP53 is a tumor suppressor gene that functions as a tran-
scriptional regulator influencing cellular responses to DNA
damage. TP53 mutations/deletions have been described in
about 2/3 of cases of DLBCL- RT. TP53 can be acquired at
the time of transformation and is not necessarily present at
diagnosis or progression of CLL. MYC gene encodes a multifunctional, nuclear phosphoprotein that controls a variety
of cellular functions, including cell cycle, cell growth, apoptosis, cellular metabolism and biosynthesis, adhesion, and
mitochondrial biogenesis. MYC or associated genes (e.g.
MGA) are altered in >40% of cases of DLBCL-
RT. CDKN2A
is a negative regulator of cell cycle transition from G1 phase
to S phase and its deletion has been reported in 30% of
DLBCL- RT cases. Among all mutations, NOTCH1
mutations represent the only validated risk factor for
DLBCL- RT. Among patients with CLL and mutated
NOTCH1, the cumulative risk of developing DLBCL- RT is
45% as compared with only 4% for CLL with wild- type
NOTHC1. PTPN11, a positive regulator of the MAPK- RASERK signaling pathway, is reported to be overexpressed in
DLBCL- RT samples. SETD2, a tumor suppressor regulator,
has shown alterations in about 1/3 of DLBCL- RT cases.
PTPRD, a tumor suppressor gene that can be silenced via
hypermethylation, is recurrently altered in DLBCL- RT
cases. Notably, BTK, PLCG2, and BCL2mutations have not
been reported in DLBCL- RT patients, which makes an
argument for the use of BCR pathway inhibitors and
BCL2inhibitors in this patient population.
In terms of DLBCL- RT immune microenvironment, distinct immune signatures between bone marrow, peripheral
blood, and lymph nodes from patients with DLBCL- RT have
been represented in multiple immunologic studies.
DLBCL- RT samples, unlike DLBCL de novo, are characterized by enhanced PD- L1 expression in histiocytes and
increased PD- 1 expression in neoplastic B- cells, in addition
to infiltration of FOXP3- positive T cells and CD163- positive
macrophages. These findings depict a particular DLBCL- RT
immune microenvironment that potentially may explain the
higher response rates to immune checkpoint inhibitors.
Lastly, an increased lymphocyte activating 3 gene (LAG3)
expression has been reported in RT, a characteristic which
again differentiates this entity from DLBCL de novo and
other transformed lymphomas. LAG3membrane protein is
expressed on both neoplastic B- cells and/or tumor- infiltrating
lymphocytes and is involved in the delivery of inhibitory
stimuli on activated T cells. Overexpression of LAG3 is
another potential targetable opportunity that is currently
being investigated through using LAG3inhibitors [16].
Conclusion
CLL is a heterogenous disease with distinct cell of origin
depicted as IGHV mutation status, chromosome alterations,
molecular mutations, microRNA changes, and epigenetic
events contributing to its heterogeneity. An in- depth understanding of the BCR pathway and BCL2 family proteins has
resulted in some of the most magnificent drug developments
for the patients with CLL. These therapeutic options have
truly transformed the treatment landscape for patients with
CLL. They have overcome historically adverse prognostic
features with conventional CIT and have been for the most
part proved to be well tolerated in old and frail patients with
multiple comorbidities. It is yet to be seen whether the incidence and mutational landscape of RT is going to change in
the era of novel agents. Currently, there is a growing need for
improved therapies for patients with Richter syndrome. A
meticulous understanding of Richter biology should open
the door for developing effective therapeutics in the future.
Further reading
Balatti, V., Pekarky, Y., and Croce, C.M. (2015). Role of microRNA in
chronic lymphocytic leukemia onset and progression. J. Hematol.
Oncol. 20 (8): 12. https://doi.org/10.1186/s13045- 015- 0112- x. PMID:
25886051; PMCID: PMC4336680.
Burger, J.A. and Chiorazzi, N. (2013). B cell receptor signaling in
chronic lymphocytic leukemia. Trends Immunol. 34 (12): 592–601.
https://doi.org/10.1016/j.it.2013.07.002. Epub 2013 Aug 5. PMID:
23928062; PMCID: PMC3898793.
