Dexamethasone benefits in multiple myeloma ‘fade into oblivion’ after a couple months
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Key takeaways:
- Patients with multiple myeloma who had dexamethasone dose reductions achieved similar PFS and OS as those who maintained a full dose.
- Most individuals required a lower dose due to toxicities.
Decreasing the amount of dexamethasone that individuals with newly diagnosed multiple myeloma received did not affect survival, according to a secondary analysis of completed clinical trials.
Nearly 70% of patients treated with dexamethasone required dose reductions due to grade 3 toxicities.
“After 1 to 2 months, I would argue for the vast majority of patients who are getting any form of a modern triplet or quadruplet, the benefits of dexamethasone start to fade into oblivion, and the risks [associated with] dexamethasone remain constant,” Rahul Banerjee, MD, FACP, assistant professor in the clinical research division at Fred Hutch Cancer Center and in the division of hematology and oncology at University of Washington School of Medicine, told Healio.
Background
Clinicians have used dexamethasone as part of therapy for newly diagnosed multiple myeloma for more than 3 decades. The agent can help induce myeloma cell apoptosis and also help with symptom management.
“It’s a fast-burn medication,” Banerjee said. “People will automatically feel better very quickly with it.”
However, dexamethasone can cause adverse events, such as insomnia, high blood sugars, pedal edema, irritability, anxiety and cataracts.
Patients treated with dexamethasone may not think they are experiencing adverse events but can develop them over the long term, Banerjee said.
For years, clinicians who treated multiple myeloma had a mindset of “more is more,” Banerjee said — believing more dexamethasone over longer periods produced better results.
Results of the ECOG E4AO3 trial, however, contradicted that theory.
Patients who received 40 mg dexamethasone once a week achieved longer survival than those who received 40 mg in 4-day pulses.
Treatment for multiple myeloma has evolved significantly in the past 2 decades, as well.
“Bortezomib is now the standard of care,” Banerjee said. “Carfilzomib is a proteasome inhibitor for the front-line setting. In the last 5 years we’ve seen CD38 monoclonal antibodies like daratumumab [Darzalex, Janssen] and isatuximab [Sarclisa, Sanofi] be added on.
“Dexamethasone, 30, 40 years ago, was all we had for myeloma,” he added. “It still kind of lives on as part of our treatment regimens, but no one’s really looked at how necessary it is.”
Methods and results
Banerjee and colleagues reviewed two completed randomized SWOG trials for individuals with multiple myeloma — the phase 3 S0777 trial and the phase 2 S1211 trial — to investigate.
Trial participants received dexamethasone in combination with a variety of other drugs, including bortezomib, lenalidomide and elotuzumab (Empliciti, Bristol Myers Squibb).
Dexamethasone doses varied, ranging from 40 mg once a week for six 4-week cycles, to 20 mg during eight specific days of each cycle, to eight 20 mg doses over a 21-day cycle.
Both trials prohibited patients from lowering dexamethasone dose unless they experienced grade 3 or worse adverse events.
Median follow-up was 78 months for S0777 and 67 months for S1211.
Survival and the frequency with which trial participants required dexamethasone dose reductions served as primary endpoints.
Of 541 participants who completed induction therapy, 69% received dexamethasone dose reductions.
Overall, trial participants who received full-dose dexamethasone and low-dose dexamethasone achieved similar median PFS (37 months vs. 34 months) and median OS (92 months vs. 77 months).
“I think [the OS difference comes] down to patient fitness and unmeasured confounders,” Banerjee said. “Patients who can maintain full dose dexamethasone 40 mg weekly for a good 6 months are probably fitter patients.”
Individuals aged 70 years or older and those who had baseline thrombocytopenia had worse PFS and OS. Individuals who received bortezomib, lenalidomide and dexamethasone had improved outcomes regardless of dexamethasone dose.
‘Down with dex’
Banerjee described the results as “striking” — particularly how many patients required dose reductions.
