Bortezomib has become a staple in the multiple myeloma (MM) treatment landscape. The antineoplastic agent was first approved by the US Food and Drug Administration (FDA) in 2003,1 and by the European Union in 2004,2 based on results from the phase II SUMMIT trial. It even landed a spot on the World Health Organization’s Model List of Essential Medicines in 2019, which lists “the most efficacious, safe, and cost-effective medicines for priority conditions.”3
Due to its long-standing efficacy, Rahul Banerjee, MD, an Assistant Professor in the Clinical Research Division at the Fred Hutchinson Cancer Center in Seattle, Washington, described bortezomib as the “mainstay” of MM therapies, particularly in the newly diagnosed setting.
However, for 21 years, the standard of care (SOC) for bortezomib has remained largely the same: twice-weekly injections for two out of every three weeks or three out of every four weeks.
“That’s just how the initial studies of this medication were done,” Dr. Banerjee said. “Historically, clinical trials have been based on the model of the original chemotherapy studies from decades ago that were singularly focused on the idea of the maximum tolerated dose. The thought was always that bigger is better, and more often is better.”
However, recent scientific literature reveals the benefits of decreasing the bortezomib dose. A 2020 trial led by Joselle Cook, MBBS, a hematology specialist at the Mayo Clinic in Rochester, Minnesota, investigated outcomes with different administration schedules of bortezomib in combination with lenalidomide and dexamethasone. The overall response rate was 73% with once-weekly administration versus 66% with twice-weekly, while the progression-free survival (PFS) was 36.2 months with once-weekly versus 38.9 months with twice-weekly.4
To understand perceptions of how bortezomib should be dosed, Dr. Banerjee and colleagues conducted a global online survey of 217 clinicians. Over 90% of respondents prefer once-weekly bortezomib for their patients due to comparable responses and less neuropathy.5
“A more accurate definition of SOC regimens involves how typical physicians in the field would approach a given situation,” Dr. Banerjee and colleagues wrote.5
Now, myeloma experts are brainstorming strategies to shift the SOC and redesign clinical trials to match how they want to treat patients.
Once-Weekly Versus Twice-Weekly Bortezomib
A 2023 study co-led by Fieke Hoff, MD, PhD, a Resident Physician at the University of Texas (UT) Southwestern Medical Center, and Dr. Banerjee investigated bortezomib dosing patterns in the United States. Of 2,522 patients, 927 (36.8%) received twice-weekly bortezomib and 1,522 (63.2%) received once-weekly bortezomib. There were no significant associations between gender, International Staging System stage, practice setting, insurance category, or baseline creatinine.6
Replicating previous data, there were no statistically significant differences in real-world PFS between the two cohorts (37.3 months with once-weekly vs 39.2 months with twice-weekly).6
“The main additional factor we wanted to study was neuropathy,” said Gurbakhash Kaur, MD, an Assistant Professor in the Department of Internal Medicine at UT Southwestern Medical Center and senior author of the study. “We found that peripheral neuropathy incidence was 18.5% with once-weekly and 34.7% with twice-weekly bortezomib. That is one of my main factors in dosing this medication.”
Similarly, a 2017 trial led by Surbhi Sidana, MD, an Assistant Professor at Stanford University School of Medicine, found that “lower neuropathy risk translated into longer treatment duration” when subcutaneous bortezomib was administered weekly.7
While improved safety and comparable efficacy are the main reasons clinicians are pushing for dose reductions, they also believe that convenience should be factored into the equation.
“It’s much more convenient for patients who come from long distances to come to the clinic to get their therapy once a week versus twice a week,” said Thomas Martin, MD, Clinical Research Director at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center.
In fact, some patients travel up to 300 miles for treatment at his center. “Sometimes, it’s a two-day adventure,” Dr. Martin continued. “They drive up the day before to get their therapy, then after therapy they drive home that whole next day. It’s a full-time job, and it’s very difficult.”
Once-weekly visits to a treatment center are not only more convenient, but they also boost patient compliance. When given the option, patients will choose a treatment once every two weeks versus once a week, Dr. Martin explained.
In their 2023 published paper, Dr. Banerjee and colleagues reported that 93% of the clinicians they surveyed agreed that their patients preferred once-weekly bortezomib administration over twice-weekly.5
“Having someone come in once a week for an injection works just fine in terms of efficacy,” Dr. Banerjee added.
A Modern Era of Myeloma Treatment
If once-weekly bortezomib is safer, more convenient, and just as efficacious as twice-weekly, then why is the SOC unchanged?
“You would think that the die has been cast, the game has been won, the world should be using once-weekly bortezomib. Unfortunately, that’s not the case,” Dr. Banerjee said.
In fact, about a third of patients are still receiving twice-weekly dosing. Dr. Banerjee believes this is because the oncologist either hasn’t seen the data or doesn’t know the dosing can be changed.
Fifty-nine percent of clinicians surveyed by Dr. Banerjee and colleagues were aware of at least one study showing comparable PFS with the two dosing cohorts, and 63% were aware of studies showing less neuropathy with once-weekly dosing.5
“I’ve had scenarios where physicians have come to me and said, ‘I agree with you, but my pharmacist won’t let me change it because it’s not what’s been studied in the trials.’ Pharmacists are busy, and the chemotherapy order sets are typically copied and pasted from the trial and put into the chemotherapy plans,” Dr. Banerjee explained.