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136 Molecular Hematology
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Condoluci, A. and Rossi, D. (2022). Biology and treatment of Richter
transformation. Front. Oncol. 22 (12): 829983. https://doi.org/10.3389/
fonc.2022.829983. PMID: 35392219; PMCID: PMC8980468.
Crombie, J. and Davids, M.S. (2017). IGHV mutational status testing in
chronic lymphocytic leukemia. Am. J. Hematol. 92 (12): 1393–1397.
https://doi.org/10.1002/ajh.24808. Epub 2017Jul 29. PMID: 28589701;
PMCID: PMC5675754.
Goldin, L.R. and Slager, S.L. (2007). Familial CLL: genes and environ-
ment. Hematol. Am. Soc. Hematol. Educ. Program.: 339–345. https://
doi.org/10.1182/asheducation-
Jaramillo, S., Agathangelidis, A., Schneider, C. etal. (2020). Prognostic
impact of prevalent chronic lymphocytic leukemia stereotyped subsets: analysis within prospective clinical trials of the German CLL
Study Group (GCLLSG). Haematologica 105 (11): 2598–2607.
Kikushige, Y. (2020). Pathogenesis of chronic lymphocytic leukemia
and the development of novel therapeutic strategies. J. Clin. Exp.
Hematop. 60 (4): 146–158. https://doi.org/10.3960/jslrt.20036. Epub
2020Nov 4. PMID: 33148933; PMCID: PMC7810248.
Marti, G.E., Rawstron, A.C., Ghia, P. etal. (2005). Diagnostic criteria for
monoclonal Bhttps://doi.org/10.1111/j.1365- 2141.2005.05550.x.
Mattsson, M., Sandin, F., Kimby, E. et al. (2020). Increasing preva-
lence of chronic lymphocytic leukemia with an estimated future
rise: a nationwide populationE36–E38. https://doi.org/10.1002/ajh.25681.
Mukkamalla, S.K.R., Taneja, A., Malipeddi, D. etal. (2023). Chronic
lymphocytic leukemia. In: StatPearls [Internet]. Treasure Island (FL):
StatPearls Publishing. [Updated 2023Jan 15]. Available from: https://
www.ncbi.nlm.nih.gov/books/NBK470433/.
Nadeu, F., Royo, R., Clot, G. etal. (2021). IGLV3-
aggressive biological subtype of chronic lymphocytic leukemia
with intermediate epigenetics. Blood 137 (21): 2935–2946. https://
doi.org/10.1182/blood.2020008311.
cell lymphocytosis. Br. J. Haematol. 130 (3): 325–332.
2007.1.339.
based study. Am. J. Hematol. 95 (2):
21R110identifies an
Parikh, S.A., Leis, J.F., Chaffee, K.G. et al. (2015).
Hypogammaglobulinemia in newly diagnosed chronic lymphocytic
leukemia: natural history, clinical correlates, and outcomes. Cancer
121 (17): 2883–2891. https://doi.org/10.1002/cncr.29438. Epub 2015
Apr 30. PMID: 25931291; PMCID: PMC4545721.
Rawstron, A.C., Villamor, N., Ritgen, M. et al. (2007). International
standardized approach for flow cytometric residual disease monitoring in chronic lymphocytic leukaemia. Leukemia 21 (5): 956–964.
https://doi.org/10.1038/sj.leu.2404584. Epub 2007 Mar 15. PMID:
17361231.
Shanafelt, T.D., Ghia, P., Lanasa, M.C. et al. (2010). Monoclonal B-
lymphocytosis (MBL): biology, natural history and clinical management. Leukemia 24 (3): 512–520. https://doi.org/10.1038/leu.2009.287.
Epub 2010Jan 21. PMID: 20090778; PMCID: PMC3913172.
Ueda, M., Berger, M., Gale, R.P., and Lazarus, H.M. (2018).
Immunoglobulin therapy in hematologic neoplasms and after
hematopoietic cell transplantation. Blood Rev. 32 (2): 106–115.