“All were equally old [with] equal performance statuses [and] equal M-spike compared with the patients who didn’t have dexamethasone dose reduction,” he said. “It really came down to who had more toxicities. The fact that 70% of patients cannot maintain that level of dose intensity is really telling.
“If this was a new drug being studied in the FDA in a phase 1/phase 2 study, there is no way that dexamethasone 40 mg weekly would have been the maximum tolerated dose or the recommended phase 2 dose,” he added.
Banerjee emphasized dexamethasone has value. It can reduce bone pain and inflammation, treat individuals who have cord compression, and limit infusion site reactions.
However, those benefits only last for one or two treatment cycles.
“Very soon thereafter, the risks start to outweigh the benefits,” he said.
Dexamethasone treatment can last months, if not years.
“I love the phrase ‘down with dex,’” Banerjee said. “I'm not saying down all the way to zero. I’m saying dial it down. However you want to dial it down, whatever works for your patient, dial it down, but please, do not keep it at 40 mg forever.”
Banerjee has seen firsthand how dexamethasone dose reduction can help patients.
“A lot of patients, psychologically, feel terrible,” he said. “Their spouse and their loved ones are the ones who comes to me, and they say, ‘I hate the days my loved one is on treatment because he’s a monster to us. He doesn’t pick up anything. He yells. He’s very irritable.’ Lower the dexamethasone, and instantly people start to feel better.”
Banerjee also recalled a woman who required bridging prior to chimeric antigen receptor T-cell therapy and had previously responded well to carfilzomib, but she refused it because she felt the carfilzomib had prevented her from sleeping, caused her to eat a lot and made her feel jittery.
The therapy had included 40 mg dexamethasone pulses, as well.
Banerjee lowered the dose of dexamethasone but kept the carfilzomib as is.
“She sailed through it great,” he said.
Next steps
Banerjee had long suspected a randomized trial would be necessary to compare patients treated with full-dose 40 mg dexamethasone with patients who received dose reductions.
“I think this study shows that is not a practical approach because if not even your patients on trial can maintain that level of dexamethasone dose intensity, there is no point in trying to do a randomized study like that,” he said.
Banerjee also said he would expect a randomized trial designed to evaluate 12 mg vs. 8 mg vs. no dexamethasone would only affect adverse events, not outcomes.
“The question will be the tolerability of the side-effect profile, who needs dexamethasone and who doesn’t,” he said.
Banerjee and colleagues are opening a study to investigate isatuximab, carfilzomib, lenalidomide and dexamethasone (Isa-KRd) and dropping the dexamethasone dose entirely unless necessary. They will allow up to 12 mg dexamethasone after that “no questions asked, but we’re saying it really should not be 20 or 40 mg,” he said.
“Some people still need low-dose dexamethasone with carfilzomib,” Banerjee added. “Carfilzomib can cause infusion reactions and nausea sometimes, and some patients like the dexamethasone.”
Additional research into dexamethasone is necessary because of the number of additional therapies in development for multiple myeloma, Banerjee said.
“There may be an arena where bispecific antibodies are part of the front-line regimen for myeloma ... or even moving to front-line CAR-T,” Banerjee said. “For those patients, there is a real risk that dexamethasone is going to impair T-cell fitness or knockout T cells entirely and make collection tougher. I think that would be the other impetus — not just side effects, not just a lack of survival benefit, but truly that for all the reasons that we used to think dexamethasone is a helpful drug for myeloma treatment, in the future, it may actually be a detrimental drug for myeloma treatment.”
As more studies are conducted, clinicians could use the results as “a shield” for lowering dexamethasone if concerns persist, Banerjee said.
“If any pharmacist, nurse or patient is nervous about lowering the dexamethasone dose, you can say, ‘Even in these studies, lowering the dexamethasone has no bearing on progression free survival, so let’s do it,’” he said. “You might as well do it and feel better with your life. You always can add it back if needed, but your default really should be ‘down with dexamethasone’ and not maintaining dexamethasone.”
For more information:
Rahul Banerjee, MD, FACP, can be reached at rahulban@uw.edu.
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