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1712 Part XI: Malignant Lymphoid Diseases Chapter 105: Plasma Cell Neoplasms: General Considerations 1713

RAS/RAF/MEK/ERK (rat sarcoma protein subfamily of small GTPase/ models of MBD, treatment with OPG and OPG-like compounds pre-
RAF protooncogene serine and threonine protein kinase/MAPK vented both bone destruction and myeloma growth in vivo. 119,120 Simi-
kinase/extracellular signal–regulated kinase) and JAK2/STAT3 (Janus larly, in patients with myeloma treated with thalidomide or autologous
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kinase 2/signal transducers and activators of transcription 3). Engage- stem cell transplantation responding to therapy, the RANKL-to-OPG
ment of these pathways results in upregulation of proteins that control ratio normalized and bone resorption was inhibited. In aggregate, these
cell cycle progression (e.g., D cyclins and Myc) and those that protect findings indicate the RANK-RANKL-OPG axis is an important thera-
myeloma cells from programmed apoptotic cell death (e.g., BCL2, BCL- peutic target for MBD.
x , and MCL1).
L
The interplay of myeloma and mesenchymal cells is not the same
in all subtypes of the disease. Instead, the genetic makeup of myeloma B-CELL ACTIVATION FACTOR
determines, in part, the interaction of tumor with the nonmalignant BAFF is a myeloma cell-promoting member of the TNF superfamily
stromal cells in the marrow environment. For instance, myeloma cells of proteins that is expressed by OCs and BMSCs. BAFF is significantly
harboring a MAF (v-MAF oncogene homologue)-activating chromo- increased in the serum of patients with myeloma. In a preclinical study
somal translocation, t(14;16), overexpress the adhesion factor, integrin using a mouse model of myeloma, targeting BAFF by means of a neu-
β . This results in enhanced tumor cell adhesion to bone mesenchy- tralizing antibody led to reductions in tumor burden and osteolytic
7
mal stem cells (BMSCs) relative to myeloma cells not containing a bone disease and increased survival.
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t(14;16). Signaling pathways that govern interactions of myeloma DKK1 is an inhibitor of the WNT signaling pathway that plays
and normal marrow cells also promote neoangiogenesis in the TME. a major role in MBD. DKK1 inhibits OB differentiation and pro-
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The formation of new blood vessels, which is driven to a large extent by motes OC maturation. Patients responsive to myeloma drugs exhibit
CXCL12/CXCR4 signaling and production of VEGF, B-FGFs, matrix reduced serum levels of DKK1.
metallopeptidases (MMPs), IGF-1, interleukins (e.g., IL-8, IL-1), angio- Activin A, a member of the TGF-β superfamily of proteins, acti-
poietin 1, transforming growth factor β (TGF-β), platelet-derived vates a signaling pathway that results in phosphorylation of SMADs
growth factor (PDGF), and hepatocyte growth factor (HGF), is critical (homologues of Drosophila’s mothers against decapentaplegic [MAD]
for myeloma progression and thus an important target of myeloma drug and Caeno Rhabditis elegans’ small body size [SMA] proteins) followed
development. by execution of a complex SMAD-dependent gene-expression program.
Activin A is a stimulator of osteoclastogenesis and is overexpressed in
myeloma. IL-3, another stimulator of OCs, can induce the secretion
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MYELOMA BONE DISEASE of activin A by resident macrophages in the myeloma marrow microen-
vironment, providing a mechanism for the upregulation of activin A in
Increased bone resorption and suppressed bone formation leads to patients with myeloma. Levels of activin A in the marrow plasma of
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osteolytic lesions in patients with myeloma. 111,112 The main cytokines myeloma patients with osteolytic lesions (OLs) are increased. RAP-
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involved in that process are IL-6, receptor activator of NF-κB ligand 011 is a soluble mouse activin A receptor that was shown to inhibit mye-
(RANKL)/osteoprotegerin (OPG), BAFF, chemokine (C-C motif) lig- loma-like tumors and prevent OLs in laboratory mice. 124,126 Sotatercept
and 3 (CCL3)/macrophage inflammatory protein (MIP)-1α, and VEGF. (ACE-011), the human version of mouse RAP-011 is a soluble receptor
The main cell adhesion and integrin signaling pathways involved in that of activin A and is undergoing clinical trials in patients with myeloma.
process are VLA-4/VCAM-1 and LFA-1/ICAM-1. 112,113 WNT/β-catenin
signaling antagonists that inhibit osteoblast differentiation in myeloma
also play an important role in the natural history of MBD. These include BRUTON TYROSINE KINASE
Dickkopf 1 (DKK1), soluble-frizzled receptor-like proteins (sFRPs), The metalloprotein, BTK, is a member of the Scr-related Tec fam-
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and sclerostin. Inhibition of osteoblast differentiation drives the bone ily of protein kinases. BTK is a regulator of OC differentiation that is
disease and, presumably, facilitates the expansion of myeloma cells expressed in OCs (but not in OBs) and has been implicated in bone
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because upregulation of β-catenin–dependent osteoblast activity in vivo resorption. BTK is expressed in myeloma cells. 127,128 Genetic evidence
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results in significant inhibition of myeloma cell growth, relying on indicates BTK may be crucial for neoplastic plasma cell development in
an ill-defined mechanism that appears to involve the small leucine-rich laboratory mice. 129
proteoglycan, decorin. 117
RANK/RANKL/OPG PATHWAY MYELOMA STEM CELL

The receptor activator of NF-κB (RANK)/RANKL/OPG pathway is Major progress has been made in the treatment of newly diagnosed
arguably one of the most important regulatory systems for homeostatic myeloma patients with 80 percent achieving either a complete remis-
bone remodeling. RANK, a membrane-anchored signaling receptor of sion (CR) or near CR (nCR) and more than 50 percent surviving
the TNF receptor family, is expressed on osteoclast (OC) precursors. 10 years. However, many patients ultimately relapse. Gene-expression
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Binding of its ligand, RANKL, expressed by osteoblasts (OBs) and profiles (GEPs) remain abnormal in myeloma patients with long-
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BMSCs, induces osteoclastogenesis and activation of mature OCs. OPG, lasting remission (>10 years). This finding suggests that the per-
a soluble member of the TNF receptor family, is also produced by OBs sistence of a myeloma cell population with low proliferative capacity
and BMSCs. Because OPG acts as a soluble decoy receptor for RANKL, and limited sensitivity to our most intensive therapies, points to the
it blocks RANK-dependent OC maturation and activation. Thus, it concept of a myeloma stem cell problem. There is no agreement on
is easy to understand that the ratio of RANKL and OPG significantly the specific phenotype of the myeloma stem cell, but side-population
impacts the balance of bone resorption and bone deposition. Indeed, (SP) cells, which constitute a minor fraction of the myeloma cells, have
compared to normal individuals, marrow plasma of myeloma patients the features of stem cells. Such cells have a greater clonogenic poten-
contains elevated levels of RANKL and reduced levels of OPG, con- tial and drug resistance, whether isolated from myeloma cell lines
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sistent with a proosteoclastogenic TME. Also, low serum levels of OPG or primary myeloma samples. 132,133 Many different groups have tried
correlate with advanced MBD in patients with myeloma. In mouse to identity the phenotype of myeloma stem cells. A drug-resistant
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