ASH 2019: Late-Breaking Abstract of Carfilzomib-Daratumumab in Relapsed Refractory MM: the CANDOR study. (Late-Breaking abstract-6)
The combination of Daratumumab, Carfilzomib and Dexamethasone was compared with Carfilzomib + Dexamethasone only in relapsed/refractory multiple myeloma patients (1 to 3 previous lines of therapy) in the randomised phase 3 study CANDOR. Of the 466 patients, 90% were previously exposed to Bortezomib and 42% to Lenalidomide. Overall 33% were refractory to Lenalidomide. The treatment was continued in both arms until progression.
*Carfilzomib at 56 mg/m2 administered twice weekly; 20 mg/m2 administered on days 1 and 2 of cycle 1 only
‡The first dose of daratumumab is split over two days (8 mg/kg each).
CrCl, creatinine clearance; ECOG PS, Eastern Cooperative Oncology Group Performance Status; LVEF, left ventricular ejection fraction; PD, progressive disease; RRMM, relapsed or refractory multiple myeloma
With a follow up of 16.9 months, the primary endpoint of the study Progression Free Survival was met. PFS is superior in the KdD arm, with a hazard ratio of 0.63 corresponding to a risk reduction of progression or death of 37% (median PFS not reached, versus 15.8 months in the Kd arm)
Importantly, the PFS benefit was also observed in the patients previously exposed to Lenalidomide (HR 0.52) and in that refractory to Lenalidomide with an HR of 0,45 (median PFS not reached versus 11,1 months in the Kd arm).
Overall, the safety profile is consistent with the known safety profiles of each agent, except for an imbalance in treatment-emergent fatal AEs, which might be partially explained by longer treatment exposure, age, and frailty status.
In ASH Highlights Prof. Christoph Renner also discussed this "Late-Breaking" abstract on healthbook
ASH 2019: Efficacy of KRd-D quadruplet in transplant-eligible newly diagnosed MM: MASTER trial. (abstract 860)
This phase 2 study of weekly KRd- Dara showed that a Dara-KRd induction, autologous transplant and Dara-KRd consolidation guided by MRD is feasible, safe and leads to high proportion of patients achieving CR/sCR, IMWG MRD-negative CR, imaging plus MRD-negative CR and MRD <10-6. With observing unprecedented rates (82%) of MRD-negative responses in NDMM, authors concluded that this approach can form the basis for clinical efforts to reduce the burden of continuous therapy in those with confirmed MRD-negative remissions.
ASH 2019: 8 cycles of weekly KRd-Dara in newly diagnosed Multiple Myeloma: A clinical and correlative phase 2 study. (abstract 862)
In this study, 77% of evaluable patients achieved MRD negativity without ASCT. The median time to MRD negativity was 6 cycles and no major clinical toxicity compared to the authors’ institution standard of care biweekly KRd were observed.
ASH 2019: KRd plus ASCT in high risk Smoldering Myeloma – 3 year follow-up of the GEM-CESAR trial. (abstract 781)
The phase 2 study analyzed the use of KRd + HDT/ASCT + consolidation with KRd + Rd maintenance in high-risk Smoldering Myeloma. In this study 56% of patients achieved MRD negativity after ASCT. The authors concluded that KRd presents a promising curative strategy, considering the improvement in the quality of response (CR and MRD-negativity) over time and the survival rates, with 92% of patients being progression-free and 96% alive at almost 3 years follow-up.
ASH 2019: KRd in NDMM – pooled analysis of 4 phase 1/2 studies in the transplant eligible and non-transplant eligible NDMM setting (abstract 1891)
More Carfilzomib @ ASH 2019: further data in different combinations in NDMM (KCD; KRd; KTd) are available upon request here.
IMW 2019: Real World Data of Kd in MM patients with cardiac history, commented by X. Leleu on eCancer
The elderly subgroup presented with comorbidities
in nearly all patients, and experienced more AEs Gr3+ than younger patients. Despite this, elderly Kd patients received similar CFZ administration compared to younger patients and achieved a similar response rate.
EHA 2019 : Carfilzomib Real World Data of KRd
EHA 2019: Carfilzomib in the frail MM patient
The frail Myeloma patient benefits from Carfilzomib, independent from frailty score (subgroup analyses from ENDEAVOR and ASPIRE, and from A.R.R.O.W; posters from Facon et al. & Mateos et al).
EHA 2019: FORTE trial - value of KRd plus ASCT vs KRd continuous in high risk NDMM, commented by F. Gay
EHA 2019: KRd once-weekly.
KRd56 once weekly
until progression demonstrated promising efficacy in RRMM (poster from C. Gruchet et al.)
