Doseage Response of BMAs
Clinicians should consider decreasing the frequency of zoledronic acid dosing to 12 weeks (compared to the standard 4-week interval), as this is associated with non-inferior SRE outcomes and similar adverse event rates in patients with metastatic carcinoma or multiple myeloma. Clinicians should consider long-term use of BMAs to reduce skeletal related events in patients with multiple myeloma.

Rationale

The question of zoledronic acid (ZA) dosing interval, i.e. less frequent dosing, has been addressed in several non-inferiority trials, in breast cancer patients (Hortobagyi, 2017; Amadori, 2013), and in a heterogeneous cohort of patients with multiple myeloma and metastatic carcinomas (Himelstein, 2017).  These studies compared ZA 4mg dosed every 4 weeks to every 12 weeks, either upfront or after 12-15 months of 4-week ZA (Amadori, 2013).  In each study, SRE rates were similar between groups, as were adverse event rates. In one study including myeloma and breast cancer patients, ZA 4mg IV was found to be superior to pamidronate 90mg IV (Rosen, 2004).  ZA also has established efficacy in patients with non-small cell lung cancer and solid tumors other than breast and prostate carcinoma (Rosen, 2004).  The PICO question which guided the literature search did not yield information concerning denosumab that could be included.  Therefore, no recommendation regarding denosumab was included in the final Guideline.

It should be noted that there are other studies that did not meet the strict scope for inclusion that examine several established BMA options for prevention of SREs in patients with multiple myeloma and metastatic carcinoma.  Pamidronate 90mg IV every 3-4 weeks was found to reduce SRE's compared to placebo (Lipton, 2000; Hortobagyi, 1998). ZA 4mg IV was found to be superior to clodronic acid (Morgan, 2013). Denosumab was found to reduce risk of SREs, relative to ZA, in multiple tumor types (Lipton, 2012).  Adverse event profiles differ; denosumab was associated with higher rates of hypocalcemia, while zoledronic acid was associated with acute phase reactions and renal toxicity more often. Jaw osteonecrosis rates were similar. Studies evaluating longer dosing intervals are only available for ZA, not pamidronate or denosumab.

There are few studies designed to address the question of duration of treatment with BMA's. One study in multiple myeloma patients compared ZA treatment for 4 years to 2 years, and longer treatment was associated with lower SRE rates, with similar adverse events (Aviles, 2017).  Duration of treatment in a majority of the other BMA studies ranges from 1 to 3 years.Further discussion on the use of BMAs in multiple myeloma can be found in the updated American Society of Clinical Oncology (ASCO) CPG on the Role of Bone-Modifying Agents in Multiple Myeloma (Anderson, 2018).

Future Research

Future research may further explore questions of treatment duration and decreased dosing frequency, with regard to not only SRE's, but also cost effectiveness and quality of life.


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