3 – Therapy
Bisphosphonates: the mainstay of therapy
Bisphosphonates are pyrophosphate analogues that readily bind the exposed mineralized bone and are taken up by osteoclasts during bone resorption. They inhibit osteoclast recruitment and maturation, prevent the development of monocytes into osteoclasts, induce osteoclast apoptosis, and interrupt their attachment to the bone. Several organizations have provided recommendations for the management of MM with bisphosphonates [9–13].
Oral clodronate, intravenous pamidronate, and intravenous zoledronic acid have been licensed for the management of myeloma bone disease. All MM patients, with or without detectable osteolytic bone lesions in conventional radiography, who are receiving anti-myeloma therapy as well as patients with osteoporosis or osteopenia due to myeloma should be treated with bisphosphonates. Intravenous zoledronic acid and pamidronate exhibit comparable efficacy in reducing SREs in patients with MM, and are both recommended for preventing SREs in patients with active MM [14–16]. Moreover, zoledronic acid is preferred over oral clodronate because it is significantly more efficacious at preventing SREs and because of its potential anti-myeloma and survival benefit: zoledronic acid is the only bisphosphonate shown to increase survival in the whole studied population of a prospective randomized trial [17–19].
Bisphosphonates are recommended, at doses used in patients with osteoporosis, for patients with low and intermediate risk asymptomatic MM (AMM) or monoclonal gammopathy of undetermined significance (MGUS) if osteoporosis is identified by a dual energy X-ray absorptiometry (DXA) scan. For high-risk AMM or if one cannot differentiate between MM-related versus age-related bone loss, the treating physician should consider using dosing and schedule of bisphosphonates as with symptomatic MM, especially in patients with abnormal MRIs [20–22]. Bisphosphonate therapy is not indicated for patients with a solitary lytic lesion and no evidence of osteoporosis. However, these patients should have a whole body magnetic resonance imaging (MRI) to exclude systemic disease .
Bisphosphonates should be administered at 3- to 4-week intervals over a 2-year period in patients with lytic bone disease on plain radiographs and patients with osteopenia or osteoporosis, and then consideration for discontinuation should be made depending on patient demonstrating response or stable disease. According to the latest recommendations by the International Myeloma Working Group (IMWG) the use of zoledronic acid beyond 2 years and until disease progression is supported for patients not in complete remission or very good partial response (vgPR), because there are no data for survival or SRE advantages among patients achieving complete remission or vgPR. For those patients who discontinue bisphosphonate use after 2 years, the drug should be re-administered if relapse occurs .
Bisphosphonates adverse events
Even though bisphosphonate therapy is generally well tolerated in patients with MM, clinicians should be alert about symptoms suggesting adverse events and patients be instructed on how to recognize them. These include inflammatory reactions at the injection site and acute-phase reactions after intravenous administration of amino-bisphosphonates, gastrointestinal discomfort after oral administration, hypocalcemia, and hypophosphatemia. Renal impairment and osteonecrosis of the jaw (ONJ) represent infrequent but potentially serious adverse events with bisphosphonate use. Hypocalcemia is usually relatively mild and asymptomatic in most patients with MM treated with bisphosphonates, although severe hypocalcemia has been observed. Patients should routinely receive calcium and vitamin D3 supplementation . Calcium supplementation should be used with caution in patients with renal insufficiency.
Intravenous bisphosphonates have the potential to cause acute or chronic renal dysfunction [25,26]. All treated patients should have creatinine clearance (CrCl), serum electrolytes, and urinary albumin monitored. Zoledronic acid and clodronate dosages should be reduced in patients who have pre-existing renal impairment (creatinine clearance of 30–60 mL/min) . Zoledronic acid and pamidronate have not been studied in patients with severe renal impairment (CrCl <30 mL/min) and are not recommended in this setting. Pamidronate 90 mg infused over 4–6 hours is recommended for patients with extensive bone disease and existing renal impairment. Bisphosphonate therapy can be resumed, after withholding zoledronic acid or pamidronate in patients who develop renal deterioration during therapy, when serum creatinine returns to within 10% of baseline.
ONJ is a rather uncommon but potentially serious complication of intravenous bisphosphonates, characterized by the presence of exposed bone in the mouth. The incidence may vary from 2 to 10% and increases with longer exposure [27,28]. The major risk factor is invasive dental procedures, while minor risk factors include poor oral hygiene, age, and duration of myeloma. Preventive strategies should be adopted to avoid ONJ. Patients should receive a comprehensive dental examination and be educated regarding optimal dental hygiene. Existing dental conditions should be treated before initiating bisphosphonate therapy . Temporary suspension of bisphosphonate treatment for 90 days before and after invasive dental procedures (tooth extraction, dental implants and surgery to the jaw) should be considered. Bisphosphonates do not need to be discontinued for routine dental procedures including root canal. Initial treatment of ONJ should include discontinuation of bisphosphonates until healing occurs. The decision to restart bisphosphonates should be individualized, especially in the relapsed/refractory MM setting . Table 6.1 includes the most recent recommendations of the IMWG regarding the use of bisphosphonates in myeloma bone disease.
Kyphoplasty and vertebroplasty
Balloon kyphoplasty should be considered for symptomatic vertebral compression fractures and is the procedure of choice to improve quality of life in patients with painful fractures. The role of vertebroplasty for myeloma patients is less clear as there is no randomized trial of vertebroplasty in myeloma patients [30,31].