Yan, H., Tian, S., Kleinstern, G. etal. (2020). Chronic lymphocytic leuke-
mia (CLL) risk is mediated by multiple enhancer variants within CLL
risk loci. Hum. Mol. Genet. 29 (16): 2761–2774. https://doi.org/10.1093/
hmg/ddaa165. PMID: 32744316; PMCID: PMC7530532.
Yang, S.M., Li, J.Y., Gale, R.P., and Huang, X.J. (2015). The mystery of
chronic lymphocytic leukemia (CLL): why is it absent in Asians and
what does this tell us about etiology, pathogenesis and biology? Blood
Re v. 29 (3): 205–213.
Yao Y, Lin X, Li F (2022) etal. The global burden and attributable risk
factors of chronic lymphocytic leukemia in 204 countries and territories from 1990 to 2019: analysis based on the global burden of disease
study 2019. Biomed. Eng. Online 21(1): 4. doi: https://doi.org/10.1186/
s12938-
021- 00973- 6. PMID: 35016695; PMCID: PMC8753864.
Zhou, W., Goldin, L., Wang, M. etal. (2018). Combined somatic muta-
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cell
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Chapter10
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The molecular biology of
multiplemyeloma
Udit Yadav1 and Wilson I. Gonsalves
1
Division of Hematology, Mayo Clinic, Phoenix, AZ, United States
2
Division of Hematology, Mayo Clinic, Rochester, MN, United States
Introduction, 137
Normal plasma cell development, 137
Development of myeloma cell, 138
Progression to multiple myeloma, 140
2
Introduction
Multiple myeloma (MM) is a clonal plasma- cell disorder and
is the second most common hematologic malignancy in
adults, with an estimated 35,730 new cases accounting
for 1.8% of all new cancer diagnoses and contributing to
12,590 deaths which are 2.1% of allcancer- related deaths in
the United States in 2023. MM arises from the malignant
transformation of a post- germinal center plasma cell. It is
biologically heterogeneous due to the evolution and competition between different sub- populations of monoclonal
plasma cells as they acquire additional cytogenetic abnormalities leading to complex and genomically unstable
subclones. It represents a part of the continuum of the disease
spectrum, beginning with its origin as a premalignant condition, known as monoclonal gammopathy of undetermined
significance (MGUS), to smoldering MM (SMM), and eventually to full- blown disease presenting with end- organ dysfunction like lytic bone disease, kidney failure, hypercalcemia,
and anemia (Table10.1). MM is considered incurable, however a better understanding of the biology of the disease and
pro
fusion of approved novel therapies have led to improvement in patient outcomes with the average five- year survival
increasing to 59.8% compared to 32% in the late 1990s,
although outcomes in patients with high- risk cytogenetics
still remain suboptimal and have not mirrored the significant
progress made in patients with standard- risk disease.
Classification and risk stratification of myeloma, 143
Conclusion, 143
Further reading, 143
Normal plasma cell development
Plasma cells normally constitute less than 1% of lymphoid
cells. They represent the terminal cell of differentiation in
the B- lymphoid lineage cascade. The initial production
and development of B cells occurs in the bone marrow.
After initial development, the B cells exit the bone marrow
and circulate in the secondary lymphoid organs, where
they undergo final maturation. The rearrangement of the
gene segments encoding for the variable region of the
immunoglobulin is responsible for generating immunoglobulin diversity. This is the VDJ segment of the heavy
chain that is located on chromosome 14 and the VJ segment of the light chain, located on chromosome 2 for
Kappa and chromosome 22 for lambda, respectively. The
variable gene segment recombination occurs early in the
course of B cell development. This is accomplished by the
assistance of the nucleases, RAG1 and RAG2, causing
double- stranded DNA breaks guided by recombination
signal sequences. The B cell maturation then progresses
with either T cellnisms. The latter is a complex, multi- step process leading
to B cell differentiation into plasma cells and memory B
cells. Two other B- cell- specific gene modifications like
isotype switching and somatic hypermutation contribute
further to affinity maturation and are the hallmark of postgerminal center B cells. Both these steps are regulated by
independent or T cell- dependent mecha-
Molecular Hematology, Fifth Edition. Edited by Drew Provan and Hillard M. Lazarus.
