Safety Of Carfilzomib Research Articles

Real-life effectiveness of carfilzomib in patients with relapsed multiple myeloma receiving treatment in the context of early access: The CARMYN study.

The real-life retrospective observational study CARMYN aimed at investigating the long-term efficacy and safety of carfilzomib in combination with dexamethasone and lenalidomide (KRd, 159 patients). These patients (62% in first and 38% in second relapse, median age 62 yo) were treated between 02/2014 and 02/2017. Most had been pre-exposed to bortezomib (98.2%) and to an IMID (75.4%). At the time of collection, 90% had permanently discontinued carfilzomib. Data collection was conducted from January to July 2021 in 27 participating sites, after a median of 39 months follow-up. For patients treated with KRd, an overall response rate of 78.4% translated in a median progression free survival (PFS) of 24.0 months (95% CI 18.8-27.6) and a median overall survival (OS) of 51.1 months (95% CI 41.3-not reached). Results were poorer but difficult to interpret in the small cohort of Kd recipients. The study is one of the longest real-life studies of carfilzomib treatment in patients in first or second relapse. CARMYN confirmed the real-life long-term efficacy of carfilzomib in combination with lenalidomide and dexamethasone with results similar to those of clinical trials. The KRd regimen is thus an option to consider for late relapses in the current context of MM management.

Real-world use of carfilzomib combined with lenalidomide and dexamethasone in patients with multiple myeloma in Europe and Israel.

Clinical trials have demonstrated the efficacy and safety of carfilzomib in patients with relapsed/refractory multiple myeloma (RRMM); however, prospective real-world data are limited. This real-world, prospective, observational study evaluated carfilzomib use, effectiveness and safety in adults with RRMM. Data are presented for a subset of patients (n=383) who received carfilzomib in combination with lenalidomide and dexamethasone (KRd). The overall response rate (ORR) was 83.6% among 360 evaluable patients. Treatment responses were better when KRd was administered at earlier therapy lines than at later lines of therapy (ORR: second line, 85.3%; third line or later, 81.0%). In patients with the anti-CD38 antibody-refractory disease, ORR was higher when KRd was administered earlier than at later therapy lines (second line/third line, 75.0%; fourth line or later, 60.0%). An ORR of 68.1% and 82.0% was achieved in the lenalidomide-refractory and not lenalidomide-refractory subgroups, respectively. KRd was consistently administered per the European label (twice weekly dose of 27mg/m2) and the median time to discontinuation was 14.6 months. The safety profile of KRd was consistent with previous studies. These real-world data highlight the effectiveness of KRd as a treatment for patients with RRMM, including those with disease refractory to lenalidomide or anti-CD38 antibodies.

Addition of carfilzomib as a third agent in lenalidomide-refractory multiple myeloma: Switching from doublet to triplet.

e20002 Background: Carfilzomib is an epoxyketone proteasome inhibitor of second generation, proved to be effective and safe in relapsed and refractory Multiple Myeloma (rrMM), in combination with dexamethasone or lenalidomide and dexamethasone. In this retrospective observational trial, it has been evaluated efficacy and safety of carfilzomib, in combination with lenalidomide-dexamethasone (KRD) as salvage regimen in patients with rrMM, refractory to lenalidomide, where lenalidomide-based regimens have no proven efficacy. Methods: 41 patients (23 M/18 F), with rrMM, median age at diagnosis 63.7 years (r. 43-82), median age at start of treatment 67 years (r. 48-84) previously treated with several lines of treatments (median 3, r. 2-11), underwent to KRD regimen (ASPIRE trial schedule) for a median treatment cycles of 8 (r 2-18). ISS was equally distributed, and all patients had previously been treated with bortezomib and IMIDs, and were refractory to this agents. 61% (19/31) of them had undergone at least to a single ASCT. Results: According to IMWG criteria, after a median follow-up of 9 months (r. 2-18), ORR was 68,2% (28/41: 9 CR, 12 VGPR, 7 PR) with 5 progressive diseases (PD) and 8 patients in stable disease (SD): this can be considered as an impressive result in this subset of rrMM patients, refractory to lenalidomide. In particular, for 11 patients, KRD was, after having achieved at least a PR, a bridge to second/third autologous SCT. Median time to response was 1.3 months (r.1-4), median OS from diagnosis was 62 months (r. 9-170), median OS from start of Carfilzomib was 11 months (r. 2-18). Carfilzomib was well tolerated, with grade 2 anemia in 39%(16/41) of patients, successfully managed by ESAs, without necessity of blood transfusions; 29% (12/41) grade 3-4 neutropenia (pegfilgrastim in primary prophylaxis was given, no ospedalization was required, no septic shocks were observed); 34% (14/41) grade 2, 21% (9/41) grade 3 and 12% (5/41) grade 4 thrombocytopenia, without hemorrhagic events and transfusion-dependency. Moreover, it was observed pneumonia in 39% (16/41) of patients, treated by common antibiotic drugs and always solved. A cardiac monitoring was performed for all patients: hypertension (grade 2-3) in 34% (14/41) of patients; fatigue in 39% (16/31) of patients. Conclusions: Carfilzomib-Lenalidomide-Dexamethasone has shown significant efficacy in a particularly severe setting of patients, relapsed and refractory to all available therapeutic resources, also lenalidomide, and it could be considered as a bridge to a second autologous or allogenic SCT. Clinical trial information: A108.

