Management of acute spinal cord compression in multiple myeloma
Cranial Nerve Palsy May Be Present After Cilta-Cel For Multiple Myeloma
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A subgroup of patients from the 3 CARTITUDE trials experienced cranial nerve palsy after treatment, most of whom were men.
Cranial Nerve Palsy May Be Present After Cilta-Cel for Multiple Myeloma
At a median of 3 weeks post-infusion, there was a subgroup of patients with multiple myeloma who were treated with ciltacabtagene autoleucel (cilta-cel; Carvykti) in the 3 different CARTITUDE trials experienced cranial nerve palsy (CNP), according to findings from a poster presentation from the 2024 Oncology Nursing Society Conference.1
Cases of CNP were experienced mostly in male patients and were low-grade, with most cases resolving after a short time on corticosteroid treatment. Additionally, those with cytokine release syndrome or immune effector-associated neurotoxicity syndrome (ICANS) were not found to be at a higher risk of having CNP.
This presentation assessed results from the phase 1/2 CARTITUDE-1 (NCT03548207), phase 2 CARTITUDE-2 cohorts A, B, and C (NCT04133636), and phase 3 CARTITUDE-4 studies (NCT04181827).2,3,4 CARTITUDE-1 (n = 97) included patients with relapsed/refractory multiple myeloma with 3 or more prior lines of therapy. In cohort A of CARTITUDE-2 (n = 20), patients with progressive multiple myeloma after 1 to 3 lines of prior therapy and who were refractory to lenalidomide (Revlimid) were included, cohort B (n = 19) included those with progressive multiple myeloma after early relapse, and cohort C (n = 20) included those with relapsed/refractory multiple myeloma. CARTITUDE-4 (n = 176) included patients with lenalidomide-refractory multiple myeloma and 1 to 3 prior lines of therapy.
To grade CNP adverse effects, the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 was used. For patients with CNP, cerebral spinal fluid analyses and MRI were performed at the investigator's discretion. Additionally, in order to assess CNP, flow cytometry was used for peripheral blood levels of cilta-cel and CAR-positive T cells with memory phenotypes. A multiplex sandwich immunoassay measured the serum cytokine levels.
Across the 3 studies, CNP was observed in 6.3% of patients. Most CNP events were grade 2 and presented as facial nerve palsy, and 3 patients had impairment of an additional cranial nerve.
Overall, 81% of patients with CNP were male. Prior to CNP, 1 patient experienced grade 2 ICANS, and no patients with CNP had movement and neurocognitive toxicity. Post–cilta-cel use and before CNP, 5 patients had bacterial infections, and 2 had cytomegalovirus.
In CARTITUDE-1, 3.1% of patients had CNP; for CARTITUDE-2 cohort A, it was 5.0%, cohort B was 5.3%, and cohort C was 0%; and in CARTITUDE-4, it was 9.1%. The median time to onset of CNP was 22 days (range, 1-101). Regarding the laterality of CNP, 71.4% had unilateral CNP, and 28.6% had bilateral CNP.
CNP at a maximum severity of grade 3 occurred in 33.3% of patients in CARTITUDE-1 and 12.5% in CARTITUDE-4. Cranial nerve VII involvement occurred in 100% of patients in each group except for cohort C, which was not evaluated. Cranial nerve involvement plus cranial nerve VII occurred in 33.3% of patients in CARTITUDE-1 and 12.5% in CARTITUDE-4. The amount of resolved CNP was 100% for CARTITUDE-1 and CARTITUDE-2 cohorts A and B as well as 87.5% for CARTITUDE-4.
For 17 patients who received an MRI and 14 with CSF analysis, there was no evidence of infections or malignant causes. Of note, 7 patients had facial nerve enhancement based on MRI. Corticosteroids were given to 19 patients for a median duration of 15 days. In 21 patients, 90.5% had a resolution of CNP with a median duration of 66 days.
For patients who received the total steroid dose of 250 mg or more vs 250 mg or less, there was no difference in CNP duration.
References
Carvykti Provides Good Long-Term Quality Of Life In Pretreated Myeloma
Patients with heavily pretreated myeloma tended to have "really amazing results" with the CAR-T cell therapy, Carvykti.
"We found that patients who are more heavily treated didn't have a harder quality of life overall," an expert told CURE®.