© 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.
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137
138 Molecular Hematology
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Table10.1 International Myeloma Working Group- 2014 diagnostic criteria forMultiple Myeloma andother plasma cell disorders
Plasma cell disorder Definition
IgM MGUS • Serum monoclonal protein <30 g/L
Non-
• Clonal bone marrow plasma cells <10%
• Absence of myeloma- defining events
IgM MGUS • Serum IgM monoclonal protein <30 g/L
• Clonal bone marrow plasma cells <10%
• Absence of myeloma- defining events and constitutional symptoms, hyperviscosity, lymphadenopathy,
orhepatosplenomegaly
Light chain MGUS • Abnormal FLC ratio (<0.26 or >1.65), with increased level of the involved light chain
• Clonal bone marrow plasma cells <10%
• No immunoglobulin heavy chain expression on immunofixation
• Urinary monoclonal protein <500 mg/24 h
• Absence of myeloma- defining events
Solitary plasmacytoma • Biopsy- proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells
•
Normal bone marrow with no evidence of clonal plasma cells
• Normal bone imaging except for the primary lesion
• Absence of myeloma defining event
Solitary plasmacytome
with minimal marrow
involvement
Smoldering multiple
myeloma
Multiple myeloma • Clonal bone marrow plasma cells 10–60% or biopsy- proven bony or extra- medullary plasmacytoma
Plasma cell leukemia • Confirmed diagnosis of Multiple Myeloma
• Biopsy- proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells
• Clonal bone marrow plasma cells <10%
• Normal bone imaging except for the primary lesion
• Absence of myeloma defining event
• Serum monoclonal protein (IgG or IgA) ≥30 g/L or urinary monoclonal protein ≥500 mg/24 h and/or
clonal bone marrow plasma cells 10–60%
AND
• Absence of myeloma- defining event or amyloidosis
AND
• Any one or more of the following myeloma- defining events:
◦ Evidence of end- organ damage that can be attributed to the underlying plasma cell proliferative
disorder, specifically:
– Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or
>2.75 mmol/L (>11 mg/dL)
– Renal insufficiency: creatinine clearance <40 mL/min or serum creatinine >177 μmol/L (>2 mg/dL)
– Anemia: hemoglobin value of >2 g/dL below the lower limit of normal, or a hemoglobin value
<10 g/dL
– Bone lesions: one or more osteolytic lesions on skeletal radiography, computed tomography (CT), or
positron emission tomography- CT (PET- CT)
◦ Clonal bone marrow plasma cell percentage ≥60%
◦ Involved: uninvolved serum free light chain (FLC) ratio ≥100 (involved free light chain level must be
≥100 mg/L)
◦ >1 focal lesions on magnetic resonance imaging (MRI) studies (at least 5 mm in size)
AND
• Plasma cells ≥5% of white blood cells on conventional peripheral blood smear (manual white blood cell
differential count)
activation- induced cytidine deaminase (AID). Errors during the maturation of post- germinal center B cell could
lead to the development of aberrant plasma blasts and are
thus considered to be the cell of origin in plasma cell
dyscrasias.
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Development ofmyeloma cell
The initial event in the development of MM is the formation
of an MGUS like clone of plasma cells, preceding the development of MM by several years to decades. In majority of
The molecular biology of multiplemyeloma 139
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patients, MGUS is a benign paraproteinemia; most commonly detected incidentally as an abnormal serum protein
electrophoresis or serum immunofixation. Male sex, family
history, and African American ancestry are associated with
an increased risk of development of MGUS, and the role of
environmental factors remains unclear. The prevalence of
MGUS is about 5% in individuals over 50 years of age and is
associated with a risk of progression to MM of about 1%
annually. Some MGUS clones can lead to development of
other related plasma cell disorders like immunoglobulin
light chain (AL) amyloidosis, Waldenstrom’s macroglobulinemia, and plasmacytoma. AL amyloidosis is a very rare
condition that can present with myriad symptoms from the
involvement of different organ systems due to the deposition
of amyloid protein derived from fragments of monoclonal
light chains. This chapter will only focus on the molecular
pathobiology of MM. MGUS with any of the following additive risk factors: M- spike of more than ≥1.5 g/dL, non- IgG
subtype and abnormal serum- free light chain ratio is associated with a higher risk of progression to MM.
