Although by definition patients with MGUS have no osteolytic lesions, population based studies demonstrate an increased fracture risk in MGUS patients compared to their matched controls [16, 17]. Low lumbar bone mineral density is a major risk factor associated with significantly high fracture risk in this patient population [18]. The exact pathophysiology of increased fracture risk in MGUS patients is not well established. Intriguingly, using a high-resolution peripheral quantitative computed tomography imaging of the distal radius, patients with MGUS were shown to have significantly increased cortical bone porosity and reduced bone strength [19, 20]. In addition, serum markers for both increased osteoclastic and decreased osteoblastic activities were significantly elevated in patients with MGUS. Dickkopf-related protein (DKK1), a secreted Wnt pathway inhibitor is a critical mediator of bone disease in myeloma through inhibition of Wnt-regulated osteoblastic differentiation [21]. Importantly, DKK1 is also implicated in increased osteoclastic activity through upregulation of RANKL and inhibition of OPG secretion [22]. Notably, one study showed significantly elevated serum DKK1 levels in MGUS patients compared to matched control subjects [20], although the increase was statistically insignificant in another study [23]. Finally, patients MGUS have significantly high serum level of osteoclast stimulating cytokine, macrophage inflammatory protein-1α (MPP-1α), when compared to matched healthy controls [20]. In conclusion, the altered bone microstructure and an imbalance between bone resorption and formation seem to be responsible for increased fracture risk even in patients with MGUS.

Bone disease in MM is a major cause of morbidity leading to poor quality of life. Hypercalcemia and skeletal related events such as bone pain, vertebral compression fractures, and pathologic fractures occur due to osteolytic bone disease in a large proportion of patients. Notably, pathologic fractures negatively impact the survival with 20 % increase in the risk of death compared to patients without fractures [24, 25]. Under normal circumstances, continuous turn over and remodeling of adult skeletal occurs through a highly regulated network of interactions between bone microenvironment and the bone cells creating a balance between bone resorption by osteoclasts and formation by osteoblasts. Deregulated bone remodeling due to increased osteoclastic activity and decreased osteoblastic differentiation is the principle cause of excessive bone resorption in MM. The increased osteoclastic activity and the resultant bone resorption typically occur in the areas adjacent to the malignant plasma cells [26]. Moreover, histomorphometric studies also demonstrated an increase in the number of osteoclasts and osteoblasts early in the course of myeloma development [27]. Clonal plasma cells and other elements of bone marrow (BM) microenvironment cooperate with each other through a complex network of signaling factors and cytokines that ultimately result in uncoupling of osteoclastic and osteoblastic activities. A variety of cellular and non-cellular components of BM microenvironment including BM cells (clonal plasma cells, stromal cells, immune cells); extracellular matrix containing collagen, laminin, fibronectin, and extracellular fluid rich in cytokines and other growth factors contribute to the pathogenesis of osteolytic bone disease [28].

Osteoclasts are hematopoietic in origin derived from differentiation and fusion of the monocyte-macrophage lineage precursor cells to form inactive osteoclasts. Activated osteoclasts are responsible for bone resorption and eventually undergo apoptosis [29]. In contrast, osteoblasts arise from mesenchymal stem cells and factors such as platelet-derived growth factor, fibroblast growth factor, and transforming growth factor B enhance their growth and differentiation. Bone microenvironment plays a critical role in the formation of osteoclasts through macrophage colony-stimulating factor and receptor activator of nuclear factor-kB (RANK) ligand (RANKL) produced by the osteoblasts and stromal cells [30]. Osteoblasts and stromal cells have surface expression of RANKL, which bind to the RANK receptor on the osteoclast precursor cells and induce the osteoclast formation [31]. In contrast, osteoprotegerin (OPG), a decoy soluble receptor of RANKL, normally present in the bone marrow binds to the RANKL inhibiting the RANK-RANKL interactions, thereby limiting osteoclastogenesis [32]. The ratio of OPG/RANKL regulates the osteoclast development, and the unbalance of this ratio is associated with bone disease in MM.

The other unique feature of bone disease in MM is the absence of new bone formation in the areas of osteolysis unlike any other tumor metastasis. Importantly, lack of new bone formation due to decreased osteoblastic differentiation and activity explain the pure lytic bone lesions, a typical finding in MM unlike other solid tumor metastases [31]. The key factor involved in this mechanism is DKK1 produced by clonal plasma cells which inhibits Wnt regulated osteoblastic differentiation [21]. This would also explain the persistence of lytic lesions in MM patients in remission despite the absence of increased plasma cells in the bone marrow. In addition to RANKL and DKK-1, several other key factors are involved in uncoupling of osteoclastic and osteoblastic activities including interleukin-3 (IL-3), Interleukin-6 (IL-6), MIP-1a, MIP-1B, BAFF, and activin A, and a detailed discussion is beyond the scope of this chapter. In conclusion, uncoupling of osteoclastic and osteoblastic activities is responsible for the formation of bone lytic lesions that are typical of MM. Understanding the mechanisms involved in this process has led to the development of several therapeutic targets for myeloma bone disease.