Clinical impacts of frailty, poor performance status, and advanced age in carfilzomib-containing treatment for relapsed/refractory multiple myeloma: post hoc investigation of the KOTOSG multicenter pilot prospective observational study.

We conducted a post hoc analysis of our previous pilot observational study on the efficacy and safety of carfilzomib (CFZ)-containing therapy in 50 patients with relapsed/refractory multiple myeloma in routine practice to clarify the relationships between three major criteria for vulnerability (frailty, poor performance status [PS], and advanced age [≥ 75years]) and their clinical impact on efficacy and adverse events (AEs). Sixteen patients fulfilled at least one and five patients fulfilled all three criteria. The overall response rate was not significantly affected by frailty, poor PS, and/or advanced age; however, frailty and advanced age were significantly associated with shorter progression-free survival (PFS). In contrast, no significant difference in PFS was observed between patients with PS0-1 or PS2-4. The three criteria for vulnerability were associated with more frequent hematologic AEs: frailty, poor PS, and/or advanced age significantly increased the risk of grade 3-4 anemia and lymphopenia. However, these criteria were not associated with increased risk of other non-hematologic AEs except infection. Collectively, these results demonstrate the need to carefully manage severe hematologic AEs in vulnerable patients and perform disease-specific assessment of frailty to predict prognosis.

Phase 2 Study of Carfilzomib in Combination with Induction Chemotherapy in Children with Relapsed or Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)

Phase 2 Study of Carfilzomib in Combination with Induction Chemotherapy in Children with Relapsed or Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)

Outcome of treatment with carfilzomib before and after treatment with daratumumab in relapsed or refractory multiple myeloma patients.

Real world evidence is important since most patients cannot be included in randomized clinical trials (RCTs). In a nationwide, cohort of relapsed/refractory multiple myeloma patients treated with daratumumab (N=635), we retrospective studied patients treated with carfilzomib (N=251). Data were collected by audit of medical records. We compared characteristics of patients treated with carfilzomib before daratumumab (Car-Da; N=150) and after daratumumab (Da-Car; N=101) with those not treated with carfilzomib (N=384). Furthermore, we examined effectiveness and safety of carfilzomib. The group of patients treated with carfilzomib differed from patients not treated with carfilzomib in the following parameters: They were younger, more were treated up-front with high dose melphalan and autologous stem cell transplantation (HDM-ASCT)and had relapse within 18 months thereafter, and more had high-risk cytogenetic abnormalities (CA) and amplification 1q (amp1q). In patients treated with Car-Da, 30.3% had high-risk CA and 30.1% had amp1q and in Da-Car it was 43.3% and 41%, respectively. In the Car-Da cohort, 34.4% experienced early relapse after HDM-ASCT versus 47.4% in the Da-Car cohort. The percentage of patients with very good partial remission was higher in patients treated with Car-Da compared to Da-Car (31.7% vs. 17.4%). The median duration of treatment and time to next treatment (TNT) of Car-Da/Da-Car were 4.6/4.3 months and 7.1/4.3 months and only a trend toward superior TNT for Car-Da was found (p=0.06). Toxicity of carfilzomib was the same as reported in RCT. A similar poor TNT of daratumumab was found when used before (5.6 months) or after carfilzomib (4.9 months). In this cohort of patients with sequential treatment with carfilzomib and daratumumab or vice versa, a high percentage of patients were high-risk by CA, amp1q, and early relapse after HDM-ASCT. Outcome of Car-DA and outcome of Da-Car were equally poor. These patients should be considered for new promising treatment strategies.