The genetic abnormalities that lead to this abnormal
clone’s development are called primary cytogenetic abnormalities (Table 10.2) and are the initial and foundational
genetic events in the path to MM. The precise mechanism by
which they occur is unclear, but it has been postulated that
persistent antigen stimulation pressure could play a key role,
causing continuous exposure to the potential mutagenic
effect of AID. These errors develop during the process of
gene segment modifications unique to B- cell development
like isotype switching and somatic hypermutation. Following
the development of a malignant plasma cell, they then home
to the bone marrow, which provides the microenvironment
for their continued survival and growth.
At the molecular level, two distinct lineages of MM cells
are formed, with approximately half with hyperdiploidy/
trisomies (HRD) and the rest are non- hyperdiploid (nonHRD) which would include predominantly MM cell lineage
with IgH translocations. These two primary cytogenetic
abnormalities are considered mutually exclusive, pointing to
them being acquired early during disease development.
However, in 10% of cases, they can exist together. They are
discussed further below.
Hyperdiploidy/trisomies
Approximately 45% of MM are hyperdiploid (48–75 chromosomes), which means they contain an aneuploidy of one or
more odd- numbered chromosomes involving chromosomes
3,5,7,9,11,15,19, and 21. HRD tumors in general tend to have
a more favorable prognosis with excellent long- term outcomes
and median overall survival of 7–10 years. They are present
more commonly in elderly patients and tend to present with a
higher incidence of bone disease.
IgH translocations
Around 40% of the MGUS clones develop errors with IgH
translocation during isotype switching, reinforcing the theory
of post- germinal center B- cell origin of plasma cells. As a
result of these translocations, an oncogene gets juxtaposed to
an IgH enhancer leading to their increased expression, which
promotes the expansion and development of the abnormal
clone.
The proportion of patients with IgH translocations
increases with disease grade, with 50% of MGUS or SMM
patients harboring translocations, compared with 55–73% in
patients with active MM, and >85% in plasma cell leukemia.
This would further support the fact that IgH translocated
MM is biologically more aggressive and associated with
worse outcomes compared with HRD myeloma.
t(11;14)(q13;q32)
The three Cyclin D genes activate CDK4 and CDK6, which
in turn cause RB1 phosphorylation and inactivation allowing
cell- cycle progression. t (11;14) involves the translocation of
proto- oncogene CCND1, resulting in the overexpression
ofcyclin D1. This is the most common IgH translocation in
MM occurring in 15–20% of cases. t(11;14) represents a
Table10.2 Primary cytogenetic abnormalities inmultiple myeloma
Primary abnormality Gene affected Frequency Risk
Hyperdiploidy/trisomies Multiple genes affected due to trisomies affecting odd- numbered
IgH translocation
t(11;14) CCND1 15–20% Standard risk
t(4;14) NSD2/MMSET/WHSC1 and FGFR3 10–15% High risk
t(6;14) CCND3 1–5% Standard risk
t(14;16) C- MAF <5% High risk
t(14;20) MAFB <1% High risk
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45% Standard risk
chromosomes except chromosomes 1,13, and 21
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unique subtype of myeloma associated with CD20 expression, non- secretory disease, lymphoplasmacytic morphology, IgM, and light chain subtype. In addition, in about half
of all patients with light chain amyloidosis, the clonal plasma
cells carry this cytogenetic abnormality. Biologically, it is
usually considered to be associated with a favorable prognosis; however, in some patients, it can present with an aggressive disease course, with a higher incidence of primary
plasma cell leukemia. t(11;14) myeloma is also notable for
higher BCL- 2 expression, making this subtype of MM an
attractive target for BCL2inhibitors like venetoclax.
t(12;14) and t(6;14) are much rarer, occurring in 1% and
1–5% of cases, and lead to increased expression of CCND2
and CCND3, respectively.
t(4;14) (p16;q32)
t(4;14) is the second most common translocation, occurring
in 10–15% of newly diagnosed patients with MM. This
results in the creation of two derivative chromosomes that
places FGFR3 and NSD2 (also known as MMSET, WHSC1)
close to the IgH enhancer, leading to their overexpression.
