The treatment of relapsed/refractory multiple myeloma dramatically changed in recent years with the emergence of therapies such as chimeric antigen receptor (CAR) T-cell products and antibody-drug conjugates. While these therapies have significantly improved outcomes, they can come with some unusual side effects.
Immune Effector Cell (IEC)-Associated Enterocolitis
About 2 years ago, a patient treated with CAR T-cell therapy came to Rahul Banerjee, MD, of Fred Hutchinson Cancer Center in Seattle, with a serious case of diarrhea.
The pathology report said it resembled graft-versus-host disease (GVHD), "but it wasn't GVHD," Banerjee said.
During conversations with colleagues around the country, Banerjee found some were seeing the same strange complication -- an inflammation of the gastrointestinal tract characterized by prolonged diarrhea and abdominal pain.
It turned out to be a new toxicity, known as IEC-associated enterocolitis, seen mostly after treatment with ciltacabtagene autoleucel (cilta-cel; Carvykti), one of two CAR T-cell therapies approved for relapsed/refractory multiple myeloma.
In October, the FDA mandated that the prescribing information for cilta-cel include a boxed warning for IEC-associated enterocolitis after trials and postmarketing adverse event data revealed reports of the complication weeks or months following infusion.
Last year, Banerjee and colleagues published a retrospective analysis of patients with diarrhea, enterocolitis, or colitis following treatment with cilta-cel or idecabtagene vicleucel (ide-cel; Abecma) at 11 centers within the U.S. Multiple Myeloma Immunotherapy Consortium, and identified 14 cases of IEC-associated enteritis and/or colitis -- 13 that followed treatment with cilta-cel and one that followed ide-cel.
According to Banerjee and colleagues, this corresponded to an incidence rate of 1.2% overall across all study centers, with product-specific incidences of 2.2% with cilta-cel and 0.2% with ide-cel.
"We in the myeloma field are not entirely sure why this [didn't seem to occur] in the clinical trials of cilta-cel or ide-cel," Banerjee said. "It may be something about real-world patients [being] sicker or frailer, [with] more comorbidities compared to patients treated in clinical trials."
In Banerjee's study, patients developed acute-onset symptoms (typically non-bloody grade ≥3 diarrhea) with a negative infectious workup beginning at a median of 92.5 days after CAR-T therapy.
Systemic corticosteroids were initiated in 10 patients a median of 25.5 days following symptom onset, with symptom improvement in 40%. Subsequent infliximab (Remicade) or vedolizumab (Entyvio) led to improvements in 50% and 33% of corticosteroid-refractory patients, respectively.
Five of the 14 patients died from bowel perforation or treatment-emergent sepsis, suggesting that "further research into the pathogenesis of this toxicity is critical to understand this novel complication," the researchers wrote.
As far as diagnosing the condition, "there are two big things to rule out" -- infection and T-cell malignancy, Banerjee said, adding that hematopathology, gastroenterology, and infectious disease specialists need to work together on this.
One important takeaway, he noted, is that clinicians should not treat this toxicity like GVHD.
"It may look like GVHD, and you can do corticosteroids for a couple of days, but 2 months of corticosteroids is not the optimal strategy," he said.
What seemed to work were biologic drugs typically used for Crohn's disease, like infliximab and vedolizumab, to "shut down the actual biological machinery here," Banerjee added. "And that seems to work quite well."
"We're still evolving, and in 5 years I hope that we'll get better answers to what's going on," he said.
Ocular Toxicity
Last month, the FDA again approved belantamab mafodotin (Blenrep) in combination with bortezomib (Velcade) and dexamethasone for the treatment of adults with relapsed or refractory multiple myeloma who have received at least two prior lines of therapy.
The drug was previously granted accelerated approval in 2020 for patients who had received at least four prior therapies, but it was pulled from the market 2 years later after the DREAMM-3 confirmatory trial failed to meet the primary endpoint of progression-free survival.
The recent approval of the antibody-drug conjugate came despite various concerns -- including ocular toxicities -- raised by an FDA advisory committee in July.
The ocular toxicity issue is not unique to belantamab, but is associated with antibody-drug conjugates as a class.
"There is something weird about that conjugate, because we have drugs, and we have antibodies, and neither one of those necessarily cause eye issues," said Krina Patel, MD, MSc, of the University of Texas MD Anderson Cancer Center in Houston. "But it's that antibody-drug conjugate that, for some reason, causes different eye symptomology, so it's not just Blenrep. I still don't think we know 100% why."
In the case of belantamab, prescribing information includes a boxed warning for the risk of ocular toxicity, including corneal epithelium changes resulting in vision deterioration. Among those receiving belantamab in DREAMM-7 -- the results of which led to its approval -- ocular toxicity occurred in 92% of patients, including grade 3/4 in 77%, with 83% requiring dosage modification.
Because of this risk, belantamab is available only through a Risk Evaluation and Mitigation Strategy program.
Thus, it is particularly important to partner with eye care specialists in order to manage these toxicities, Patel said, noting that she has treated several patients with the drug on a compassionate-use basis every 8 to 12 weeks, and at a lower dose level.
"Sometimes my ophthalmologist will see a little bit of keratopathy and suggest holding a dose and give it once it is improved," she said. "But the majority of my patients do really well."
Patel pointed out that most of her patients don't notice any symptoms and only become aware of the keratopathy after a physical exam.
"It's important to watch for sure ... it's something you just can't forget about. But we've learned how to do it without really affecting quality of life," she noted.
Disclosures
Banerjee reported relationships with AbbVie, Adaptive Biotech, Bristol Myers Squibb, Caribou Biosciences, Genentech, GSK, Janssen, Karyopharm, Legend Biotech, Novartis, Pack Health, Pfizer, Prothena, Sanofi, and SparkCures.
Patel reported relationships with Bristol Myers Squibb/Celgene, Kite, Oricell Therapeutics, AbbVie, AstraZeneca, Janssen, Legend Biotech, Merck, Novartis, Pfizer, Regeneron, Takeda, Indapta Therapeutics, and Nektar.
https://www.medpagetoday.com/spotlight/multiple-myeloma/118326
