The Antimyeloma Effects of Bone-Targeted Agents
There is strong preclinical evidence from various mouse models of multiple myeloma using injection of primary myeloma cells or the 5T2 multiple myeloma cell line to suggest that N-BPs such as zoledronic acid have anticancer activity including inhibition of angiogenesis, enhancement of antitumor immune responses, and direct or indirect modulation of the proliferation and survival of myeloma cells. This has been confirmed by a number of clinical trials showing that bisphosphonates improve survival and extend the time to progression in myeloma patients. These findings further support the notion that the interaction between myeloma cells and the surrounding bone marrow microenvironment (Figure 1) constitutes an important factor that needs to be taken into account in the development of novel therapeutic strategies.
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Figure 1.
Mechanisms of tumor-associated osteolysis in solid tumors and multiple myeloma. Tumor cells secrete different factors (such as PTHrP, PGE2, IL-1, IL-6, IL-8, and IL-11, M-CSF and MIP-1α) that stimulate osteoclast differentiation and maturation through the activation of the RANKL/RANK pathway (by increasing the ratio of RANKL to OPG). In solid tumors, metastatic cancer cells also directly interact with osteoclast precursors, promoting osteoclastogenesis through activation of the Jagged1/Notch signaling pathway. Moreover, tumor cells secrete components (DKK-1, and activin A) that inhibit osteoblast differentiation. This leads to enhanced bone destruction and, as a consequence, to the release of bone derived-factors (TGF-β) that stimulate tumor growth. There is therefore a "vicious cycle" whereby tumor cells stimulate osteoclast-mediated bone resorption, and growth factors released from resorbed bone stimulate tumor growth. Bone marrow stromal cells and immune cells are recruited to tumors and regulate tumor growth in bone. The drawings were produced using Servier Medical Art (www.servier.com). CCL3 = chemokine C-C motif ligand 3; DKK-1 = dickkopf-1; IL = interleukin; M-CSF = macrophage-colony stimulating factor; OPG = osteoprotegerin; PGE2 = prostaglandin E2; PTHrP = parathyroid hormone-related peptide; RANK = receptor activator of nuclear factor kB; RANKL = RANK ligand; TGF-β = transforming growth factor-β; VEGF = vascular endothelial growth factor.
In vivo, N-BPs may also affect progression of myeloma by blocking the release of cytokines and growth factors from the bone matrix, thereby breaking the "vicious cycle" of bone destruction and cancer growth. In addition, the anticancer effects of BPs have been demonstrated to have synergy with agents that are used in the treatment of myeloma, including dexamethasone, thalidomide, and bortezomib. Preclinical mouse models of myeloma indicate that the antimyeloma effect of N-BPs may be mediated via the inhibition of protein prenylation and consequent inhibition of the RAS-RAF-MAPK pathway, a mechanism of action not shared by non-N-BPs. Based on the preclinical theory and promising early results in patients, the MRC Myeloma IX trial, a large randomized trial was conducted to evaluate the role of BPs in 1960 patients newly diagnosed with myeloma and receiving either intensive (ie, high dose) chemotherapy with stem cell rescue or nonintensive (ie, standard dose) chemotherapy regimens; a summary of the trial design is presented in Table 1 . Patients were randomly assigned to receive either monthly zoledronic acid or daily oral clodronate. Patients treated with zoledronic acid had a better chance of survival with an improvement in median OS of 5.5 months compared with patients treated with clodronic acid (ie, sodium clodronate) (hazard ratio [HR] of death = 0.84; 95% confidence interval [CI] = 0.74 to 0.96; P = .04). Notably, the survival benefit with zoledronic acid, observed within the first 6 months, remained statistically significant after adjustment for SREs, and thus it was consistent with clinically meaningful antimyeloma activity.
In multiple myeloma, the interaction between bone marrow stem cells and myeloma cells results in increased expression of receptor activator of nuclear factor kappa B ligand (RANKL) and decreased production of the osteoclast inhibitor, osteoprotegerin (OPG), favoring bone resorption. Denosumab, a human neutralizing antibody against RANKL that mimics the endogenous effect of OPG, has been tested in patients with myeloma. Denosumab has been investigated in two phase II studies of patients with myeloma who were previously treated with BPs, and both studies confirmed its efficacy in reducing SREs. In one of the trials using denosumab as a single agent to treat plateau phase or progressive myeloma, patients showed no substantial reduction in tumor burden, but some patients with progressive disease experienced disease stabilization. More recently, Henry et al. reported the results of a phase III randomized trial that directly compared denosumab with zoledronic acid on skeletal morbidity and survival in patients with myeloma. Consistent with the other studies, denosumab was at least as effective as zoledronic acid in reducing the time to first SRE; however, in an unplanned analysis, the group treated with denosumab appeared to have a less favorable survival outcome (HR of death = 2.26, 95% CI = 1.13 to 4.50). Therefore, current findings indicate that both BPs and denosumab can effectively reduce SREs, but in multiple myeloma, denosumab may not have the antitumor activity of zoledronic acid.