Examining Efficacy, Toxicity, and Cost-Effectiveness of Myeloma Therapies
In an interview with Targeted Oncology, Doris Hansen, MD, delved into the background, methods, design, and results from 3 recent myeloma studies.
Doris Hansen, MD
Three recent studies offer valuable insights into treatment strategies for multiple myeloma, according to Doris Hansen, MD.
The first delved into the effectiveness of daratumumab (Darzalex), lenalidomide (Revlimid), and dexamethasone (DRd) compared with bortezomib (Velcade), lenalidomide, and dexamethasone (VRd) for the treatment of patients with newly diagnosed myeloma. Findings from this trial ultimately showed that DRd was associated with a longer time-to-next-treatment or death compared with VRd treatment.
The second study investigated the association between proinflammatory state and peak cytokines with toxicity and early response in patients treated with idecabtagene vicleucel (ide-cel; Abecma), a chimeric antigen receptor (CAR) T-cell therapy. The study found that high plasma cell burden is associated with systemic inflammation and may impact T-cell function. Additionally, high peak interleukin-2 was linked with developing a partial response or better.
The third presentation analyzed the cost per responder of another CAR T-cell therapy, ciltacabtagene autoleucel (cilta-cel; Carvykti) for the treatment of patients with lenalidomide-refractory multiple myeloma. In the analysis, cilta-cel was shown to be a more cost-effective option compared with the physician's choice, which consisted of daratumumab plus pomalidomide (Pomalyst) and dexamethasone (DPd) or pomalidomide plus bortezomib and dexamethasone (PVd), suggesting that cilta-cel not only provides clinical efficacy, but that it is also economically beneficial.
In an interview with Targeted OncologyTM, Doris Hansen, MD, assistant member, Moffitt Cancer Center department of blood and marrow transplant and cellular immunotherapy, delved into the background, methods, design, and results from each of these studies.
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Targeted Oncology: Can you discuss your study comparing frontline DRd vs VRd in transplant ineligible multiple myeloma?
Hansen: I presented a comparison of time-to-next-treatment or death between patients treated with frontline daratumumab, lenalidomide and dexamethasone or bortezomib, lenalidomide, dexamethasone in transplant-ineligible patients with newly diagnosed myeloma. Essentially, the objective of the study was to look at the comparative effectiveness between these 2 treatments. There have been no randomized, controlled clinical trials that compare them head-to-head, so we intend to look at these treatments, or the efficacy of this treatment, specifically the time-to-next-treatment or death, using an [electronic medical record] database, which does have extensive information on medications, orders fills, medication administration, which made it a perfect database for the purposes of time-to-next-treatment calculation. The type of methodology used was an accepted methodology known as the inverse probability of treatment waiting to adjust baseline characteristics between the groups.
Who was included in the study?
Essentially, we had 643 eligible patients in the study, 302 weighted patients in the DRd cohort, and 341 weighted patients in the VRd cohort. Overall, baseline characteristics were fairly similar between the 2 groups. There were some minor imbalances in age, race, and index year; however, these are adjusted for in a doubly robust Cox model.
What were the findings observed regarding time-to-next-treatment or death?
In terms of results, we found that frontline daratumumab, lenalidomide, and dexamethasone were associated with a longer time-to-next-treatment or death. It had a 42% lower likelihood of progressing to another therapy or dying, and the median time-to-next-treatment was 38 months with DRd and 19 months with VRd. Our study certainly has limitations as this was a retrospective database. There is some administrative censoring, and we are missing a few variables. Time-to-next-treatment is not a direct proxy for [progression-free survival], but overall, it does support the existing evidence supporting the use of DRd over VRd, and hopefully will assist clinicians and informed decision making when treating patients in this clinical setting.
Can you discuss your abstract on proinflammatory state and peak cytokines and their association with toxicity and early response in patients treated ide-cel?