Carfilzomib Is Safe and Effective in Newly Diagnosed Patients with Multiple Myeloma with Renal Involvement

Background. Carfilzomib is a proteasome inhibitor, currently approved for use in relapse-refractory Multiple Myeloma (RRMM).1 There is mixed data on safety of Carfilzomib in patients (pts) with renal impairment (RI) and minimal in the upfront setting, partly due to exclusion of these pts from trials. Pooled data from phase 2 studies of single-agent Carfilzomib in RRMM, noted 24.1% acute kidney injury (AKI), including 23.8% of pts with moderate to severe renal dysfunction (CrCl<50 mL/min).2 Interestingly, severity of renal insufficiency did not have an effect on incidence of toxicity nor overall response rate.3 However, in FOCUS (single agent Carfilzomib vs Dexamethasone +/- Cyclophosphamide in RRMM), grouped renal events were three times more common in patients with baseline CrCl<30ml/min than those with CrCl>50 ml/min.4We previously reported on 71 pts receiving induction Carfilzomib, whose baseline RI was associated with incidence of AKI. Of pts with normal renal function, 36% developed AKI, compared to 59% and 62.5% of those with mild and moderate impairment, respectively.5 Current management dictates dose reduction only once CrCl ≥ 15ml/min.6 The aim of this retrospective study is to report on the safety profile and efficacy of induction Carfilzomib in pts with RI of newly diagnosed MM as evidenced by proteinuria.Methods. Patients were selected from the CarBiRd study (induction Carfilzomib and Dexamethasone; with subsequent Clarithromycin, Lenalidomide, and Dexamethasone; with Lenalidomide maintenance) at the Weill Cornell Medicine Myeloma Center. Pts were grouped based on renal involvement of myeloma. Baseline renal function was established by measuring pre-enrollment GFR using the Modification of Diet in Renal Disease (MDRD) equation. Subjects were stratified into 3 sub-groups: normal function (GFR>80 ml/min/1.732), mild impairment (GFR 50-80 ml/min/1.732), and moderate impairment (GFR 30-49 ml/min/1.732). Incidence of AKI was assessed during induction with Carfilzomib and Dexamethasone only. AKI was defined by increased serum creatinine (sCr) according to the National Cancer Institute's Common Terminology Criteria for Adverse Events Version 4.0.6 sCr and m-protein were measured prior to therapy and upon completion of Carfilzomib/dex induction. Overall response and toxicity were also assessed.Results. 75 patients were enrolled in the CarBiRd study. One withdrew for fever and AKI. Of the 61 patients with evaluable urine m-protein, 23 had normal kidney function, 15 mild impairment, and 3 moderate impairment. AKI was seen in 34.8% of patients with normal renal function, 53.3% with mild and 33.3% with moderate impairment. Of the 17 patients who had AKI, 70.6% had a return sCr within 0.15 mg/dl of baseline. Mean number of cycles of Carfilzomib was 5 (range 3-12). The mean fall in m-protein at end Carfilzomib was 87.4%.Of patients without proteinuria, 10 had normal kidney function, 7 had mild impairment, and 3 had moderate impairment. In pts with normal function 40% developed AKI, whereas those with mild and moderate impairment reported 71.4% and 66.6%, respectively. Mean number of cycles of Carfilzomib was 6.2 (range 3-14). Of the 11 patients who developed AKI, 91% had a return to serum creatinine within 0.15 mg/dl of baseline.Discussion. Data on renal toxicity of carfilzomib in patients with renal involvement of myeloma are limited to date, confounded by exclusion of renal impairment from studies, data mainly in the RRMM setting where prior or concurrent drug exposure may play a role. Previous data indicate baseline renal impairment may predict AKI. We report on a cohort of pts with newly diagnosed myeloma who received carfilzomib/dexamethasone induction, where renal involvement did not predict increased toxicity. In addition, most cases of reported AKI resolved prior to next week dosing, and required no intervention beyond hydration. We acknowledge the small cohort and single-arm, single-center nature of the study. As seen previously, response to therapy does not appear to be affected by renal impairment. At this time, myeloma kidney and decreased GFR should not preclude use of carfilzomib in pts with myeloma. [Display omitted] DisclosuresPerry:celgene: Honoraria. Pekle:celgene: Honoraria; BMS: Honoraria. Niesvizky:BMS: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Amgen: Consultancy. Rossi:Thrassos: Consultancy; Celgene: Consultancy.