Having a one-time treatment like Carvykti (ciltacabtagene autoleucek; cilta-cel) that offers a long period without maintenance therapy is a "big deal" for patients with pretreated multiple myeloma, explained Samantha Gagnon, a clinical research nurse at Moffitt Cancer Center.
Earlier this month, the Food and Drug Administration (FDA) approved Carvykti for patients with relapsed or refractory myeloma that is refractory to Revlimid (lenalidomide) and previously received a proteasome inhibitor and an immunomodulatory drug.
"These patients who are currently receiving [Carvykti] under the FDA guidelines are pretty heavily pretreated and might not have as many options moving forward — though they still have options, of course," Gagnon said in an interview with CURE®. "We've seen patients who are sometimes on their eighth or ninth line of therapy now are able to have access to Carvykti. We saw really great results with it in clinical trials."
Carvykti is a CAR-T cell therapy that works by extracting patients' T cells and reengineering them to find and fight cancer. The cells are then multiplied outside of the body and then reinfused.
Side Effect Monitoring After Carvykti TreatmentAfter receiving Carvykti, patients are closely monitored for side effects — namely neurotoxicity and cytokine release syndrome — for about a month, Gagnon said.
READ MORE: CAR-T Cell Therapy Side Effects: Know What to Look Out For
The period after CAR-T cell therapy is "similar to the transplant process … where you need to stay in a bit of a bubble for a while [and not go too far from the treatment center]" Gagnon said. "Once that acute period of about 30 days is over, patients will still be coming in for frequent lab draws and seeing their provider to manage any symptoms and side effects, but overall, they can ease back into their normal life."
As patients with myeloma go back to their lives after CAR-T cell therapy — and perhaps an extended period when they do not need any treatment — it is important that they know what kind of side effects and late effects to look out for.
"When patients get a CAR-T product, they get a very extensive education on calling [their health care team] at the first sign of anything unusual that comes in," Gagnon said. "They get a little wallet card that they take with them and are supposed to be carrying around no matter what. So even if they end up at an emergency room or somewhere where they're not treated, they can say, 'I had this treatment. There are a lot of specific guidelines to keep me safe because there are new cells running through my body trying to fight off myeloma.'"
Longer-Term Quality of Life After CAR-T Cell TherapyNeurotoxicity and cytokine release syndrome typically happen in the acute phase soon after CAR-T cell infusion, but there was not much research into how patients feel long-term on these therapies, according to Gagnon.
So, last year, she and colleagues researched the health-related quality of life two or more months after patients received CAR-T cell therapy.
"We found that patients who are more heavily treated didn't have a harder quality of life overall. We saw really amazing results in the quality of life, and it was all self-reported," Gagnon said. "We looked at age, sex, race, ethnicity and prior lines of therapy and we were pleasantly surprised that there wasn't a ton of difference [in quality of life] between those cutoffs."
Gagnon mentioned that the experience for one person who received Carvykti or another CAR-T cell therapy may not be the same for the next. However, having this patient-reported data could help patients decide if this is the right therapy for them.
"We don't want to give false hope to somebody or say that this is definitely what's going to happen or how you're going to react," Gagnon said. "But there is some information where there wasn't any before, and that's a really scary thing to go into. The treatment is intimidating. … So it really gives us the opportunity to tell those future patients [about what others experienced]."
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Age, Disease Burden Are Factors In Early Use Of Selinexor In Multiple Myeloma
During a Case-Based Roundtable® event, Jonathan L. Kaufman, MD, discussed treatment approaches and the tolerability of a selinexor-containing regimen in a patient with relapsed/refractory multiple myeloma in the first article of a 2-part series.
Jonathan L. Kaufman, MD
David Bankes Glass Multiple Myeloma Professorship
Professor, Department of Hematology and Medical Oncology
Emory University School of Medicine
Medical Director and Section Chief, Ambulatory Infusion Centers
Winship Cancer Institute of Emory University
Atlanta, GA
CASE SUMMARY
Three years later
DISCUSSION QUESTIONS
LOUAY HANNA, MD: What about selinexor [Xpovio], bortezomib, and dexamethasone [XVd]? We have strong data in the second line, especially if this patient needs [therapy for] high disease burden.1 You want some completely new mechanism of action. I would think XVd might be a better option. But if this patient had soft relapse on 10 mg of lenalidomide, I wouldn't say they're completely resistant to IMiD [immunomodulatory imide drug]. So maybe they could receive carfilzomib [Kyprolis] and pomalidomide [Pomalyst] or bortezomib plus dexamethasone, or lenalidomide, bortezomib, and dexamethasone.
