A recent Face-Off program hosted by CancerNetwork® pitted experts from Vanderbilt University Medical Center (Commodores) and Emory University Winship Cancer Institute (Eagles) head-to-head on recent research on multiple myeloma and acute lymphocytes. We discussed the data. Leukemia (all). Panelists discussed data from various trials in the space and focused on different treatment combinations for patients with multiple myeloma or ALL.
CARTITUDE-4 Trial
The Phase 3 CARTITUDE-4 trial (NCT04181827) enrolled patients with multiple myeloma refractory to lenalidomide (Revlimid).1 A total of 419 patients were randomly assigned to receive ciltakabutagene autoleucel (cilta-cel; Carvykti; n = 208) or physician’s choice of effective standard treatment (n = 211). To be eligible, a patient must have received one to three types of treatment in the past and have a measurable disease.
The primary endpoint of this trial was progression-free survival (PFS). Secondary endpoints included complete response (CR) rate, minimal residual disease (MRD)-negative rate, and overall survival (OS).
Median follow-up was 15.9 months. Median PFS was not reached in the experimental arm and was 11.8 months (95% CI, 9.7-13.8) in the standard-of-care arm. PFS at 12 months was 75.9% (95% CI, 69.4% to 81.1%) in the cilta-cel group and 48.6% (95% CI, 41.5% to 55.3%) in the standard-of-care group. In the cilta-cel and standard-of-care groups, respectively, 84.6% vs. 67.3% experienced an overall response, 73.1% vs. 21.8% experienced CR or better, and 60.6% vs. 15.6% experienced absence of MRD .
A total of 39 patients in the cilta-cel group and 46 patients in the standard-of-care group died during the study (HR, 0.78; 95% CI, 0.5 to 1.20). Among those receiving cilta-cel, 76.1% had cytokine release syndrome, 4.5% had immune effector cell-related neurotoxicity, 9.1% had cranial nerve palsy, and 2.8% had chimeric antigen receptor (CAR) T cell therapy-related He was suffering from peripheral neuropathy. .
Use of treatment combinations before trial data are published
Patel: What about all the early deaths that happened in the early days of those who waited? [for treatment]?
Joseph: What about the cilta-cel arm?
Patel: yes.
Joseph: Of the 208 patients in the cilta-cel treatment group, only 176 received a pre-infusion. [which] This was due to the progression of the disease.
Patel: Do you think that would happen in the real world, when in the real world there are separate contracts, insurance authorizations, apheresis slot manufacturing, etc., or is it even worse than what we saw in the real world? Do you think there is a possibility that [in the study]?
Joseph: The challenge is to select the patients correctly.We need patients who are willing to wait, and that’s the same either way. [the patient is in the] 4th or 1st line [of treatment]. Patients are more likely to be able to wait for their first relapse than for their fourth relapse. That’s just the natural history of this disease. Granted, some high-risk patients will need a bridge, but it was allowed in this trial. Of her 30 patients who were unable to receive cilta-cel upfront, two-thirds later received cilta-cel. If effective bridging therapy is available, patients are more likely to receive effective bridging therapy if their disease is less refractory.
Doraria: I would like to get your comments on the control arm.Most of the newly diagnosed patients in the study were taking immunomodulatory drugs [IMiD] The exposure was high and there were only IMiD-based triplets in the control arm.Daratumumab does not exist [Darzalex] In combination with carfilzomib [Kyprolis] and dexamethasone [Kd] or isatuximab-irfc [Sarclisa] Plus Kd in control arm confirmed in IKEMA Phase 3 study [NCT03275285] [that examined] 3 year PFS [of this drug combination] Relapsed/refractory myeloma.2 If there is research that could enable a second generation of hydrolysis-based drugs; [HR] Is it still clinically meaningful?
Joseph: That’s a valid point.this [patient population has] Has received 2 to 4 treatments.regardless of [which treatment] If you try it, you’ll probably still not get a good response after three years. The IKEMA study was 36 months old, and that was one to three lines ago.
