Bisphosphonates in multiple myeloma: a fractured consensus

Lytic bone disease is the most common complication of symptomatic multiple myeloma (MM) and contributes to most morbidity associated with this disease [1]. The introduction and more routine use of bisphosphonates have altered the landscape of bone disease in myeloma as it has in other cancers with bone metastasis as a prominent complication. It has been known for over a decade that bisphosphonates reduce the risk of bone events in myeloma, but controversy still surrounds selection of the specific drug as well as the monitoring of bone disease and ideal duration and frequency of use of this class of drugs in MM [2]. The survival of patients with MM has significantly improved in the last decade, and is in no small part due to the improved supportive care, a major component of which is management of bone disease [3]. The Medical Research Council (MRC) IX randomized clinical trial unequivocally demonstrated a survival improvement with use of zoledronic acid compared with oral clodronate, irrespective of the presence of lytic disease [4]. Whether the incremental improvement in survival seen in this trial is still true in the setting of more effective therapies than the cyclophosphamide–thalidomide–dexamethasone (CTD) combination used in that trial is open to debate. While it answered the utility of an intravenous bisphosphonate over an oral one, it left unanswered whether zoledronic acid can be substituted with another intravenous bisphosphonate such as pamidronate, and what the ideal duration and frequency of administration should be and whether it can be guided by the activity of bone disease.

In the current issue, Sanfilippo and colleagues report the results of a retrospective study examining the pattern of use of bisphosphonates among veterans with myeloma as well as clinical outcomes [5]. They report a significant improvement in overall survival associated with the use of zoledronic acid compared with pamidronate in 1018 patients with newly diagnosed MM treated within the Veterans Health Administration system between 1 October 2002 and 30 September 2009. Employing sensitivity analyses and correcting for confounding factors, the authors clearly show a 22% reduction in the risk of death when treated with zoledronic acid. Interestingly, the authors were also able to demonstrate a reduced risk of skeletal related events with zoledronic acid compared to pamidronate by 25%.

Let us leave aside the question of which bisphosphonate to use, for an instant. What is clear is that every patient diagnosed with symptomatic myeloma requiring treatment should be started on an intravenous bisphosphonate. The clarity ends there. The current study indicates a survival improvement with the use of zoledronic acid, and in the context of the MRC data makes a convincing case for using zoledronic acid as the default choice. One of the concerns in this comparison has been the increased risk of osteonecrosis of the jaw (ONJ) with the use of bisphosphonate, and prior retrospective studies suggesting an increased risk associated with zoledronic acid compared with pamidronate [6]. Unfortunately, the current study could not address this issue conclusively, although it demonstrated a higher frequency of ONJ with zoledronic acid. Increasing awareness of this complication and active surveillance for its development appear to have decreased the overall risk of ONJ in the myeloma patient population. Patients should have a comprehensive dental evaluation prior to initiation of bisphosphonate followed by regularly scheduled dental care to minimize the risk of this dreaded complication. Another consideration in the choice of therapy is the presence of underlying renal dysfunction, which is common among patients with myeloma. Zoledronic acid should be used with the dose modifications as suggested based on renal clearance, or consideration should be given to the use of pamidronate in this circumstance.

The issue of ONJ is intricately tied in with the question of frequency and duration of bisphosphonate therapy, given the relatively long half-life and retention in the bone. The current American Society of Clinical Oncology (ASCO), Mayo Clinic and European Myeloma Network guidelines recommend 18 months to 2 years of therapy followed by less frequent dosing guided by disease activity [7–9]. This approach has not been validated in a prospective trial. While the MRC trial employed continuous use, it did not examine a shorter duration of therapy. While the current recommendation is monthly administration of the drug, this is clearly not based on randomized trials. Ongoing clinical trials are examining the question of bisphosphonate therapy guided by the use of bone disease activity markers. At least one clinical trial examined the use of 30 mg versus 90 mg of pamidronate and demonstrated no advantage to using the higher dose [10]. This also raises the question of the ideal dose intensity, given the long-term administration of this class of drugs. Recent reports have also raised the concern of atypical femur fractures in patients receiving long-term bisphosphonates, which is of increasing concern as patients with myeloma live longer with their disease [11]. Is there a happy medium of a lower dose administered less frequently, or bone marker guided dosing that will allow less cumulative dose and probably less likelihood of ONJ and other complications associated with long-term use? The dose intensity of bisphosphonates also needs to take into context the highly improved efficacy of current therapies. Of particular note is the osteoblastic activity associated with use of bortezomib, a commonly used therapy in MM, that has been demonstrated in vitro as well as in the clinical setting [12].

Given the potential catastrophic consequences of bone disease in MM, and increasing pivot toward earlier treatment of MM and intervention in smoldering MM (SMM), it is only natural that trials have started looking at the utility of bisphosphonates in patients with early stage disease. However, current evidence does not support the routine use of bisphosphonates in patients with SMM or monoclonal gammopathy of undetermined significance (MGUS), even in the presence of osteoporosis, where the use of bisphosphonates should follow the guidelines established for osteoporosis. Clearly, many questions remain unanswered with respect to the optimal treatment strategy with bisphosphonates in myeloma, but current guidelines regarding the routine use in all patients for at least 2 years should be followed until more data emerge to modify these.

Potential conflict of interest

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