Long-Term Follow-up of a Prospective Clinical Trial of Carfilzomib, Rituximab and Dexamethasone (CaRD) in Waldenstrom's Macroglobulinemia

The proteasome-inhibitor bortezomib is active in Waldenstrom's macroglobulinemia (WM) though is associated with considerable peripheral neuropathy (PN) that results in frequent dose reduction and treatment discontinuation. We therefore examined the efficacy and safety of carfilzomib, a neuropathy-sparing proteasome-inhibitor, along with rituximab, and dexamethasone (CaRD) in 31 proteasome inhibitor-naive and rituximab-naive symptomatic WM patients. The preliminary findings of this study were previously published (Treon et al, Blood 2014), and herein we provide a long-term update of this study. The median baseline characteristics for patients enrolled on this prospective clinical trial were as follows: Age 61 (range 47-75 years), prior therapies 0 (range 0-1), hematocrit 32.3%, serum IgM 3,375 mg/dL, serum B2M 3.6 mg/L, and bone marrow disease involvement 60%. Therapy consisted of IV carfilzomib 20mg/m2 (cycle 1) and 36mg/m2 (cycles 2 and beyond) along with IV dexamethasone 20 mg on days 1, 2, 8, 9. Rituximab 375 mg/m2 was administered on days 2, 9 of each 21-day cycle. Treatment consisted of six 21-day induction cycles, followed by maintenance therapy that was given every 8 weeks for eight cycles and consisted of carfilzomib 36 mg/m2 and IV dexamethasone 20 mg on days 1, 2. Rituximab was given at 375 mg/m2 on day 2 of each maintenance cycle. Following protocol therapy, the median serum IgM levels declined to 561 mg/dL at best response (p<0.00001). Median hematocrit rose to 41.9% (p<0.00001). Thirty patients completed induction therapy, with reduction in bone marrow tumor burden from a median of 60% to 7.5% at end of induction (p<0.0001). Twenty patients completed maintenance therapy and had a bone marrow tumor burden reduction to 2.5% at end of maintenance treatment (p<0.0001 versus pre-treatment baseline; p=0.0088 versus end of induction). The best overall response was 80.64% (1 CR, 11 VGPR, 10 PR, 3 MR), and major response rate was 71%. Median time to response (MR or better) was 2.1 months. As shown in Figure 1A, the median progression-free survival (PFS) for all patients was reached at 46 months (range 2-63 months). PFS was associated with depth of response. Patients who achieved at least a VGPR have not reached median PFS, whereas the median PFS was 52 months for those who attained a PR, and 4 months for those with less than a PR (Figure 1B; Chi-square 35.5, p<0.0001). All patients are alive, and 14 patients remain in follow-up without a progression event.Grade >2 treatment-related toxicities included elevated lipase (12.9%), steroid-related hyperglycemia (6.45%), neutropenia (9.67%), and reversible cardiomyopathy in a patient with multiple risk factors (3.22%). Only one grade 2 PN (3.2%), and no grade 3/4 PN events occurred. At baseline, the median serum IgA level was 47 mg/dL, versus 46 mg/dL at last follow-up (p=0.11). Conversely, median serum IgG levels declined from 715 mg/dL at baseline to 372 mg/dL at last follow-up (p=0.0004). Treatment related IgG hypogammaglobulinemia was associated with recurring sino-bronchial infections, and necessitated IVIG treatment in 6 (19.4%) patients. Discontinuation of protocol therapy occurred for non-response (n=8), hypogammaglobulinemia associated with infections (n=2), grade 2 PN (n=1), cardiomyopathy (n=1), progressive disease (n=1), and prolonged hold of protocol therapy for an unrelated procedure (n=1). The long-term results of this study show that CaRD is an active, PN-sparing regimen that is associated with durable responses in symptomatic patients with WM. PFS is impacted by depth of response, and IgG hypogammaglobulinemia is commonly encountered with this regimen. [Display omitted] DisclosuresCastillo:Pharmacyclics: Consultancy, Research Funding; Millennium: Research Funding; Abbvie: Research Funding; Janssen: Consultancy, Research Funding. Treon:Pharmacyclics: Consultancy, Research Funding.

