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Bisphosphonates underused among older patients with myeloma
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SAN DIEGO — Only about half of Medicare beneficiaries with myeloma received recommended treatment with bone-modifying agents, according to results of a population study presented at ASH Annual Meeting and Exposition.
Patients who used bone-modifying agents — such as zoledronate, pamidronate or denosumab (Prolia/Xgeva, Amgen) — demonstrated a reduced risk for skeletal-related events and improved OS.
“Our motivation [for conducting this research] came from our prior research in multiple myeloma, in which we observed variation in the use of myeloma therapy according to insurance-related factors,” Adam J. Olszewski, MD, assistant professor at Alpert Medical School of Brown University, told HemOnc Today. “We were interested to see if parenteral bone-modifying agent use may differ according to nonclinical factors and various types of therapy (sometimes all oral), and if we could reproduce the results of a clinical trial in the population setting.”
Guidelines from the International Myeloma Working Group and ASCO recommend use of bone-modifying agents for all patients initiating therapy for myeloma. Trials have shown these agents reduced the risk for skeletal-related events and are associated with improved OS.
Because adherence to these recommendations in clinical practice was unknown, Olszewski and colleagues examined the use of bone-modifying agents among Medicare beneficiaries with myeloma using the SEER-Medicare database.
The analysis included 4,670 patients (median age, 76 years; 50% women) diagnosed with myeloma between 2007 and 2013. All patients had complete Medicare claims and received outpatient chemotherapy.
Median follow-up from the start of chemotherapy was 4.6 years.
Fifty-one percent of patients received a bone-modifying agent within 90 days of starting chemotherapy. Among them, 83% received zoledronate, 16% received pamidronate and 1% received denosumab.
“This number is somewhat staggering,” Olszewski said during his presentation. “This is a subgroup of patients who are older with comorbidities, and yet they were selected for active anti-myeloma therapy. There are really few contraindications for bisphosphonates, especially now that denosumab is available.”
The median number of doses of a bone-modifying agent was five (interquartile range [IQR], 3-6) within 6 months, and nine (IQR, 5-11) within 12 months from chemotherapy initiation, indicating the intent for monthly treatment, Olszewski said during his presentation.
Results of a multivariable analysis showed that, compared with patients aged younger than 70 years, omission of bone-modifying agents was significantly more likely among those aged 80 to 84 years (RR = 1.11; 95% CI, 1.01-1.23) and 85 years or older (RR = 1.16; 95% CI, 1.05-1.29).
Patients with a higher number of comorbidities also were less likely to receive a bone-modifying agent. For instance, omission of bone-modifying agents was 17% (RR = 1.17; 95% CI, 1.07-1.28) more likely among those with chronic kidney disease, 13% (RR = 1.13; 95% CI, 1.06-1.21) more likely among those with anemia and 29% (RR = 1.29; 95% CI, 1.15-1.45) more likely among those with end-stage renal disease.
Omission appeared significantly less likely among patients with a prior skeletal-related event (RR = 0.7; 95% CI, 0.62-0.79) — defined as axial or extremity fracture, or cord compression — those with hypercalcemia (RR = 0.75; 95% CI, 0.66-0.85) and those who underwent radiation (RR = 0.7; 95% CI, 0.61-0.81).
Omission also was less likely among patients who received bortezomib with an immunomodulatory antimyeloma drug compared with other treatment regimens (RR = 0.84; 95% CI, 0.74-0.94).
One possibility as to why researchers observed this low compliance rate is that “either clinicians or patients are reluctant to administer IV therapy, which comes with an additional burden of visits and injections, whereas most of antimyeloma therapy is delivered as oral or subcutaneous drugs,” Olszewski told HemOnc Today. “However, data presented at ASH this year suggest that a pharmacist intervention may improve the rates of bone-modifying agent delivery, so perhaps the benefit of this supportive therapy seen in trials needs ongoing emphasis for clinicians and patients alike.”
In total, 729 patients experienced a skeletal-related event, for a cumulative incidence function (CIF) of 13.6% (95% CI, 12.2-15). Estimated 3-year CIF of a skeletal-related event was 11.2% among patients who received a bone-modifying agent and 14.1% among those who did not.
Patients who received a bone-modifying agent demonstrated a significantly reduced risk for a skeletal-related event in the entire cohort (subhazard ratio [SHR] = 0.83; 95% CI, 0.7-0.98) and in a propensity score-matched subcohort of 3,152 patients (SHR = 0.78; 95% CI, 0.64-0.94).