JONATHAN L. KAUFMAN, MD: I'm glad you mentioned bortezomib, selinexor, and dexamethasone…. [The BOSTON trial (NCT03110562)] is exactly the one that you mentioned. There are a lot of phase 3 data in this situation but this is one of the trials that was not talked about.
MAURIZIO BENDANDI, MD: Why does this patient have heavy tumor burden on relapse? I would expect the disease not to be explosive, since he was on DRd…. I don't know that I would engage in selinexor in a 79-year-old patient who most likely is going to have GI [gastrointestinal] toxicity. I understand they're 2 different mechanisms of action, [but] selinexor is not an easy medication.
SHEBLI ATRASH, MD: Selinexor dosed at 160 mg a week, meaning 80 mg twice a week, got the reputation of nausea, vomiting, and GI problems [in the STORM trial (NCT02336815)].2 I can tell you [that with] a dose of 40 mg a week or 60 mg a week, you still get great efficacy with very minor GI toxicity.
KAUFMAN: I say this all the time—we learn so much more about a drug after the drug is approved. [The BOSTON] study used selinexor weekly, continuous dosing every week at 100 mg. But exactly what Dr Atrash said, we don't use 100 mg every week; we use 40 mg to 60 mg for 3 out of 4 weeks. We don't have randomized data [comparing dose levels], but I'm able to maintain efficacy. This study in this similar patient population [showed benefit of] bortezomib, selinexor, and dexamethasone vs bortezomib and dexamethasone [Vd].1
BENDANDI: But how many patients in this study were [aged] 79? Even reduced-dose selinexor, at [the age of] 79, is not an easy medication in my opinion.
KAUFMAN: Let's say the patient is aged 75, or they started when they're 70 and now they're 75. Or a patient was transplanted and was progressing was on the PERSEUS [NCT03710603] regimen 2 or 3 years later on daratumumab/lenalidomide. There would be a variety of agents that could come in.
BENDANDI: I started using selinexor [soon] after it was approved in the second line with bortezomib, but for [a patient aged] 79, it's not easy.
KAUFMAN: No, we agree. [In terms of the outcomes with BOSTON], there was benefit in the primary [end point] with a statistically significant, clinically significant 4-month improvement in progression-free survival [(PFS) 13.93 months median with XVd vs 9.46 with Vd], but I don't think these are the key data.1
There was a somewhat higher [objective] response rate: 76% [with XVd] vs 62% with Vd. The median duration of response is 20 months vs 13 months, respectively. In 76% of patients [treated with XVd], you're looking at a year and a half of benefit. [Although] we don't have the [subgroup data] for the older patient population [of 75 or older], for those patients who hadn't had a prior proteasome inhibitor [PI], there was a 30-month [median PFS with selinexor] vs 10 months [without it]. It looks like there's something there because that's the key with these patients who we're seeing now with the DRd. These are very small numbers, less than 50 patients in each arm [with no prior PI], but that looks good.
If you've ever used selinexor, there's hematologic toxicity and non-hematologic toxicity. [I believe] 100 mg is not the right dose once a week. I don't think 80 mg is the right dose; I think it's somewhere between 40 mg and 60 mg, and I typically give it 3 out of 4 weeks. That's been my approach for how I use this medication.
Patient selection is critical here. For a frail 79-year-old, maybe [they should not be selected, but it could be used in] a fit younger patient who is refractory to daratumumab and lenalidomide, and maybe a patient [who] hasn't seen a PI for whatever reason. This patient hasn't seen a PI…and I agree they need a PI.
REFERENCES: 1. Grosicki S, Simonova M, Spicka I, et al. Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial. Lancet. 2020;396(10262):1563-1573. Doi:10.1016/S0140-6736(20)32292-3 2. Chari A, Vogl DT, Gavriatopoulou M, et al. Oral selinexor-dexamethasone for triple-class refractory multiple myeloma. N Engl J Med. 2019;381(8):727-738. Doi:10.1056/NEJMoa1903455
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