Carfilzomib-Lenalidomide-Dexamethasone in the Management of Lenalidomide-Refractory Multiple Myeloma

Background Carfilzomib is an epoxyketone proteasome inhibitor of second generation, proved to be effective and safe in relapsed and refractory Multiple Myeloma (rrMM), in combination with dexamethasone or lenalidomide and dexamethasone. Aims In this retrospective observational trial, it has been evaluated efficacy and safety of carfilzomib, in combination with lenalidomide-dexamethasone (KRD) as salvage regimen in patients with rrMM, refractory to lenalidomide, where lenalidomide-based regimens have no proven efficacy. Methods 41 patients (23 M/18 F), with rrMM, median age at diagnosis 63.7 years (r. 43-82), median age at start of treatment 67 years (r. 48-84) previously treated with several lines of treatments (median 3, r. 2-11), underwent to KRD regimen (ASPIRE trial schedule) for a median treatment cycles of 8 (r 2-18). ISS was equally distributed, and all patients had previously been treated with bortezomib and IMIDs, and were refractory to this agents. 61% (19/31) of them had undergone at least to a single ASCT. Results According to IMWG criteria, after a median follow-up of 9 months (r. 2-18), ORR was 68,2% (28/41: 9 CR, 12 VGPR, 7 PR) with 5 progressive diseases (PD) and 8 patients in stable disease (SD): this can be considered as an impressive result in this subset of rrMM patients, refractory to lenalidomide. In particular, for 11 patients, KRD was, after having achieved at least a PR, a bridge to second/third autologous SCT. Median time to response was 1.3 months (r.1-4), median OS from diagnosis was 62 months (r. 9-170), median OS from start of Carfilzomib was 11 months (r. 2-18). Carfilzomib was well tolerated, with grade 2 anemia in 39%(16/41) of patients, successfully managed by ESAs, without necessity of blood transfusions; 29% (12/41) grade 3-4 neutropenia (pegfilgrastim in primary prophylaxis was given, no ospedalization was required, no septic shocks were observed); 34% (14/41) grade 2, 21% (9/41) grade 3 and 12% (5/41) grade 4 thrombocytopenia, without hemorrhagic events and transfusion-dependency. Moreover, it was observed pneumonia in 39% (16/41) of patients, treated by common antibiotic drugs and always solved. A cardiac monitoring was performed for all patients: hypertension (grade 2-3) in 34% (14/41) of patients; fatigue in 39% (16/31) of patients. Conclusions Carfilzomib-Lenalidomide-Dexamethasone has shown significant efficacy in a particularly severe setting of patients, relapsed and refractory to all available therapeutic resources, also lenalidomide, and it could be considered as a bridge to a second autologous or allogenic SCT. Disclosures Lucchesi: Incyte: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Martinelli:Amgen: Consultancy; Celgene: Consultancy, Speakers Bureau; Jazz: Consultancy; Incyte: Consultancy; Pfizer: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy; Daichii Sankyo: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Janssen: Consultancy.