However, Dr. Banerjee urged clinicians to act. “You are allowed to deviate from the historical trial to do what makes the most sense for the patient sitting in front of you,” he said. “Once-weekly bortezomib is the way to do that.”
Dr. Kaur provided additional insight into how clinicians make dosing decisions for their patients.
“When doctors are dosing, we look at references and clinical trial data. If the data aren’t there, then it’s less likely to be done that way,” she said. “Many practices have pathways they use to select the regimens, and [clinicians] need to work with [their] pharmacy team to change the dosing of drugs.”
While this offers a quick fix, once-weekly bortezomib is still firmly rooted as the SOC in MM.
“The most long-term solution is really to change our trials,” Dr. Banerjee said. “The issue here is not physicians doing anything wrong, but that our trials are not matching how we actually want our patients to receive therapy.”
Now that clinicians have figured out the what and the why of bortezomib dosing, they’re stuck on the how. After all, redesigning clinical trials may be easier said than done.
“It’s been frustrating,” Dr. Banerjee admitted. “It’s a systems issue. I’m not faulting community physicians at all, but a lot of our partners in industry are reluctant to move to once-weekly bortezomib. The FDA is seemingly not willing to budge on what is defined as the [SOC], because they haven’t seen trials of once-weekly bortezomib. It’s a circular logic. We’re kind of stuck.”
However, Dr. Banerjee has hope that his survey will drive change in the field without the need for a clinical trial. In fact, such a practice-changing feat has been achieved before. Without as much clinical trial data, subcutaneous bortezomib has been adopted as the SOC due to less neuropathy than intravenous bortezomib. This change is owed to a medical error in France, in which a patient accidentally received subcutaneous bortezomib, Dr. Martin explained.
“We’re hoping to see the same with bortezomib dosing,” Dr. Banerjee said. “There’s no reason for clinical trials to keep getting stuck in this way of the past.”
The Only Exceptions
When clinicians were asked if there are any instances in which patients should receive twice-weekly dosing, acute cast nephropathy shone through.5
“For patients who are having kidney failure because of the myeloma churning out these light chains, that is a very reasonable scenario in which to use twice-weekly bortezomib,” Dr. Banerjee explained, “but only for that first cycle. As soon as the kidneys are improving, [patients] should move to once-weekly dosing.”
There wasn’t a large uptick of physicians who felt that twice-weekly bortezomib should be administered purely based on cytogenetic risk, he elaborated.
Twice-weekly dosing is also preferred when a patient has aggressive or high-risk disease. “They have hypercalcemia, a cord lesion, renal insufficiency, or some other reason, then we give twice-weekly bortezomib for the fastest response,” Dr. Martin said.
In fact, researchers found that time to best response was shortest with twice-weekly administration (3.6 months) compared with once-weekly (3.9 months).5 However, Dr. Banerjee doesn’t believe this outcome is advantageous in the larger picture.
“In the grand scheme of things, does two weeks really make a difference?” he asked.
The Future of Myeloma Treatment
While the percentage of patients receiving once-weekly dosing is increasing over time,6 it’s still not anywhere near the 100% clinicians want to achieve.
“We’ve come a long way in myeloma treatments,” Dr. Kaur said. “While the treatment landscape changes every few months, I still think bortezomib will remain a part of myeloma treatment.”
Clinicians are also trying to push for dose reductions of other drugs, namely carfilzomib and dexamethasone. There’s even a #DownWithDex hashtag on X, formerly known as Twitter, which is advocating for clinical trials to reflect how the corticosteroid is being administered in practice. While most myeloma experts drop dexamethasone after a few cycles, many community physicians aren’t aware that they are allowed to do so, according to Dr. Banerjee.
Despite the remaining obstacles in the myeloma treatment landscape, Dr. Kaur hopes her study serves as a reference that clinicians can use to advocate for the incorporation of once-weekly bortezomib.
“The more data that we have to show that the efficacy is the same and the neuropathy risk is lower, that can make a change,” she concluded. “It will start a conversation at least.”
Melissa Badamo is an Assistant Editor for Blood Cancers Today.
References
- Drugs@FDA: FDA-approved drugs. FDA. Accessed July 22, 2024. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=021602
- Velcade (bortezomib). European Medicines Agency. Accessed July 22, 2024. https://www.ema.europa.eu/en/medicines/human/EPAR/velcade
- 21st World Health Organization Model List of Essential Medicines. World Health Organization. 2019. Accessed July 22, 2024. https://iris.who.int/bitstream/handle/10665/325771/WHO-MVP-EMP-IAU-2019.06-eng.pdf?sequence=1
- Cook J, Johnson I, Higgins A, et al. Outcomes with different administration schedules of bortezomib in bortezomib, lenalidomide and dexamethasone (VRd) as first-line therapy in multiple myeloma. 2020. Am J Hematol. doi:10.1002/ajh.26074
- Banerjee R, Wang B, Anderson LD, et al. Once-weekly bortezomib as the standard of care in multiple myeloma: results from an international survey of physicians. 2023. Blood Cancer J. doi:10.1038/s41408-023-00937-0
- Hoff FW, Banerjee R, Khan A, et al. Retrospective observational study on real-world bortezomib prescribing patterns and outcomes in newly diagnosed multiple myeloma. 2023. Blood. doi:10.1182/blood-2023-178950
- Sidana S, Narkhede M, Elson P, et al. Neuropathy and efficacy of once weekly subcutaneous bortezomib in multiple myeloma and light chain (AL) amyloidosis. 2017. PLOS One. doi:10.1371/journal.pone.0172996
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