EHA 2019: Kd maintenance.
EHA 2019: Carfilzomib in Smouldering Myeloma GEM-CESAR
Curative strategy for high-risk Smouldering Multiple Myeloma: KRd as induction followed by HDT-ASCT, consolidation with KRd and maintenance with Rd, commented by M-V. Mateos.
ASH 2018, Kd effective in lenalidomide-exposed and refractory patients and Overall Survival in MM patients with Early or Late relapse
Kd effective in Lenalidomide-exposed and refractory patients
In this combined analysis of ENDEAVOR, CHAMPION-1 and ARROW of Kd at first relapse, M-V. Mateos showed that median PFS was 15.6 months for lenalidomide-refractory patients (n = 32), and this is similar in magnitude to the median PFS of novel triplet therapies. (abstract#1963)
According to the authors, these data support demonstrate that Kd is an effective treatment option in MM patients relapsing on or after lenalidomide, including patients refractory to lenalidomide.
Overall Survival in MM patients with Early or Late relapse
Regardless of whether they had an early or late relapse, patients with KRd and Kd had longer OS benefit compared with those who received Rd and Vd. Late relapsers had a numerically greater magnitude of OS benefit with KRd and Kd compared with control arms than early relapsers. (analysis from ASPIRE and ENDEAVOR studies)
Posters presented by M-V. Mateos at ASH 2018 (abstracts #1963, #1964) are available for download
ASH 2018: ARROW Study sub-analyses: Kd70 once weekly by Age and by Prior lines
Once-weekly Kd70 demonstrated improved efficacy and comparable safety vs twice weekly Kd across age subgroups, including the elderly patients ≥75 years the incidence of ≥ grade 3 cardiovascular events was numerically similar or lower in Kd70 once weekly vs. Kd27/2x weekly in all age groups. Maximal benefit was achieved by patients aged < 65 years.
Once-weekly Kd resulted in a favorable benefit risk profile regardless of the number of prior lines (either 2 or 3). Although the median PFS was prolonged in both groups, the PFS was better if used earlier. Importantly, low incidences of heart failure were reported across all subgroups and no additional toxicities were found.
The posters of ARROW (abstracts #3277; #3244) presented by MA. Dimopoulos and by P. Moreau are available here
ASH 2018: Further phase 2 trials with Carfilzomib and trial updates in RRMM and NDMM
- EMN011/HO114 MM trial with KPd, by P. Sonneveld
- MUKfive (KCyd vs VCyd fixed duration plus K maintenance in first relapse) two analyses, by K. Yong: Outcomes based on Long-term follow up and cytogenetic risk in patients in first relapse (#306), and Effect of Carfilzomib maintenance on MRD following KCyd (#802)
- Venetoclax plus Carfilzomib in R/R multiple myeloma by L. Costa. (#303)
The EMN011 phase 2 trial with KPd in MM patients refractory to bortezomib and lenalidomide demonstrates that KPd is a feasible, effective and safe triple drug regimen in RRMM patients who have been previously treated and/or are refractory to bortezomib and refractory to lenalidomide. An 87% overall response rate including 31% CR/sCR is clinically relevant in this population. Since median OS has not been reached, longer follow-up is needed.
The slides of the four Orals
CoMMpass observational study: KRd vs VRd in real-word patients with NDMM
(Oral presented by O. Landgren, ASH 2018)
Patients treated with KRd demonstrated statistically significant improvements in event-free survival, and a faster and deeper response (sCR) compared to those treated with VRd.
This observational study suggests that KRd is effective and may be a superior treatment option to VRd for patients with NDMM.
FORTE trial: KRd vs KCyd in Newly Diagnosed Multiple Myeloma
F. Gay presented the analysis of efficacy and safety of KRd induction-ASCT-KRd consolidation versus KRd 12 Cycles versus KCyd induction-ASCT-KCyd consolidation.
The treatment with KRd (+/-transplant) led to deeper responses than KCyd in the transplant-eligible NDMM setting. Although longer follow up is needed, the analysis of KRd Induction-ASCT-KRd consolidation versus KRd 12 Cycles showed that KRd 12 cycles achieves a comparable MRD- rate (51% vs 58% with ASCT) pre-maintenance.
presentation of FORTE is available here
GEM-CESAR update: KRd in high-risk Smouldering Myeloma
The poster (abstract #2142) presented by M-V. Mateos is available here
ASCO & EHA 2018
ARROW Study – MV. Mateos demonstrated in her presentation that the once weekly application with Carfilzomib and dexamethasone in patients with relapsed/refractory Multiple Myeloma achieved a better progression free survival with a better tolerance compared to the twice weekly application.