Low-dose radiation therapy (up to 30 Gy) can be used as palliative treatment for uncontrolled pain, for impending pathologic fracture, or impending SCC. Upfront external beam radiation therapy should be considered for patients with plasmacytoma, extramedullary masses, and SCC. However, the use of radiotherapy for local disease control and palliation should be used judiciously and sparingly depending on the patient’s presentation, need for urgent response, and prior treatment history and response. It should be limited as much as possible to spare the patient’s marrow function, since current novel agents work rapidly and should decrease the need for palliative radiotherapy .
Orthopedic consultation should be sought for impending or actual long-bone fractures, bony compression of the spinal cord, or vertebral column instability. Consideration and indications for surgery should be done in consultation with the treating oncologist/hematologist and the orthopedic and neurosurgeon to determine when MM treatment can be safely restarted .
Table 6.1 International Myeloma Working Group recommendations for the use of bisphosphonates in multiple myeloma.
CLO, clodronate; CR, complete response; IV, intravenous; MM, multiple myeloma; PAM, pamidronate; VGPR, very good partial response; ZOL, zoledronic acid. Reproduced with permission from © American Society of Clinical Oncology, 2013. All rights reserved. Terpos et al .
Agents interfering with bone marrow microenvironment
RANKL–RANK pathway regulators: targeting the osteoclast
RANKL is overexpressed in the marrow microenvironment by myeloma cells and stromal cells, while OPG is downregulated and further degraded by myeloma cells in patients with MM. The net result is an increased RANKL/OPG ratio in the bone marrow microenvironment that enhances osteoclast differentiation and function, leading to bone lytic disease , rendering RANKL a desirable target for the development of a novel therapeutic agent for diseases of bone homeostasis. Denosumab is a fully human monoclonal antibody that specifically inhibits primate RANKL with high affinity and specificity and inhibits RANKL–RANK interaction, mimicking the endogenous effects of OPG. Several trials in patients with MM or solid tumor-induced osteolytic disease have demonstrated efficacy of denosumab in decreasing bone resorption [33,34].
Activin is an osteoclast agonist that is involved in osteoclast development and differentiation through stimulation of RANK expression as well as an osteoblast antagonist. Its levels are elevated in the serum of patients with MM and correlate with features of advanced disease, extensive bone involvement, and inferior survival [4,5]. Sotatercept is a fusion protein of the extracellular domain of the high-affinity activin receptor IIA and human immunoglobulin G (IgG). Sotatercept treatment demonstrated clinically significant increases in biomarkers of bone formation, decreases in bone pain, and anti-tumor activity as well as increase in hemoglobin levels in patients with osteolytic bone lesions due to MM compared with placebo .
Wnt pathway regulators: helping the osteoblast
DKK-1 plays an important role in the dysfunction of osteoblasts observed in MM. Serum DKK-1 is increased not only in symptomatic MM patients at diagnosis and but also in relapsed MM, correlating with advanced disease features and the presence of lytic lesions . BHQ880, a phagederived IgG antibody, the first-in-class, fully human anti-DKK-1 neutralizing antibody in combination with zoledronic acid and anti-myeloma therapy, was well tolerated and demonstrated potential clinical activity in patients with relapsed or refractory multiple myeloma in a Phase IB multicenter dose-determination study .
Sclerostin is another Wnt inhibitor, specifically expressed by osteocytes, which inhibits osteoblast-driven bone formation and induces mature osteoblast. Elevated circulating sclerostin correlates with advanced disease features and abnormal bone remodeling in symptomatic myeloma . Romosozumab, an investigational humanized monoclonal antibody that inhibits the activity of sclerostin, was associated with increased bone mineral density and bone formation, and with decreased bone resorption in postmenopausal women . Studies in MM are planned to start soon.
Novel antimyeloma agents and myeloma bone disease
Bortezomib is a first-in-class proteasome inhibitor with well-established activity against myeloma. It also affects osteoclast differentiation and function in a dose-dependent manner, reducing subsequent bone resorption. In addition, bortezomib may also increase osteoblast activity, inducing new bone formation [39–41]. Another proteasome inhibitor, carfilzomib, has been reported to increase bALP in patients with relapsed⁄refractory MM that responded to therapy . These findings suggest that proteasome inhibition in addition to their antineoplastic effects on tumor cells, may directly stimulate osteoblast differentiation and function, and lead to increased bone formation and bone mineral density, at least in responders (see Figure 6.1). However, it is unclear if bortezomib alone is sufficient to reverse bone disease in MM patients and heal lytic lesions.
Thalidomide, lenalidomide, and pomalidomide are highly active agents in the treatment of both newly diagnosed and relapsed/refractory MM . These agents activate cellular and innate immunity, enhance humoral anti-tumor immune responses, induce antiangiogenesis, inhibit cytokines, modify the interactions between malignant plasma cell and the bone marrow microenvironment, and alter abnormal bone metabolism in MM. An intermediate dose of thalidomide in combination with dexamethasone in relapsed/refractory MM patients has been reported to reduce sRANKL/OPG ratio and bone resorption markers (CTX and TRACP-5b) but showed no effect on bone formation, as assessed by serum levels of bALP and osteocalcin, and no healing of the observed lytic lesions . Lenalidomide also produced a reduction of CTX and sRANKL/OPG only in responders, while non-responders had increased TRACP-5b serum levels after three cycles of treatment compared with baseline. In both responders and non-responders, there was no effect on bone formation .