Although traditionally t(4;14) has been considered a highrisk mutation, in reality, about 30–40% of patients with this
translocation really behave as high risk. In some studies,
FGFR3 expression was not correlated with poor prognosis.
Recently, it was suggested that the risk is driven by the location of the translocation breakpoint in the NSD2 gene, with
a “late” disruption, that is within the NSD2 gene being associated with a poorer prognosis. In addition, the co- occurrence
of other high- risk abnormalities like del(17p) or gain 1(q)–
so- called “double hit”– increases the disease risk. There is
evidence to suggest that some of the risk associated with
t(4;14) can be overcome with the use of proteasome inhibitors, but whether this just reflects the subset of patients with
a “late” disruption is unclear.
t(14;16) (q32;q23) andt(14;20) (q32;q11)
t(14;16) (C- MAF) and t (14;20) (MAFB) are the least common types of IgH translocations, together occurring in about
less than 5% of newly diagnosed patients. These are considered high- risk translocations associated with inferior outcomes with standard therapy and tend to present with a
greater incidence of kidney failure as the initial MM- defining
event.
Cyclin D dysregulation
Cyclin D dysregulation has been proposed as an initial and
unifying event in plasma cell disorders. Cyclin D proteins
partner with CDK4/CDK6 during the early G1 phase of the
cell cycle. The Cyclin D- CDK4/CDK6 complex in turn
inactivates the retinoblastoma (RB) protein through
phosphorylation, which allows the activation of transcription factor E2F, thereby enabling and promoting cell cycle
progression. The different cytogenetic abnormalities ultimately lead to increased expression of the cyclin D genes
compared to normal plasma cells. In HRD MM, there is
increased expression of CCND1 or both CCND1 and
CCND2. t(11;14), t(12;14), and t(6;14) lead to increased
expression of CCND1, CCND2 and CCND3 respectively.
t(4;14) causes increased levels of CCND2 and C- MAF and
MAFB translocations cause overexpression of CCND2. A
small proportion of MM tumors do not have increased
levels of a cyclin D gene. They have little or no RB1 expression, bypassing the need for cyclin D gene expression.
Progression tomultiple myeloma
Following the development of an MGUS clone, progression
to MM is characterized by a complex interplay of additional
genetic insults or “hits” (termed secondary cytogenetic
abnormalities) (Table 10.3), epigenetic changes such as
histone modification and DNA methylation, which lead to
abnormal intracellular signaling. MM is recognized as a
heterogeneous entity with multiple competing subclones.
The subclones harbor mutations that confer survival benefit,
exert selection pressure, and thus outcompete normal plasma
cells and other clones with less- aggressive cytogenetic profile.