The phase 3 study investigated the once weekly application of Carfilzomib (70mg/m2 on days 1, 8 and 15; over 30 minutes infusion) in combination with dexamethasone compared to a twice weekly administration of Carfilzomib (27mg/m2 2x per week: day 1, 2, 8, 9, 15, 16) in combination with dexamethasone in relapsed and refractory patients. Patients must have received at least 2 previous therapies including bortezomib and IMiDs. In both arms Carfilzomib in the first cycle has been initiated on day 1, resp. on day 1 and 2 with a starting dose of 20mg/m2 before escalating on day 8 to the target dose of 70mg/m2 resp. 27mg/m2.
The primary endpoint was the superiority of the once weekly dosis of 70mg/m2 in PFS. One of the most relevant secondary endpoints was the tolerance of the higher, elevated weekly Carfilzomib dose.
Per eligibility criteria only patiens in the 3rd or 4th therapy line could be enrolled to the study.
The primary endpoint PFS has been clearly achieved with a significantly improved PFS of 11,2 months with Carfilzomib 70mg/m2 once weekly versus 7,6 months with Carfilzomib 27mg/m2 twice weekly. This resulted to a longer treatment duration in the once weekly arm with a comparable safety profile between both arms. Thus the study could demonstrate that the once weekly application of Carfilzomib in a higher dose is effective and well tolerated and for patients a more comfortable alternative to the twice weekly application.
At study entry almost 75% of patients were refractory to lenalidomide and about 45% were refractory to bortezomib. That means that this patient population was more advanced compared to the patients in both studies ASPIRE (KRd27 2x/week) and ENDEAVOR (Kd56 2x/week) and had a median of 3 prior therapies.
In addition updates of two randomised studies FORTE (KRd vs KCyd in Newly Diagnosed Patients with MM) and MUKfive (KCyd vs. VCyd as second line therapy) were presented, as well as some phase 2 studies, that analysed Carfilzomib in various combinations and dosings.
ASPIRE Overall Survival analysis – Oral presentation by AK. Stewart
At ASH 2017 the final Overall Survival data of the ASPIRE study were presented (KRd27 vs Rd in patients with relapsed or refractory multiple myeloma). The addition of Carfilzomib to Rd prolonged the survival of patients of a median 7,9 months and could reduced the risk of death by 21%.
ASPIRE and ENDEAVOR subgroup analysis Early vs. Late relapse – Poster presentation by MV. Mateos
The subgroup analysis of Early vs. Late relapse of the ASPIRE (KRd27 vs Rd) and ENDEAVOR study (Kd56 vs. Vd) in patients with RRMM could show that all patients independent of the kind of relapse could benefit of Carfilzomib vs. Standard of Care in terms of PFS.
In the ASPIRE study the addition of Carfilzomib to lenalidomide and dexamethasone could prolong the median PFS by 10,7 months in patients with early relapse vs. Rd alone. In patients with a late relapse the prolongation of PFS was 11,5 months.
In the ENDEAVOR-study Carfilzomib (Kd56) compared to bortezomib (Vd) could extend the median PFS by 8,2 months in patients with early relapse and by 12 months in patients with late relapse.
This analysis shows, that even patients with an early, aggressive disease progression can benefit from a therapy with Carfilzomib.
ENDEAVOR Overall Survival subgroup analysis by age- Poster presentation by R. Niesvizky
The subgroup analysis showed for the Carfilzomib arm for all age groups a clinical relevant prolongation of overall survival, including the patients with 75 years and older. These data reinforce the favorable benefit-risk-ratio of Kd56 in patients with relapse or refractory multiple myeloma.
ENDEAVOR Overall Survival subgroup analysis by renal function - Poster presentation by MA. Dimopoulos
This subgroup analysis showed that Carfilzomib is effective independent of the renal function (in terms of PFS and OS), including patients with a poor creatinine clearance (CrCL ≥15 to <50 mL/min).
In addition the randomised study MUKfive
(KCyd vs. VCyd as 2L therapy in multiple myeloma) was presented as an Oral
IMW 2017 (International Myeloma Workshop)
ENDEAVOR Overall Survival analysis – oral presentation by MA. Dimopoulos
The overall survival data of the ENDEAVOR study have been presented at this congress. The addition of Carfilzomib to dexamethasone prolonged the survival of patients by a median of 7,9 months compared to Vd (median OS 47,6 months for Kd56 vs 40,0 months for Vd, HR = 0,79, 95% CI: 0.65, 0.96; p = 0,01) and could reduce the risk of death by 21%.
CLARION primary analysis – oral presentation by T. Facon
Presentation of the CLARION study of KMP vs VMP in non-transplant eligible patients with NDMM.
Slide deck is available for download
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