General MM

MM-induced bone disease: an overview and updated guidelines

Bone disease is a hallmark of Multiple Myeloma (MM), affecting 80-90% of patients during their disease course, with an increased risk of skeletal-related events (SREs). Statistics have shown that up to 40% of MM patients suffer from pathological fractures in the first year after diagnosis, increasing the risk of death by more than 20% in comparison to patients without fractures.1

Why is bone density affected in MM?

Bone remodeling is a continuous process which balances old bone resorption involving osteoclasts (OCs) and new bone formation involving osteoblasts (OBs). In a healthy person, this process is a well-balanced equilibrium, but in the bone marrow (BM) of MM patients, malignant plasma cells disrupt this balance, leading to the development of osteolytic lesions. This occurs due to an increase in bone resorption by OCs, which drive suppression of osteoblasts, thereby reducing bone formation. The receptor activator of nuclear factor-kB ligand (RANKL)/receptor activator of nuclear factor-kB (RANK) pathway as well as osteoprotegerin (OPG), play important roles in the formation, function, and survival of OCs,2,3 and are therefore involved in the development of such osteolytic bone disease.

RANKL is produced by bone marrow stromal cells (BMSCs), OBs, and activated T-lymphocytes, and signals via its receptor RANK on precursor OCs to stimulate differentiation into mature OCs. This causes a reduction in OC apoptosis leading to increased osteoclastic activity. OPG protects from excessive bone resorption by binding to RANKL and preventing it from binding to its receptor, RANK.4 Interestingly, RANKL expression has been associated with a decrease in OPG levels in MM patients, and a separate study showed that elevated serum levels of soluble RANKL correlate with bone disease.5 In addition, the RANKL: OPG ratio was shown to be an independent prognostic factor for MM.

How can bone disease in MM be treated?

Until recently, bisphosphonates such as pamidronate and zoledronic acid (ZA) were the treatment of choice for MM-induced bone disease. However, while the combination of ZA with other anti-myeloma agents improves the quality of life and progression-free survival (PFS) in some MM patients, the side-effects of ZA include renal impairment and osteonecrosis of the jaw (ONJ). In patients with renal insufficiency, which is a common complication in MM, ZA is not an ideal treatment and therefore other treatment options are required.   

This month saw the approval of denosumab (Xgeva), a monoclonal antibody that inhibits the activity of RANK Ligand (RANKL), for the treatment of MM-related bone disease, by the US Food and Drug Administration (FDA) – see MM Hub article. Denosumab has already been used to treat decreased bone density in post-menopausal women with breast cancer and men with prostate cancer, with limited side-effects (which include breathlessness, bone and muscle pain, arm or leg pain and diarrhea).

Denosumab, a fully human monoclonal antibody, specific to RANKL, inhibits RANK activation, osteoclastogenesis, and osteoclast activation. In a phase III clinical trial, denosumab was shown to be non-inferior to ZA in delaying the time to first skeletal-related events as well as fewer adverse events related to renal toxicity – see previous MM Hub article. The current recommendation for MM is a dosage of 120 mg administered as a subcutaneous injection every four weeks.6

What are the recommended guidelines for the treatment of MM-related bone disease?

The American Society of Clinical Oncology in Clinical (ASCO) Practice recently updated their guidelines for the use of bone-modifying agents (BMAs) in MM, and this was published in the Journal of Clinical Oncology on 17 January 2018.  The last version was published in 2007 and focused on the role of bisphosphonates. The guidelines used evidence from 35 relevant studies in the literature, along with recommendations from the experts on the ASCO panel, which includes Kenneth Anderson and Robert A. Kyle and are summarized in the tables below.

Table 1. Summary of the recommendations regarding bone-modifying agents (BMA) in MM

Table 2. Summary of dosing and selection of BMA

Table 3. Management of BMAs
 
Are any other BMAs in development for MM?

A number of potential drugs have been assessed in preclinical and clinical studies to target the RANK/RANKL pathway. Use of recombinant RANK-Fc led to reduced MM-induced osteolysis and a concurrent decrease in tumor burden and recombinant OPG (AMGN-0007) in MM-bearing animals prevented the development of lytic bone lesions.A phase I study in which a single dose of a recombinant OPG was administered led to the suppression of bone resorption in MM with good tolerance.8 However, the use of recombinant OPG is complicated by the fact that it also binds TNF-related apoptosis-inducing ligand (TRAIL), resulting in the tumor cells being protected from the apoptotic effect of TRAIL9. Similarly, recombinant RANK-Fc has not been pursued in clinical trials as denosumab (a RANKL blocking antibody) appeared on the scene and is currently the most effective immunotherapy for MM-bone related events.  

References
  1. Oranger A. et al. Cellular mechanisms of multiple myeloma bone disease. Clin Dev Immunol. 29 May 2013. DOI: 10.1155/2013/289458
  2. Terpos E. et al. Pathogenesis of bone disease in multiple myeloma: from bench to bedside. Blood Cancer Journal. 12 January 2018. DOI: 10.1038/s41408-017-0037-4
  3. Bingham N. et al. An Evidence-Based Approach to Myeloma Bone Disease. Current hematologic malignancy reports. 12 April 2017. DOI: 10.1007/s11899-017-0370-5
  4. Fili S. et al. Mechanism of bone metastasis: The role of osteoprotegerin and of the host-tissue microenvironment-related survival factors. Cancer Letters. 28 September 2009. DOI:10.1016/j.canlet.2009.01.011
  5. Hu J. et al. Targeting signaling pathways in multiple myeloma: Pathogenesis and implication for treatments. Cancer Letters. 1 February 2018. DOI: 10.1016/j.canlet.2017.11.020
  6. Anderson Ket al. Role of Bone-Modifying Agents in Multiple Myeloma: American Society of Clinical Oncology Clinical Practice Guideline Update. 17 January 2018. DOI: 10.1200/JCO.2017.76.6402
  7. Terpos E. et al. Soluble receptor activator of nuclear factor kappaB ligand-osteoprotegerin ratio predicts survival in multiple myeloma: proposal for a novel prognostic index. Blood. 1 August 2003. DOI: 10.1182/blood-2003-02-0380
  8. Croucher P.Iet al. Osteoprotegerin inhibits the development of osteolytic bone disease in multiple myeloma. Blood. 15 December 2001. DOI: 10.1182/blood.V98.13.3534
  9. Body J.J. et al. A phase I study of AMGN-0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases. Cancer. 1 February 2003. DOI: 10.1002/cncr.11138
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