Table10.3 Secondary abnormalities inmultiple myeloma
Secondary
abnormality Genes affected Frequency
Deletion 13(q) RB1, DIS3 50%
RAS/MAPK NRAS (chr 1)/KRAS (chr 12)
(40%), BRAF (chr 7, 7%),
FGFR3 (chr 4, 2%)
NF-
kB TRAF3 (chr 14), TRAF2
(chr 9), NFkB2 (chr 10),
NFkB1 (chr 4), CYLD
(chr 16), TACI (chr 17)
MYC translocation
(chr 8)
Deletion 17(p) TP53 5%
Gain/amplification
1(q)
Deletion 1(p) FAF1, CDKN2C 11%
Ig partners (37%): IgH
(chr 14, 14%), IgL
(chr 22, 10%), IgK (chr 2,
5.5%)
non- Ig partners (63%):
NMSCE2 (chr 8, 8.5%),
TXNDC5 (chr 6, 7%),
FAM46C (chr 1, 3%),
CSMD3 (chr 8, 2%)
Multiple 30–40%
15–20%
20–50%
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The molecular biology of multiplemyeloma 141
Bone marrow
microenvironment
c
https://t.me/med1917
IgH translocation
Cyclin D
dysregulation
Figure10.1 Model for the development of multiple myeloma. The first “hit” occurs in a post- germinal B cell, which leads to the development of an MGUS clone, which is either hyperdiploid or non- hyperdiploid. This MGUS clone is then susceptible to the acquisition of secondary
cytogenetic abnormalities or “hits,” leading to genomic instability, abnormal intracellular signaling, and cell cycle dysregulation. This occurs in the
backdrop of an enabling bone marrow microenvironment. All these events lead to the progression of an MGUS sub- clone to myeloma, which
then presents with end- organ damage like kidney failure, anemia, and lytic bone disease.
G0 phase
(resting)
G
1
M
S
G
2
Multiple myeloma
Hyperdiploidy
MGUS
Secondary cytogeneti
abnormalities
Gene mutations
Lastly, the bone marrow, under the influence of pro- growth
signals, provides a nutritious and enabling microenvironment for the growth and propagation of MM (Figure10.1).
Del (13q)
Chromosome 13 deletion is present in almost 50% of cases of
newly diagnosed MM, of which about 85% are monosomies,
and the remaining are interstitial deletions. Del(13q) leads to
loss of RB1, which prevents cell cycle progression by binding
to E2F transcription factor. The other gene associated with
del (13q) is DIS3, which is mutated in about 10% of MM.
When first discovered by metaphase cytogenetics del (13q)
was initially considered a high- risk marker and detected in
nearly 15% of patients. However, more sensitive testing
methods like FISH showed it was much more prevalent. This
questioned whether del (13q) was in fact associated with
worse outcomes, as it often co- occurred with other high- risk
genetic abnormalities and with conventional cytogenetics,
it perhaps served more as a surrogate marker for other
high- risk features like hypodiploidy, IgH translocations,
or proliferation. A more recent publication has also
suggested differential effects with chromosome 13 abnormalities, with monosomy 13 having an adverse impact
(independent of other high- risk genetic abnormalities) and
afavorable effect of partial deletion of chromosome 13q on
overall survival.
RAS abnormalities
The activation of the RAS/MAPK pathway has been implicated in the progression of MGUS to MM. These are due to
point mutations in NRAS/KRAS (40%), BRAF (7%), and
FGFR3 (2%) mutations.
MYC signaling
The development of MYC structural variant is a common
secondary cytogenetic abnormality reported in 20–50% of
patients in newly diagnosed MM with a higher incidence of
HRD myeloma (55%) compared to 25% in patients with IgH
translocation. MYC functions as a transcription factor and
is involved in the regulation of several cellular functions
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including cell growth, proliferation, metabolism, and
apoptosis. MYC translocations can involve diverse partners
involving both Ig (most frequently the heavy chain locus)
and non- Ig partners (FAM46C, FOXO3, BMP6).
Aberrant NF- κB signaling
The NFkB family of transcription factors play a major role in
the control of immune response and inflammation, required
in the survival and proliferation of cells either through canonical or non- canonical pathway. Normal NFkB signaling pathway comprises of five related transcription factors including
NFkB1 (also known as p50), NFkB2 (p52), RelA (p65), RelB,
and c- Rel. In the canonical (classical) pathway, there is activation of the IkB Kinase (IKK) complex– consisting of IKKα,
IKKβ, and IKKγ– by various stimuli through tumor necrosis
factor receptors (TNFR) and Toll- like receptors. This results
in the proteasome- mediated degradation of the inhibitory signal IkBα, allowing the formation of p50/RelA and p50/c- Rel
dimers, which then translocate to the nucleus causing gene
activation and expression. In comparison, the non- canonical
(alternate) pathway responds to a specific group of TNFR like
LTβR, BAFFR, CD40, and RANK. Upon activation, the
NFkB- inducing kinase (NIK) in conjunction with IKKα leads
to proteasome- mediated processing of NFkB2, generating the
p52 subunit and consequently the accumulation of p52/RelB
heterodimers in the nucleus. TRAF2, TRAF3, and cIAP play
an important role in this process by regulating NIK turnover.