Ide-cel is a CAR T-cell therapy that was FDA approved in 2021. There has been association with inflammatory cytokines with toxicity. However, to date, to the best of my knowledge, there has been no association with cytokines and response to ide-cel. We set out to examine the association of cytokines and pre-CAR T bone marrow composition with toxicity and response. We essentially had a patient cohort of 86 patients. Generally, they had aggressive baseline characteristics. One-third of the patients had high-risk cytogenetics. We had 31 people with penta-refractory disease, and we had about 15% with extramedullary disease. The safety profile was fairly similar. We did have three patients who died of myeloma, a complication of myeloma progression by day 90. We were able to identify tha [cytokine release syndrome (CRS)]or patients who develop CRS also had a higher concentration of peak inflammatory cytokines like interleukin-2 interleukin-6, interleukin-15, [and tumor necrosis factor alpha (TNFα)] gamma.
In addition to this in patients who had higher grades or grade 2 or more cytokine release syndrome, they had a higher peak concentration of interleukin-6, which is a known key mediator of cytokine release syndrome. In patients developing any grade neurologic toxicity, we were able to identify some baseline associations, so higher baseline concentrations of TNFα, as well as higher baseline concentrations with a minus 6 of interleukin-15 and angiopoietin 2:1 ratio, as well as higher peak concentrations of interleukin-6, interleukin-15 angiopoietin, 2:1 ratio. We were able to identify some association with responses, as I mentioned, particularly with peak cytokines like a higher peak, interleukin-2 is associated with developing a partial response or better.
We also found an association with cytokines and plasma cell burden. Patients who have high plasma cell burden have systemic inflammation as evidenced by higher concentration of proinflammatory cytokines, particularly at peak. In a subset of patients, we performed flow cytometry of the bone marrow aspirate and identified that patients will have a high plasma cell burden identified as having 50% or more plasma cells in a pre-CAR T bone marrow biopsy. These patients demonstrated markers of T-cell exhaustion and [natural killer] cell exhaustion, as well particularly higher expression of CD39 among CD4 CDA38 T cells, as well as TIGIT on CD4 cells, and higher expression of CD56 natural killer cells.
What are the main takeaways from these findings?
High plasma cell burden is associated with systemic inflammation which can lead to immune dysregulation that may impact T-cell function and fitness. Our study does provide some associations of cytokines, inflammatory markers, and bone marrow composition with toxicity and early response, and hopefully some insight into toxicity prevention and therapeutic optimization. Hopefully, with a larger cohort and a longer follow-up in the future, we will be able to better understand the complex relationships of immunity, inflammation, toxicity and response.
Finally, what can you tell me about the cost per responder analysis from the CARTITUDE-4 trial [NCT04181827]?
There was a cost per responder analysis in patients [with] lenalidomide-refractory multiple myeloma receiving cilta-cel on CARTITUDE-4. Based on CARTITUDE-4, patients have received cilta-cel vs physician’s choice. Cilta-cel has shown superior efficacy in terms of response rate, progression-free survival, as well as complete response or better rates. However, despite the clinical efficacy, we wanted to look at the total value of cilta-cel compared with the physician's choice which was DPd or PVd.
What were the methods of this research?
We created a cost per responder model where we looked at total costs between cilta-cel and physician's choice drug. We looked at cost per month in progression-free survival as well as cost per complete responder, and we did find some differences.
What are the findings that you can highlight?
We found that patients' total cost was higher with the physician's choice. Cost for complete responder was approximately $1 million [USD] in patients receiving cilta-cel compared with nearly slightly over $3.5 million in patients receiving physician’s choice, and cost per month in PFS over a 25-month period was $30 vs approximately $40,000, again, favoring cilta-cel. This was an inpatient model and we accounted for drug costs or drug acquisition.
We looked at bridging apheresis because we looked at infusion costs, management of immune-mediated toxicity, subsequent therapies, prophylactic antibiotics, using a mixed payer source, so commercial and Medicare. We also did an outpatient model which also favored cilta-cel as being the less expensive option. I think the point here is that we are hoping that this information or this cost per responder model can be utilized by payer sources to truly see the value of these novel therapies, not only clinically, but also economically. I think cilta-cel provides significant benefit, not only in clinical efficacy, but also an economic benefit to patients in this advanced line setting for multiple myeloma.
