Denosumab as a well-tolerated and effective bone targeting treatment option for multiple myeloma patients with osteolytic lesions
Multiple myeloma (MM) is a plasma cell malignancy with approximately 150,000 new cases globally each year.1 In 2016, approximately 270 new cases were reported in Hong Kong.1 As the second most frequent hematological disease worldwide, MM accounts for 0.9% of all new cancer cases and 1.1% of all cancer deaths in the world in 2018.2 With bone destruction being one devastating consequence of MM, conventional bone targeting agents such as intravenous (IV) pamidronate disodium and zoledronic acid are prescribed to manage osteolytic lesions in MM patients. However, conventional bone targeting agents are contraindicated in patients with renal dysfunction and limited by the route of administration. In a recent interview with Omnihealth Practice, Dr. Wong, Siu-Ming Raymond, Head of Division of Haematology, Department of Medicine & Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, shared his insights in using denosumab to manage MM patients with osteolytic lesions in particular to those with chronic renal impairment when no other bone targeting treatment options are available.
Burden of multiple myeloma in Asia
Characterized by osteolytic lesions, renal dysfunction, hypercalcemia, anemia, reduced levels of normal immunoglobulins, and increased infection risk, MM is a life debilitating disease where bone destruction is one potential devastating consequence that correlates with tumor burden and prognosis.1 Compared to the Western population, Asian MM patients tend to have more advanced diseases due to delayed diagnosis that can be attributed to the difference in the coverage of the local healthcare system, accessibility to healthcare and frequency of screening. In a recent observational study conducted in China, the age-standardized mortality rate of lymphoma and myeloma was estimated to be 3.74 per 100,000 population in China in 2017, which was markedly higher than the rate of 2.60 per 100,000 population in the world.2 In fact, the mortality rate of lymphoma and myeloma in China has been increasing annually by 4.5% from 2004 to 2016.2
In Hong Kong, many MM patients are diagnosed at advanced stage due to the non-specific symptoms of MM. From clinical experience, some patients were presented with back pain only and was not speculated of MM until severe systemic involvement such as end organ damage and worsening of kidney function are observed. While MM is considered an indolent disease, the delayed diagnosis until advanced disease state often translates to a higher tumor burden that results in an increased number of complications at diagnosis and an increased risk of osteolytic lesions.
Current treatment landscape for multiple myeloma patients with osteolytic lesion
To determine whether a MM disease case is active, a skeletal survey with X-ray is often used to confirm the presence and extent of osteolytic lesion in a MM patient. For better assay sensitivity, magnetic resonance imaging (MRI), positron emission tomography (PET) and the recently introduced low dose computed tomography (CT) can also be used. The presence of osteolytic lesion indicates that the MM is active and serves as a strong indication for treatment initiation. Conventionally, bone targeting treatment such as IV bisphosphonates, including zoledronic acid and pamidronate disodium, will be prescribed immediately to prevent or delay life debilitating skeletal-related events (SRE) including pathological fractures, spinal cord compression, and time to radiotherapy or surgery to the bone. In MM patients who are experiencing severe pain due to osteolytic lesions, locoregional radiotherapy can be used for pain relief and symptomatic control.
While this standard of care procedure has shown good results in the past, IV zoledronic acid is contraindicated in patients with severe renal impairment (eGFR <30mL/min).3 If renal toxicity is observed, IV bisphosphonates should be withheld or withdrawn to prevent further renal damage. The unmet needs of IV bisphosphonates have further been highlighted during the COVID-19 pandemic. Due to the IV administration route, patients are required to regularly visit hospitals or ambulatory day centres in Hong Kong for drug administration. Patients are now increasingly unwilling to visit hospitals and clinics to reduce risk of contracting COVID-19. Based on the limitations in patient selection and route of administration of IV bisphosphonates, an alternative treatment option without these undesirable restrictions would be desirable to better manage MM patients with osteolytic lesions.
Denosumab as a promising bone targeting agent in renal impaired patients
Denosumab is a fully human monoclonal antibody against the receptor activator of nuclear factor kappa-β ligand (RANKL), an important regulator of osteoclast-mediated bone resorption.4 Through the inhibition of osteoclast formation, function and survival, bone resorption can be decreased and in turn increases the bone mass.5
In the treatment of MM patients with osteolytic lesion, prevention, or delay to SRE is the major treatment goal to prevent further morbidity or mortality. In a phase 3 international, double-blind, randomized controlled trial with 1,718 patients enrolled, denosumab was demonstrated to be noninferior to zoledronic acid for the time to first SRE (HR=0.98; 95% CI: 0.85-1.14, pnoninferiority=0.010) with similar incidence in ≥grade 3 treatment-emergent adverse events (Figure 1A).6 Most notably, the incidence in osteonecrosis of the jaw (ONJ) was not significantly different between the denosumab and zoledronic acid groups (4% vs. 3%, p=0.147).6 To further explore the benefit of denosumab, a post-hoc landmark analysis at 15 months was conducted and showed that denosumab was superior to zoledronic acid for the time to first SRE (HR=0.66; 95% CI: 0.44-0.98; p=0.039) (Figure 1B).6
In another meta-analysis of three randomized controlled trials with a total of 5,544 patients with advanced solid tumors and bone metastases, denosumab was shown to be superior to zoledronic acid in delaying the time to first on-study SRE (OR= 0.82; 95% CI: 0.75-0.89, p<0.0001) and multiple SREs (RR=0.81; 95% CI: 0.74- 0.88, p<0.0001).7 Interestingly, a subgroup analysis among Asian patients revealed that there is a trend of fewer Asian patients in the denosumab group developing first on-study SRE when compared to the zoledronic acid group (38.8% vs 50.5%, HR=0.77; 95% CI: 0.48-1.26) (Figure 2).1 Based on these evidence, denosumab was included into the Hong Kong public hospitals drug formulary and has expanded the number of bone targeting treatment options available for MM patients with osteolytic lesions.
