The study that I will be discussing today is the frailty subgroup analysis of the CANDOR study, which is a phase 3 study comparing Daratumumab, Carfilzomib and Dexamethasone.
That’s Dara KD with KD that’s Carfilzomib and Dexamethasone in patients with relapse refractory, multiple myeloma. Now in the treatment of multiple myeloma sometimes efficacious treatment can result in poor outcome. If patients are FRA and cannot tolerate treatment now we know from the phase three can or study that the triplet combination of Dara KD is effective and result in a 41% relative risk reduction in progression or death compared to a Carfilzomib and Dexamethasone.
So, in this analysis, what we wanted to know was whether frail patients can stand to benefit as much from Dara KD as a fit patient. So, all patients in the candle study were categorized into a fit, intermediate fit or frail, according to the IMWG frailty index that incorporates age performance status and comorbid.
And so, what we found was that Dara KD resulted in a better progression, free survival compared to a KD across all subgroups of fit and FRA patients. And so, in fit patients, the median over the median progression free survival was not reached compared to approximately 18 months with KD.
And in the frail subgroup of patients, the median progression-free survival was approximately 19 months with Dara KD compared to only 9 months with KD. With respect to overall response rate there was an increase in complete response rate with Dara KD across all subgroups of a fit frail patients and with respect to side effects all treatment, emergent, adverse events, all grade were seen in over 95% of patients in all subgroup of fail and fit.
But what was important was that there was no increase in toxicity in the FRA subgroup of patients compared to the fit subgroup of patients. And in fact, the rate and profile of toxicity was very similar across the fit and frailty subgroup of patient. And so, what we can conclude from this study is that Dara KD resulted in a better progression, free survival compared to KD across or fit and frail subgroup of patients.
And there is not an increase. In toxicity in frail patients necessarily compared to their fit patients and that the frail patients can stand to benefit from Dara KD with respect to overall response rate and depth of response that did translate it to a better progression, free survival compared to KD.
The most common question I get asked about this study is that what dose of Carfilzomib would I use in combination with daratumumab and Dara zone in the real-world setting? And in the candle study, indeed. The dose of Carfilzomib that was used was the traditional twice weekly 56 milligram per meter squared on days 1, 2, 8, 9, 15, 16, every 28 days.
Now we know from the arrow study subsequently that a weekly schedule of car was N of 17 milligram per meter squared weekly. That stays 1, 8, 15, every 28 days resulted in a better progression, free survival, and was better tolerated compared to the twice weekly schedule. So many of us are now moving towards a weekly schedule of.
Carfilzomib when used in combination with daratumumab and dexamethasone. And I would personally use from 56 milligram per squared, weekly or 70 milligrams per squared, weekly.
This data will affect the way we treat patients today and highly relevant only because Dara KD has been approved and is now commonly used as a regimen in patients with relapse refractory in multiple myeloma in many jurisdictions in the world. And what’s important is that patients with relapse refractory multiple myeloma are commonly elderly if not frail.
So, at least based on this data clinicians can rest assured that Dara KD can be effective as well, tolerated in their elderly and frail patients with relapse refractory, multiple myeloma.
I think the one major thing that I would like on oncologist and a hematologist to be aware of and this more practical rather than to do with the clinical study is that Carfilzomib ought to be used with caution in patients with uncontrolled hypertension, with pulmonary hypertension or with cardiovascular comorbidities particularly if they are frail and elderly patients.
And in these patients, it’s important that they be monitored very closely and that the underlying comorbidities are well controlled and that the dose of Carfilzomib may need to be reduced at the outset, if not at the at the treatment emerging adverse event.
Hang Quach, MBBS(Hons), SpecCertOC, FRACP, FRCPA, MD, Haematologist with clinical and research interests in multiple myeloma, in particular myeloma, lymphoma and myeloid disorders at St Vincent"™s Health Melbourne and University of Melbourne Australia. In this video, she speaks about the EHA 2022 Abstract – Carfilzomib, Dexamethasone, And Daratumumab (Kdd) Vs Carfilzomib And Dexamethasone (Kd) In Relapsed/Refractory Multiple Myeloma (Rrmm): Frailty Subgroup Analysis Of The CANDOR Study.
