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yet been defined, but genetic, environmental, and microenvironmental components, as well as age, are
[1]
considered important factors for disease development . The clinical presentation of the disease includes the
[2]
detection of high levels of paraproteins produced by MM cells . Bone pain and fatigue are typical
symptoms and frequently the main cause of initial consultation. Formal diagnosis of MM requires the
detection of elevated monoclonal paraprotein levels, serum immunoglobulin free light chain ratio (FLCR) >
100, the presence of at least 10% myeloma cells in the bone marrow, advance imaging to detect focal bone
disease, and the display of end-organ damage, often referred to as CRAB: hypercalcemia, renal failure,
[3,4]
anemia, and bone lesions . MM is commonly preceded by a precancerous, benign condition known as
monoclonal gammopathy of undetermined significance (MGUS) . MGUS is characterized by the presence
[5,6]
of serum M paraproteins (less than 3 g/dL), clonal plasma cells in the bone marrow (less than 10%), and no
[5,6]
other major MM symptoms . MGUS has 3 different subtypes including: non-IgM MGUS, IgM MGUS,
and light-chain MGUS. Non-IgM MGUS (more common) and light-chain MGUS can progress to MM,
while IgM MGUS is commonly associated with B-cell lymphoproliferative disorders, but also can progress
to MM. Patients with non-IgM MGUS and light-chain MGUS have a 1% risk of progression to MM per
year . Smoldering MM (SMM) is distinguished from MGUS by a higher risk of progression to MM .
[5]
[4,7]
SMM patients are asymptomatic, but have higher serum M paraproteins (greater than 3 g/dL) and bone
marrow plasma cells (10%-60%) than MGUS patients. SSM patients have a 10% risk of developing MM per
year in the first 5 years . In later stages, MM can progress to an advanced disease stage called plasma cell
[4,7]
leukemia (PCL), which is diagnosed when 20% of white blood cells are abnormal plasma cells. PCL, which
can also occur de novo, without preceding MM, is a very aggressive form of MM and has a low survival
rate . If eligible, MM patients typically undergo chemotherapy and stem cell transplantation, leading to a
[8]
[2]
remission phase of variable duration . However, disease relapse is very common in MM, and is followed by
a second line of therapy and remission phase . This cycle continues until drugs are not able to stop MM
[2]
[2]
progression . Although recent advances have significantly improved overall patient survival, MM still
remains incurable due to the high rate of relapse. Thus, new therapeutic approaches to treat MM
progression and prevent disease relapse are desperately needed.

Another area where unmet medical needs remain is the management of the bone disease that accompanies
MM. Approximately 80% of patients with MM present bone lesions, which can cause severe bone pain and
pathological fractures in 60% of MM patients [9,10] . The skeletal complications have a major impact on patient
morbidity and mortality, and decrease the quality of life of MM patients. Mechanistically, the growth of
MM cells in the bone marrow disrupts bone homeostasis by increasing the number of bone resorbing
osteoclasts, stimulating apoptosis of matrix embedded osteocytes, and decreasing the number and function
of bone forming osteoblasts [9-11] . As a result, MM patients display exacerbated bone resorption and a
concomitant suppression of bone formation that leads to the formation of focal osteolytic lesions, which
weaken the bone and increase the risk of bone fractures [9,10] . Bisphosphonates, and more recently
Denosumab, a neutralizing antibody against Rankl, are potent anti-resorptive agents and the mainstay
treatment for MM-induced bone disease due to their ability to prevent bone loss and to minimize the risk of
fractures [10,12-14] . However, bisphosphonates only stop the bone disease and do not repair damaged bone.
Because the bone disease and fractures persist, even in patients in complete remission, new clinical
interventions are necessary to repair and/or build new bone in MM patients. Despite the promising results
seen with the use of bone-forming agents (anti-Sclerostin antibodies) in preclinical animal models [15-17] , no
bone anabolic therapies have been approved for the treatment of MM yet.

MM is highly dependent on the bone marrow microenvironment [18,19] . In recent years, research efforts have
focused on understanding the role of the MM tumor microenvironment in MM to identify new targets and
develop novel therapeutic approaches. The inclusion of agents targeting the supportive effects of the