Median OS was 3.1 years (95% CI, 2.9-3.2) in the total cohort.
Patients who received a bone-modifying agent experienced improved OS (adjusted HR = 0.84; 95% CI, 0.77-0.92), but survival did not significantly differ according to type of agent.
“This effect has been observed in randomizes trials, so it likely indicates primary antimyeloma activity — possibly through bone microenvironment — or the effect on patients’ skeletal health, as fractures and other skeletal-related events have a significant impact on patients’ functional status, and possibly the overall clinical course,” Olszewski told HemOnc Today. “Of course, our study is observational, so it is possible that there were unobserved differences between groups responsible for the survival difference.”
Research should focus on understanding barriers to the appropriate use of supportive care in myeloma and interventions to improve compliance with guidelines, Olszewski said.
“It will be also interesting to see in the future if the wider availability of denosumab — with its approval in myeloma in 2018 — might provide an option for patients who were not eligible or opted out of treatment with intravenous bisphosphonates,” he added. – by Alexandra Todak
Reference: Olszewski AJ, et al. Abstract 709. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018.
Disclosures: Olszewski reports research funding from Genentech, Spectrum Pharmaceuticals and TG Therapeutics, and a consultant role with Spectrum Pharmaceuticals. One other author reports research funding from Pfizer and Takeda Oncology, and honoraria from Alexion.
Perspective
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Jason Valent, MD
The use of bisphosphonates is associated with a lower risk for skeletal-related events, which have complications in and of themselves that can impact even survival of the patient. If a patient has a femur fracture, for instance, and ends up with a blood clot in their leg and a pulmonary embolism, that can be fatal and is the most dreadful complication of these events. Skeletal-related events also add to the morbidity of patients in terms of pain in particular. Spinal fractures are very common and don’t heal particularly well, so prevention is really the mainstay of treatment. The morbidity and the mortality associated with a skeletal-related event is why it’s so important to try to prevent them with bisphosphonates.
ASCO and International Myeloma Working Group guidelines state to use an agent — whether it’s zoledronic acid, pamidronate or denosumab — monthly for at least 2 years for the bisphosphonates, and then to consider extending that treatment depending on the status of the patient’s disease. In theory, all patients diagnosed with myeloma should be placed on a bone-modifying agent.
It would have been interesting if this paper could have evaluated patients who specifically had bone disease identified by imaging at diagnosis. For patients without identifiable bone disease at diagnosis, there may not be as much benefit to bone-modifying agents. Do those patients really need a bone modifying agent? The answer according to the guidelines, is yes. But you may not prevent as many skeletal-related events in someone who doesn’t have identifiable bone disease. This may have financial impacts in a Medicare system.
The proportion of patients who received a bisphosphonate in this analysis was stunning in a bad way; 51% is awful. I couldn’t hypothesize a good rationale as to why the number would be so high. If 15% to 20% of patients were not receiving a bisphosphonate, you could argue that those were the patients who did not have bone disease at diagnosis. As a myeloma doctor, it may be easier for us to include the bone-modifying agent as we do this every day. I am sure that there are some patients that we miss, but usually that is resolved by month 2 of therapy.
Another thing that is very interesting about this study is the absolute difference in skeletal-related events — 14% with nontreatment vs. 11% with a bisphosphonate. From a Medicare standpoint, those data indicate the number needed to treat is 35 to prevent one skeletal-related event. From a cost-effective standpoint, that’s not ideal. This is where it may have helped to just analyze patients who had identifiable bone disease, but perhaps it was hard to pick them out of the data. I would expect a larger difference between treatment and nontreatment groups if you were just looking at the group with identifiable bone disease. This may reduce the number needed to treat.
We’ve been looking at use of bone-modifying agents at our own institution as a quality measure. We have found that doctors are very good about explaining the chemotherapy, and we don’t focus as much on supportive care. In theory, bone-modifying agents should not be considered supportive care, they should be considered part of the patient's therapy. We had not prioritized bone modifying agents like we should be, similar to what is seen in this study. Thus, one of the big explanations is that people just don’t prioritize it the same way they do chemotherapeutics. This is what I speculate would be the cause of a 49% nonuse rate. Another approach to improve compliance would be to use the electronic health record. If you enter a diagnosis of multiple myeloma, you can build in a stop that you cannot close the record until you put in the order for a bisphosphonate. That would be a safeguard you could build in from an institutional standpoint to make sure you aren’t missing this.
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