History
Frailty scores based on age, comorbidities, and functional status can assist in identifying frail patients (pts) at risk of treatment-related toxicity or poor outcomes. An examination of carfilzomib-treated patients in the clinical trials ASPIRE, ENDEAVOR, and ARROW discovered that the efficacy and safety of carfilzomib regimens are constant regardless of frailty state (Facon Blood Adv 2020).
Targets
In the phase 3 CANDOR trial, assess effectiveness and safety across frailty subgroups in patients with RRMM treated with KdD vs Kd.
Methodology
This post-hoc analysis made use of CANDOR’s projected interim readout (June 15, 2020). (NCT03158688). Based on a frailty score of 0, 1, or 2, points were classified as fit, intermediate (int), or frail. The International Myeloma Working Group (IMWG) frailty index was used for scoring: the final score is based on age (0 if 75 years, 1 if 76-80 years, 2 if >80 years), modified Charlson Comorbidity Index (CCI [Facon Blood Adv 2020]) (0 if CCI 1, 1 if CCI >1), and Eastern Cooperative Oncology Group performance status (ECOG PS) (0 if ECOG PS= The hazard ratio (HR) and 95 percent confidence interval (CI) for progression-free survival (PFS) were determined using a stratified Cox proportional hazards model. The overall response rate (ORR) was described descriptively, with the odds ratio (OR) and 95 percent confidence interval (CI) computed using the Mantel-Haenszel technique. The Onyx Response Computer Algorithm evaluated response and progression using IMWG criteria.
Outcomes
Frailty status was roughly proportional between arms, with 27 and 35 percent of KdD and Kd, respectively, classified as fit, 43 and 36 percent int, 25 and 27 percent frail, and 5 and 2 percent unknown. Although baseline characteristics of the overall population were generally balanced, more patients had prior transplant in the KdD vs Kd arm for the int (65 percent vs 36 percent) and frail (41 percent vs 27 percent) subgroups, and fewer patients were lenalidomide exposed (37 percent vs 61 percent)/refractory (25 percent vs 46 percent) subgroup. The median length of treatment for KdD vs Kd was 99 weeks (wks) vs 68 weeks (wks) for fit patients, 82 weeks (wks) vs 31 weeks for int patients, and 51 weeks (wks) vs 21 weeks for frail patients. Not reached (NR) vs 17.6 months (HR 0.64, 95 percent CI 0.38"“1.07) for fit, NR vs 11.1 months (HR 0.44, 95 percent CI 0.28"“0.69) for int, and 18.5 vs 9.3 months (HR 0.66, 95 percent CI 0.38"“1.14) for frail points For fit points, the ORR for KdD vs Kd arms was 89 percent vs 89 percent (OR 1.09, 95 percent CI 0.35"“3.38), 87 percent vs 70 percent (OR 2.95, 95 percent CI 1.31"“6.62), and 75 percent vs 54 percent (OR 2.39, 95 percent CI 1.09"“5.22) (Figure). Treatment-emergent adverse events (TEAEs) of any grade occurred in more than 95% of patients across arms and subgroups. Grade 3 TEAEs occurred in 87 percent (KdD) and 70 percent (Kd) of fit pts, 84 percent and 71% of int pts, and 91 percent and 90% of frail pts, respectively. Fatal TEAEs occurred in 4% and 2% of fit patients, 11% and 9% of int patients, and 16% and 8% of frail patients in the KdD and Kd arms, respectively. Carfilzomib was discontinued in 25 percent vs 17 percent of fit patients, 22 percent vs 29 percent of int patients, and 35 percent vs 23 percent of frail patients due to TEAEs. Acute renal failure occurred in 0 fit patients, 3 percent vs 14 percent of int patients, and 8 percent vs 5 percent of frail patients, while infusion reactions occurred in 16 percent vs 2 percent of fit patients, 13 percent vs 4 percent of int patients, and 14 percent vs 13 percent of frail patients in the KdD vs Kd arms (Table).
Implication
PFS benefit with KdD vs Kd was evident across frailty categories, consistent with earlier results of effectiveness and safety benefits of KdD. The clinically significant ORR improvement in the fragile category may assist physicians in evaluating therapy options in this difficult group.