The first question to consider for newly diagnosed is whether patients are candidates or not for intensive chemotherapy followed by autologous stem cell transplantation (ASCT). Age and concomitant comorbidities should be taken in to account in determining transplant eligibility. In the USA, patients with physiologic age <70 years are considered ASCT eligible [42]. Active agents in MM available for treatment of frontline and relapsed myeloma patients belong to five different classes: corticosteroids (dexamethasone and prednisone), alkylating agents (Melphalan, and Cyclophosphamide), anthracyclines (Doxorubicin, and liposomal Doxorubicin), immunomodulatory derivatives or IMiDs (Thalidomide, Lenalidomide, and Pomalidomide), and proteasome inhibitors (Bortezomib and Carfilzomib), which are administered in multiple combinations.

Patients eligible for ASCT are typically treated with two to four cycles of an induction regimen prior to stem cell harvest. Many treatment options are available and the choice of the regimen is based on risk stratification, on patient comorbidities and on physician preference. Stem cell damaging agents such as Melphalan should be avoided in patients eligible for ASCT. Standard risk patients can be treated with an oral combination of Lenalidomide and low dose Dexamethasone [43]. Lenalidomide is currently preferred to Thalidomide due to superior activity and better toxicity profile [44]. Importantly, patients treated with Lenalidomide and Thalidomide should receive aspirin for thromboprophylaxis with consideration to warfarin and low molecular weight heparin in certain high-risk patients [45]. Bortezomib-containing regimens are given to intermediate and high-risk patients in combination with two additional agents, in so-called triplets. Popular combinations include VCD or CyBorD (Cyclophosphamide, Bortezomib, and Dexamethasone), VRD (Bortezomib, Lenalidomide, and Dexamethasone) and VTD (Bortezomib, Thalidomide, and Dexamethasone) [46–48]. Although VCD and VRD have not been compared in a randomized trial, the EVOLUTION trial has shown no difference between them in a small-size phase 2 study [49]. VRD is the preferred combination in patients with high-risk disease. Cisplatin and Etoposide combinations are a part of more aggressive treatment regimens (e.g., DT-PACE), typically reserved for patients with plasma cell leukemia and extramedullary disease at diagnosis [50].

The initial treatment regimens for newly diagnosed myeloma patients not eligible for ASCT due to age or comorbidities are the same as discussed for transplantation eligible patients. However, they are given for a total of 12–18 months. Addition of novel agents to the Melphalan-Prednisone (MP) backbone is associated to good clinical outcome, but the popularity of these regimens is limited in the USA in favor of the Lenalidomide–Dexamethasone combination. A meta-analysis of six randomized clinical trials showed that addition of thalidomide to MP (MPT) resulted in improvement in PFS and overall survival at the expense of increased toxicity, particularly peripheral neuropathy, and thrombosis [51]. A recent trial by the IFM group showed that a Lenalidomide–Dexamethasone combination, with Lenalidomide given continuously until progression, was superior to MPT [52]. Velcade-based regimens should also be considered in elderly patients, especially in high-risk group [46, 53].

High dose chemotherapy with autologous stem cell transplantation remains the mainstay of MM with improvement in CR rates, event free survival (EFS) and median overall survival (OS) by approximately 12 months [54, 55]. The transplant related mortality is less than 3 % [56]. Age and concomitant comorbidities should be taken in to account in determining transplant eligibility. In the USA, patients with physiologic age >70 years are considered ASCT eligible [42]. Melphalan 200 mg/m² is the standard preparatory regimen followed by stem cell rescue. However, a reduced intensity regimen with Melphalan 100 mg/m² may be considered in older patients or with comorbidities [57]. The benefit of HDT/ASCT in the current era of novel biologic agents, which induce deeper and sustained responses, is unclear. Another important question is the timing of HDT/ASCT, early with frontline therapy or delayed at the time relapse. Delayed ASCT at the time relapse is acceptable for some patients as randomized controlled trials showed no difference in overall survival between early versus delayed transplantation strategies [58, 59]. However, most clinicians prefer to use early HDT/ASCT in all eligible patients due to improved quality of life. If delayed ASCT strategy is adopted, patients should have their stem cells collected and cryopreserved typically after four cycles of induction therapy, which should be continued until disease progression or relapse. Finally, the attempts to improve outcomes of ASCT in MM have been largely been unsuccessful so far, except that double or tandem transplantation may offer some benefit in a subset of patients who fail to achieve a complete response or very good partial response after the first transplant [2, 60]. Therefore many centers prefer to collect stem cells adequate for two transplants. In conclusion, HDT/ASCT remains a key modality of therapy for MM until further data is available from prospective randomized trials incorporating novel agents up front.