Amongst sufferers who have been newly identified with a number of myeloma, Kyprolis (carfilzomib) plus Revlimid (lenalidomide) and dexamethasone (KRd) was related to enhancements in progression-free survival (PFS) in contrast with Velcade (bortezomib) plus Revlimid and dexamethasone (VRd), based on interim outcomes from the part 3 COBRA trial.
The findings, introduced through the 2025 ASH Annual Assembly, demonstrated that KRd (126 sufferers) diminished the danger of development or demise by 43% versus VRd (124 sufferers) within the intent-to-treat inhabitants at a median follow-up of 53 months. The median PFS was not reached (NR) within the KRd group versus 48.8 months within the VRd arm.
The info demonstrated constant directional advantages throughout cytogenetic subgroups. Amongst sufferers with standard-risk illness, KRd (97 sufferers) achieved a statistically important enchancment in PFS versus VRd (96 sufferers); the median PFS was NR within the KRd group in contrast with 48.8 months for VRd. On this subgroup, 27% of sufferers handled with KRd skilled development or demise versus 40% with VRd. Within the high-risk cohort, KRd (29 sufferers) once more demonstrated favorable outcomes versus VRd (28 sufferers), with 31% versus 48% of sufferers experiencing development or demise. The median PFS was NR versus 34.9 months, respectively.
Glossary
Development-Free Survival (PFS): The period of time throughout and after therapy when the most cancers doesn’t develop or worsen.
MRD (Minimal Residual Illness): A really small variety of most cancers cells that will stay within the physique after therapy — even when exams present no indicators of most cancers.
Worldwide Myeloma Working Group (IMWG) Frailty Rating: A software docs use to grasp how “match” or “frail” a affected person with a number of myeloma is.
Autologous Stem Cell Transplant: A process through which a affected person’s personal stem cells are collected, saved, after which given again after high-dose chemotherapy.
Neutropenia: A low stage of neutrophils, a kind of white blood cell that helps combat infections.
Neuropathy: Nerve harm that may trigger numbness, tingling, or ache — normally within the arms or toes.
“COBRA confirmed superior efficacy of KRd versus VRd in newly identified a number of myeloma, attaining each co-primary endpoints of MRD-negative CR at 12 months andPFS,” famous presenting creator Dr. Dominik Dytfeld. “The PFS good thing about KRd was noticed no matter cytogenetic danger, and KRd produced deeper responses, with larger charges of full response [CR] and minimal residual illness [MRD]–negativity. KRd [also] demonstrated anticipated toxicity profiles with larger charges of neutropenia and cardiac [side effects], however much less neuropathy. COBRA outcomes help additional analysis of KRd-based induction regimens in newly identified a number of myeloma.”
Dytfeld is an affiliate professor of medication on the Poznan College of Medical Sciences in Poland and founder/chief govt officer of the Polish Myeloma Consortium.
What was the design of the COBRA trial?
The COBRA trial was a multicenter, randomized, open-label part 3 research designed to match KRd with VRd in sufferers with newly identified a number of myeloma who had an Worldwide Myeloma Working Group (IMWG) Frailty Rating of lower than 2. A complete of 250 sufferers have been randomly assigned to the KRd or VRd therapy arms.
Sufferers within the KRd arm acquired as much as 24, 28-day cycles of remedy consisting of Kyprolis at 56 mg/m² administered on days 1, 8 and 15 (with twice-weekly dosing throughout cycles 1 and a couple of), Revlimid at 25 mg on days 1 by means of 21, and dexamethasone at 40 mg weekly (or 20 mg for sufferers 75 years of age or older). Stem-cell assortment occurred after cycle 4 on this transplant-deferred design. Following completion of induction, sufferers continued on Revlimid 5 mg each day as upkeep till illness development.
Sufferers within the VRd arm acquired eight 28-day cycles of Velcade at 1.3 mg/m² on days 1, 4, 8 and 11; Revlimid at 25 mg on days 1 by means of 14; and dexamethasone at 20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12. After completion of the VRd induction part, sufferers transitioned to consolidation with Revlimid and dexamethasone for 18 28-day cycles, adopted by Revlimid 5 mg upkeep till development.
How did KRd and VRd evaluate in transplant-eligible versus transplant-ineligible sufferers?
The subgroup evaluation by transplant eligibility confirmed distinct patterns in PFS favoring KRd amongst sufferers thought-about eligible for autologous stem cell transplant. Within the transplant-eligible cohort, KRd diminished the danger of development or demise by 60% relative to VRd. Solely 23% of sufferers handled with KRd skilled development or demise in contrast with 45% within the VRd arm. Median PFS was NR with KRd, whereas VRd demonstrated a median PFS of 40.1 months.
In distinction, outcomes have been comparable between the 2 regimens within the transplant-ineligible inhabitants. On this subgroup, each KRd and VRd produced equivalent development or demise charges of 30%. Median PFS remained NR with KRd versus 52.9 months for VRd, leading to no statistically important distinction between the arms.
What have been the protection outcomes of the COBRA trial?
The protection profile of KRd and VRd within the COBRA trial demonstrated that each regimens have been related to excessive charges of unwanted effects, though particular toxicity patterns differed between the therapy arms. Grade 3 (extreme) or larger unwanted effects occurred in 73% of sufferers receiving KRd and 62% of these receiving VRd, whereas any-grade unwanted effects have been almost common throughout each cohorts (96% with KRd and 94% with VRd). Remedy discontinuation as a result of unwanted effects occurred in 11% of KRd-treated sufferers and eight% of VRd-treated sufferers.
Grade 5 (deadly) unwanted effects have been rare however noticed in each arms, occurring in 5 sufferers (4%) within the KRd arm and 7 sufferers (6%) within the VRd arm. Reported deadly unwanted effects within the KRd cohort included COVID-19, stroke, pneumonia, sepsis and acute kidney failure, whereas the VRd arm included deaths from COVID-19, pneumonia, respiratory failure and two unwanted effects of unknown trigger. Neutropenia of any grade occurred in 29% of KRd-treated sufferers and 17% of VRd-treated sufferers, with grade 3 or larger neutropenia reported in 21% and 11%, respectively.
Neuropathy, a recognized Velcade-associated toxicity, was extra frequent with VRd: 56% of sufferers skilled neuropathy of any grade in contrast with 17% within the KRd arm, though grade 3 or larger neuropathy remained low in each teams (2% in every arm). Cardiac unwanted effects occurred extra steadily with KRd (18% any grade; 6% grade 3 or larger) than with VRd (10% any grade; 2% grade 3 or larger), in keeping with the recognized cardiovascular danger profile of Kyprolis. An infection charges have been excessive in each teams however have been extra frequent within the KRd arm, the place 75% skilled infections of any grade and 25% developed grade 3 or larger infections, in contrast with 60% and 23% within the VRd arm, respectively.
References
- “Carfilzomib, lenalidomide, and dexamethasone (KRd) versus bortezomib, lenalidomide, and dexamethasone (VRd) in sufferers with newly identified a number of myeloma: outcomes of the randomized part III COBRA trial,” by Dr. Dominik Dytfeld et al., Blood.
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