Denosumab Increasingly Used in Myeloma Despite High Cost

Roxanne Nelson, RN, BSN

December 18, 2019

In a niche therapeutic area, a newer drug has captured 40% of the market within 15 months despite being no better — but far more costly — than an older drug.

The treatment is bone-directed therapy for use in patients with multiple myeloma (MM). 

"All patients with myeloma need a bone-strengthening agent," commented Arjun Gupta, MBBS, an oncology fellow at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland.

"There are essentially two options: zoledronic acid (Zometa, Novartis) which has been the standard for years, at a cost of $50 per dose, and denosumab (Xgeva, Amgen), which costs about $2500 per dose and whose approval was based on a noninferiority trial — not superiority," he continued.

While zoledronic acid is a bisphosphonate, denosumab has a novel mechanism of action that involves RANKL (receptor activator of nuclear factor kappa-Β ligand).

Denosumab was approved for the additional indication of preventing skeletal related events (SREs) in MM patients in January 2018.

New data show that in 15 months after this approval, denosumab was being used in 40% of patients, Gupta and colleagues report in a study published online December 12 in JAMA Oncology.  

A head-to-head comparison of the two drugs in more than 1000 MM patients has shown that denosumab was noninferior to zoledronic acid for time to SREs, and also showed that it reduced the risk for renal adverse events. Its use has increased even in patients without renal dysfunction.

Denosumab may have a role in patients with kidney dysfunction, Gupta suggested, adding that this drug may be be preferable for some patients. "Certain patients need it if they have an intolerance to Zometa or kidney dysfunction and it has helped my own patients," he said. "It's important to note that."

However, he also pointed out that denosumab "is not a panacea for use in kidney problems…in fact, the most serious kidney dysfunction was excluded from the trial."

"There is not any good data for denosumab in severe kidney disease and it can cause severe hypocalcemia in these patients," he cautioned.

The brisk uptake of this newer drug in just 15 months suggests that it is being prescribed to patients without contraindications to bisphosphonates, and who might do just as well with zoledronic acid, Gupta said.  

Noninferior and Pricey

The large head-to-head comparison of denosumab and zoledronic acid was presented in 2017 at both the American Society of Clinical Oncology annual meeting and the European Hematology Association (EHA) 2017 Congress, as reported by Medscape Medical News.

The results showed no significant differences between the two groups in terms of the median time to the first SRE, and no overall survival advantage for denosumab. An exploratory endpoint of progression-free survival showed a difference of more than 10 months favoring denosumab, and treatment-emergent adverse events occurred in similar rates in both groups.

The authors suggested that denosumab had the potential "to be the new standard of care for multiple myeloma-related bone disease."

But what is not mentioned was the huge difference in cost between the two agents, notes myeloma expert Vincent Rajkumar, MD, a professor of medicine and a hematologist/oncologist at the Mayo Clinic, Rochester, Minnesota.

It is not yet time to declare denosumab the new standard of care, he told Medscape Medical News. For "that much increase in cost, I would like to see a survival advantage," said Rajkumar. "So far, no such advantage has been shown."

Rajkumar is a coauthor with Gupta on the current study. 

A similar study had also questioned the use of denosumab in women with breast cancer and skeletal metastases. An analysis of data from the Cancer and Leukemia Group B (CALGB)/Alliance for Clinical Trials in Oncology trial 70604 found that the mean cost of denosumab vs zoledronic acid was nine times higher over a 2-year period, as previously reported by Medscape Medical News.

Even though denosumab was more efficacious in terms of delaying time to first SRE and time to subsequent events, "there is no survival difference," lead author Charles L. Shapiro, MD, professor of medicine, Icahn School of Medicine at Mount Sinai, New York City, emphasized at the time. "This is not strong enough [evidence] to make it a preference."

Soaring Usage

For their study, Gupta and colleagues used Medicare fee-for-service claims data from January 1, 2017 to March 31, 2019.

The team identified 15,872 MM patients (mean age, 72.7 years) who had a total of 329,595 person-months of follow-up. The overall rate of denosumab use prior to approval (in January 2017) was 3.8 doses per 1000 person-months and rose to 84.1 doses per 1000 person-months following approval.

Of the total number of bone-modifying agent doses, the percentage of denosumab doses increased from 0.1% throughout 2017 to 38.1% in March 2019.

For postapproval vs preapproval, the adjusted incidence rate ratio of denosumab use was 36.0 for patients without renal dysfunction and 17.9 for those with renal dysfunction.

Characteristics that were also associated with denosumab use included older age (85 to 94 years vs 64 years or younger; incidence rate ratio, 1.26) and residing in rural areas vs urban areas (incidence rate ratio, 1.12).

The study did not assess the reasons for the rapid rise in denosumab use, but Gupta speculated that it may be a case of "clinicians think 'new' equals 'better.' Nuance of noninferiority might be lost."

They may also be swayed by purported progression-free survival benefit, as reported in the head-to-head comparison. "This trial showed approximately 35 vs 46 months progression-free survival in the post hoc analysis," Gupta said. "It is likely less valid and a statistical anomaly per Dr. Rajkumar. If the time to SRE is 23 months and most SRE usually means progression, the progression-free survival seems to be too long."

Another issue with denosumab is that discontinuation is associated with rapid bone loss, and patients will likely require subsequent treatment with bisphosphonates to limit anticipated bone loss.

Issue of Patient Preference

There is also the issue of patient preference. Denosumab needs to be given more frequently (every month) but by subcutaneous injection, while zoledronic acid is given intravenously every 3 months and requires a 15 minute infusion at a center.

Patients without intravenous lines have expressed a preference for subcutaneous injections, "but for those who are getting chemo infusions for their myeloma anyway, the subcut versus IV is less of an issue," Gupta noted.

Commenting on the study, James E. Hoffman, MD, assistant professor of clinical medicine at the Sylvester Comprehensive Cancer Center, University of Miami, Florida, thinks that part of it has to do with patient preference — "a quick shot versus IV drip."

"But sadly, it's mostly reimbursement related," he said. "It costs more, and reimbursement is higher, and pushed by pharma reps."

As previously reported by by Medscape Medical News, the current system of Medicare Part B reimbursement for drugs poses a "financial conflict" for oncologists in choosing which drug to prescribe, argues Rajkumar.

He highlighted the issue with a Twitter post:


Not surprisingly, the tweet prompted a discussion that included a variety of opinions.

Rajkumar emphasized that his tweet was not about the merits of one drug vs another, or what the guideline said or didn't say, or about finding fault with colleagues. He wanted to highlight the current system. "It's the Medicare reimbursement model that needs to change. For this, laws and regulations need to change," he wrote on Twitter.

Gupta and Rajkumar have disclosed no relevant financial relationships. Several coauthors report relationships with industry. The full list can be found with the original article.

JAMA Oncology. Published online December 12, 2019. Abstract

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