Valievich: Actually, IKEMA was 42 months old. You rightly pointed out the better toxicity profile, which is important. However, you mentioned that there is no median PFS, and the rate at which the curve is progressing seems to be below that point. So the question is, why should you consider giving someone her CAR T cell therapy early if: [the drug combination] Tests created in IKEMA research [a] Median PFS is 42 months? We know we can successfully rescue someone [with this drug combination]; I’ve seen it with cilta-cel, I’ve seen it with idecabtagene vicleucel [Abecma], and it is seen in bispecificity. Why choose to give the patient her CAR T therapy at an early stage when we know that administering CAR T will probably treat the patient well, and chemotherapy regimens and other combinations can successfully save the patient? Why don’t we know if it is? Will cell therapy be a later line?
Nonoka: When this study was designed, we did not have a phase
Three data supporting daratumumab and Kd or isatuximab and Kd [regimens].Now it’s so easy to command [the treatments]But when this study first started, they weren’t the standard of care. It is essential for us to consider it, but it is problematic to talk about why it was not included in the study.
Fair point.
Joseph: Another point is [administering] Administration of daratumumab until progression is a multimodal treatment, as opposed to a one-time CAR T. For some patients, a single infusion and 3 years of PFS may be preferable to weekly daratumumab.
Valievich: All of this is true, but there is only data when there is data. Now you have a deeper insight. This is a general point you can use. [regarding] One trial at a time. All exam designs are probably outdated, but that’s because of the foresight and foresight we have in place. [the myeloma space].I started using bortezomib. [Velcade]lenalidomide [Revlimid]and dexamethasone, nearly 8 to 10 years before data from the phase 3 SWOG S0777 trial were available. [NCT00644228] We showed its PFS and its benefits.3
Valievich: We already know the data. We will see examples of high-dose combinations of isatuximab, carfilzomib, lenalidomide, and dexamethasone being used in patients with high-risk disease in frontline settings, and this is a powerful outcome. be. These are questions we get asked all the time, so we’re thinking ahead of time about how to order all of these things. I’m a little worried about how we’re going to get people out when we start these therapies without having a clue what to do.
Do it after that.
Chemotherapy and ponatinib hydrochloride
The Phase 2 trial (NCT01424982) enrolled 86 patients with Philadelphia chromosome-positive ALL who received chemotherapy in combination with ponatinib hydrochloride (Iclusig).Four Ponatinib was administered at 45 mg daily for 2 weeks during the run-in period, followed by continuous dosing of 45 mg daily for the first 37 patients and 30 mg daily for the remaining study population to achieve a complete molecular response. At that point, the dose was reduced to 15 mg per day. Maintenance therapy consisted of daily ponatinib and vincristine-prednisone administered monthly for 2 years, followed by daily ponatinib indefinitely. The primary endpoint was event-free survival (EFS).Secondary endpoints included CR rate, grade 3 incidence, or
Four adverse effects (AEs), OS, and disease-specific survival.
With a median follow-up of 80 months (range, 16-129), EFS was 65% (95% CI, 54%-74%) and OS was 75% (95% CI, 64%-83%). ; all patients experienced CR. A total of 23% of patients had to undergo allogeneic stem cell transplantation. The cumulative complete molecular response rate was 86%.
Common grade 3 or higher AEs include infection (93%), increased hepatic transaminases (31%) and total bilirubin (15%), hypertension (17%), pancreatitis (15%), hemorrhage ( 13%), and skin rashes. (Ten%). In the 37 patients initially treated, ponatinib-related death due to myocardial infarction occurred in 3% of patients, leading to ponatinib dose modification. No additional ponatinib-related deaths were observed.
Need for chemotherapy
Patel: The question remains: Are hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone necessary? [hyper-CVAD] As the backbone of chemotherapy treatment?