MM as well as several B cell neoplasms rely on abnormal
NFkB signaling for growth, survival, and resistance to therapy.
A variety of mutations involving 11 genes involved in the regulation of the NFkb pathway, including NFKb2, TRAF2,
TRAF3, CYLD, NFKB1, TACI, and NIK were identified in
about 17% of patients and 42% of HMCLs with TRAF3
inactivation being the most common abnormality. Most of the
mutations were noted to activate the non- canonical pathway,
although the canonical pathway was impacted to a lesser
extent. The result of these mutations is the stabilization of the
NIK protein leading to constitutive activation of the NFkB
pathway that results in clonal proliferation, development,
angiogenesis, and reduced reliance on the bone marrow
microenvironment for survival.
Deletion of17p [del(17p)] including TP53
of the p53 protein due to the rapid turnover of p53 via
MDM2response to oncogenic stress like DNA damage, the p53 pathway becomes activated and ensures the integrity of the
genome by either allowing cells to repair the damaged DNA
through cell- cycle arrest, or to eradicate potential malignant
clones by inducing apoptosis. The deregulation of TP53in
MM can occur through monoallelic loss, TP53mutations,
epigenetic modification like hypermethylation of the promoter region, MiRNAs abnormalities, and MDM2 overexpression. It is associated with worse overall survival, shorter
response to standard therapies including autologous stem
cell transplant and higher incidence of CNS involvement.
mediated proteasomal degradation. However, in
Chromosome 1q gain, amplification
Gain (three copies) or amplification (four or more copies) of
the long arm of chromosome 1 occurs in about 30–40% of
patients and is considered a high- risk marker associated
with proliferative disease. The number of copies is proportionally associated with risk. While amplification(≥4 copies)
has been strongly associated with higher risk, the prognostic
impact of gain (3 copies) has been widely debated. This also
tends to occur more frequently with certain other cytogenetic abnormalities like t (4;14), t (14;16), and del 13(q),
with an inverse relationship with t (11;14). The importance
of gain 1q is evident from the fact that in gene expression
profiling GEP70, 30% of the gene expression deregulation is
mapped to chromosome 1. The exact molecular mechanism
behind the effect of increased copy number is unclear.
CKS1b overexpression was identified as a possible driver,
but this has since been debated as additional genes (PDZK1,
BCL9, ANP32E, ILF2, ADAR, MDM4, and MCL1) are
implicated too.
Del (1p32)
Chromosome 1p loss occurs in about 11% of patients with
newly diagnosed MM. Chromosome 1p loss, specifically 1p32,
is associated with poor prognosis. This locus is associated with
genes like FAF1involved in apoptosis and CDKN2C, which
prevent cell cycle progression at the G1 phase. Biallelic deletion has been shown to be associated with significantly worse
outcomes in comparison to monoallelic loss.
Deletion of 17(p) leading to loss of TP53 occurs in approximately 5% of newly diagnosed myeloma. However, the prevalence increases with higher grade disease, and is about 30%
in plasma cell leukemias and is associated with extramedullary disease.
TP53 deletion confers an extremely high- risk phenotype
and is a marker of genomic instability. TP53 is a tumor suppressor gene coding for protein p53. In normal physiologic
conditions, the p53 pathway is quiescent with low expression
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Bone marrow microenvironment
Besides cytogenetic abnormalities, the bone marrow microenvironment is believed to play a key role in the progression
from MGUS to MM. The myeloma cell interactions within a
milieu of hematopoietic stem cells, osteoblasts, osteoclasts,
extracellular matrix, and cytokines enable a conducive environment for the survival of the abnormal plasma cell clone.
These involve a complex interplay with growth- promoting
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