Unlike the conventional IV bisphosphonates, denosumab is administered through subcutaneous injection and does not require additional hospital stay. With sufficient training, denosumab can be conveniently administered by local community nurses. While improvement including pain relief may not be immediate, restoration of bone density will provide long-term improvement in quality of life as an added benefit to the ability to avoid complications of SRE. As a monoclonal antibody-based treatment, denosumab is also associated with lower renal toxicity and can be administered with no dose adjustments needed for patients with renal impairment. Whereas IV bisphosphonate and zoledronic acid are contraindicated in patients with acute renal dysfunction, denosumab is in fact recommended by the European Society for Medical Oncology (ESMO) clinical practice guidelines for bone health in cancer as the agent of choice in MM patients with an eGFR <60mL/min.8 Given its convenient route of administration and non-inferiority to conventional bone targeting agents, denosumab is a well-tolerated and effective alternative to bisphosphonate and zoledronic acid to effectively prevent or delay SRE and meet the previously unmet need of osteolytic lesion treatment in renal impaired MM patients.
Denosumab in the local clinical setting
According to current clinical guidelines, the American Society of Clinical Oncology (ASCO) recommends initiating bone-modifying agents for MM patients who, on plain radiograph or other imaging studies, havelytic destruction of the bone or compression fracture of the spine from osteopenia; the National Comprehensive Cancer Network (NCCN) recommends bone-modifying agents for all patients receiving myeloma therapy for symptomatic disease regardless of documented bone disease.3,9 Where the ASCO guidelines intend to avoid overtreatment in MM patients who do not have bone diseases including osteolytic lesions, the NCCN guidelines intend to prevent any potential SRE given the small percentage of MM patients who do not have bone disease.
In Hong Kong, imaging techniques are routinely used to detect osteolytic lesions regardless to determine whether MM is active or not and to serve as a strong indication to initiate MM treatment. In certain MM patients such as smouldering myeloma cases where diagnosis is not clearly distinguished, the presence of osteolytic lesion despite the lack of symptoms including renal damage, anemia or hypercalcemia, can still confirm the activeness of MM. In this case, bone targeting therapy should be initiated early to help prevent or delay the critically life debilitating SRE. Particularly, denosumab has demonstrated safety and effectiveness in treating MM patients with osteolytic lesions and should be prescribed in patients with chronic renal impairment when no other bone targeting treatment options are available. In fact, the ESMO clinical practice guideline has recommended denosumab as the agent of choice in MM patients with renal impairment.8
Where IV bisphosphonates are recommended to continue for a period of up to 2 years, denosumab is not recommended to be stopped abruptly due to its reversible mechanism of action.3 In clinical practice, most MM patients would complete MM induction treatment by 2 years and would be placed on maintenance therapy with oral treatment by then. Given the risk of developing ONJ with the prolonged use of IV bisphosphonate and zoledronic acid, osteolytic treatment plan should be reviewed after 2 years of treatment initiation. If patient is at stable disease, IV bisphosphonates treatment should be stopped and only be resumed upon relapse with new-onset SRE.3 On the other hand, clinical experience have demonstrated reasonable long-term safety of denosumab beyond the 2-year treatment period and denosumab can be used continuously to manage the risk of osteolytic lesions with appropriate monitoring.
Case sharing: Patient’s decision to use denosumab when choices are available
To illustrate the use of denosumab in the real-world setting, a 82-yearsold female patient presented with active MM and symptoms of anemia in early 2020 was shown to have multiple osteolytic lesions by skeletal survey. As the patient had acceptable kidney function with eGFR of above 30mL/min, she was given the choice between zoledronic acid and denosumab to manage her osteolytic lesions. Upon clarifying that the use of zoledronic acid would require ambulatory day center admissions every 4 weeks for administration, the patient had expressed concern and wished to reduce hospital exposure during the COVID-19 pandemic. Instead, the patient preferred the convenient denosumab as it required only subcutaneous injection every 4 weeks. While being suitable for both treatment options, denosumab was ultimately selected by the patient as the treatment of choice based on the convenience of administration route. This choice highlights the importance of patient acceptance as well as denosumab’s safety and effectiveness as a treatment alternative to the conventional bone targeting agents.
MM is the second most frequent hematological disease worldwide and the presence of osteolytic lesions in MM indicates that the disease is active and serves as a strong indication for treatment initiation. Conventionally, IV bisphosphonates are prescribed to help prevent or delay SRE. However, the unmet needs in the contraindications in renal impaired patients and the requirement to visit hospitals to administer these bone targeting agents have prompted the use of denosumab to better manage MM patients with osteolytic lesions. With demonstrated noninferior efficacy and similar safety profile to zoledronic acid, denosumab is a well-tolerated, effective and convenient treatment in MM patients with osteolytic lesions in particular to those with chronic renal impairment when no other bone targeting treatment options are available.
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