Veil: [This trial has] relatively healthy [patient] population, good performance status, [and] Cardiovascular comorbidities were rare, and rates of infections such as arterial and venous occlusion phenomena and pancreatitis remained significantly high.The question is not [whether] HyperCVAD is an appropriate chemotherapy to combine with this tyrosine kinase inhibitor [TKI]. [The question is]is chemotherapy necessary or can it be treated? [most] How many patients are taking a non-chemotherapy approach?
Patel: I agree 100%.Let’s take a look at the dasatinib data [Sprycel] and blinatumomab [Blincyto]However, there are also data from phase 2 trials evaluating the combination of ponatinib and blinatumomab, and these data suggest that [had a transplant].5,6 This differs from the data for dasatinib and blinatumomab.What happens if you don’t? [perform a] transplant [for] the patient? That is a question that must be answered.
Veil: Based on cyclophosphamide, bortezomib, dexamethasone [CVd]or a less intense chemotherapy, approach, immunotherapy approach, do you still have patients? [who] Are you treating with hyper CVAD and TKI?
Patel: It’s tough right now. There are many non-randomized studies. [The University of Texas] md anderson [Cancer Center in Houston], at this point it’s a choose-your-own adventure. An argument can also be made for going the mini-CVd route with ponatinib. I would use HyperCVAD and dasatinib together. It’s well tolerated and we have good experience with it, but we don’t have enough data to overturn it at this point. Non-chemotherapy approaches sound great, but treatment costs and approvals are very difficult to obtain. We’re also concerned about the potential loss of blinatumomab on the back end. I guess time will tell the data, but that’s my concern.
Veil: It’s interesting that you mentioned that last point. We are aware that there is new data regarding the use of inotuzumab ozogamicin. [Besponsa] For patients who are MRD positive and had frontline exposure to blinatumomab [setting] Or during integration. Great point, and I hope we can develop strategies to mitigate it in the future.
Doraria: Significant selection bias exists among MD Anderson patients. Patients come to Houston from all over the world. They can access her CAR T and pre-integrate there. That’s what they’re doing. If MRD is not cleared, brexcabutagene/autoleucel will be administered. [Tecartus]. It’s not the standard of care anywhere in the world. Be careful when looking at Phase 2 data from there.
The winner of the Eagles vs. Commodores showdown has been decided!
References
- San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard therapy in lenalidomide-resistant multiple myeloma. N English J Medicine 2023;389(4):335-347. doi:10.1056/nejmoa2303379
- Martin T, Dimopoulos MA, Mikhael J, et al. Correction: Isatuximab, carfilzomib, and dexamethasone in patients with relapsed multiple myeloma: updated results from the randomized phase 3 trial IKEMA. blood cancer J. 2023;13(1):152. doi:10.1038/s41408-023-00923-6
- Durie BGM, Hoering A, Abidi MH, et al. Bortezomib in combination with lenalidomide and dexamethasone versus lenalidomide and dexamethasone monotherapy in patients with newly diagnosed myeloma not intended for immediate autologous stem cell transplantation (SWOG S0777): a randomized non-randomized study. Blinded phase 3 study. lancet. 2017;389(10068):519-527.
doi:10.1016/s0140-6736(16)31594-x - Kantarjian H, Short NJ, Jain N, et al. Frontline combination of ponatinib and hyper-CVAD in Philadelphia chromosome-positive acute lymphoblastic leukemia: 80-month follow-up results. Am J. Hematol. 2023;98(3):493-501. doi:10.1002/ajh.26816
- Foer R, Bassin R, Vitale A, et al. Dasatinib-blinatumomab for Ph-positive acute lymphoblastic leukemia in adults. N English J Medicine. 2020;383(17):1613-1623. doi:10.1056/nejmoa2016272
- Jabbour E, Short NJ, Jain N et al. Ponatinib and blinatumomab for Philadelphia chromosome-positive acute lymphoblastic leukemia: a single-center, single-arm phase 2 study in the United States. Lancet hematol. 2023;10(1):e24-e34. doi:10.1016/s2352-3026(22)00319-2