MM-385: Carfilzomib-Lenalidomide-Dexamethasone in the Management of Lenalidomide-Refractory Multiple Myeloma

Background Carfilzomib is an epoxyketone proteasome inhibitor of second generation, proved to be effective and safe in relapsed and refractory Multiple Myeloma (rrMM), in combination with dexamethasone or lenalidomide and dexamethasone. Aims In this retrospective observational trial, it has been evaluated efficacy and safety of carfilzomib, in combination with lenalidomide-dexamethasone (KRD) as salvage regimen in patients with rrMM, refractory to lenalidomide, where lenalidomide-based regimens have no proven efficacy. Methods 41 patients (23 M/18 F), with rrMM, median age at diagnosis 63.7 years (r. 43-82), median age at start of treatment 67 years (r. 48-84) previously treated with several lines of treatments (median 3, r. 2-11), underwent to KRD regimen (ASPIRE trial schedule) for a median treatment cycles of 8 (r 2-18). ISS was equally distributed, and all patients had previously been treated with bortezomib and IMIDs, and were refractory to this agents. 61% (19/31) of them had undergone at least to a single ASCT. Results According to IMWG criteria, after a median follow-up of 9 months (r. 2-18), ORR was 68,2% (28/41: 9 CR, 12 VGPR, 7 PR) with 5 progressive diseases (PD) and 8 patients in stable disease (SD): this can be considered as an impressive result in this subset of rrMM patients, refractory to lenalidomide. In particular, for 11 patients, KRD was, after having achieved at least a PR, a bridge to second/third autologous SCT. Median time to response was 1.3 months (r.1-4), median OS from diagnosis was 62 months (r. 9-170), median OS from start of Carfilzomib was 11 months (r. 2-18). Carfilzomib was well tolerated, with grade 2 anemia in 39%(16/41) of patients, successfully managed by ESAs, without necessity of blood transfusions; 29% (12/41) grade 3-4 neutropenia (pegfilgrastim in primary prophylaxis was given, no ospedalization was required, no septic shocks were observed); 34% (14/41) grade 2, 21% (9/41) grade 3 and 12% (5/41) grade 4 thrombocytopenia, without hemorrhagic events and transfusion-dependency. Moreover, it was observed pneumonia in 39% (16/41) of patients, treated by common antibiotic drugs and always solved. A cardiac monitoring was performed for all patients: hypertension (grade 2-3) in 34% (14/41) of patients; fatigue in 39% (16/31) of patients. Conclusions Carfilzomib-Lenalidomide-Dexamethasone has shown significant efficacy in a particularly severe setting of patients, relapsed and refractory to all available therapeutic resources, also lenalidomide, and it could be considered as a bridge to a second autologous or allogenic SCT. Disclosures Lucchesi: Incyte: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Martinelli: Amgen: Consultancy; Celgene: Consultancy, Speakers Bureau; Jazz: Consultancy; Incyte: Consultancy; Pfizer: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy; Daichii Sankyo: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Janssen: Consultancy.

Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study

Lenalidomide and bortezomib frontline exposure has raised a growing need for novel treatments for patients with relapsed or refractory multiple myeloma. Carfilzomib in combination with daratumumab has shown substantial efficacy with tolerable safety in relapsed or refractory multiple myeloma in a phase 1 study. In this study, we aimed to compare the efficacy and safety of carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma. In this randomised, multicentre, open-label, phase 3 study, 466 patients recruited from 102 sites across North America, Europe, Australia, and Asia with relapsed or refractory multiple myeloma were randomly assigned 2:1 to carfilzomib, dexamethasone, and daratumumab (KdD) or carfilzomib and dexamethasone (Kd). All patients received twice per week carfilzomib at 56 mg/m2 (20 mg/m2; days 1 and 2 during cycle 1). Daratumumab (8 mg/kg) was administered intravenously on days 1 and 2 of cycle 1 and at 16 mg/kg weekly for the remaining doses of the first two cycles, then every 2 weeks for four cycles (cycles 3-6), and every 4 weeks thereafter. Patients received 40 mg dexamethasone weekly (20 mg for patients ≥75 years old starting on the second week). The primary endpoint was progression-free survival assessed by intention to treat. Adverse events were assessed in the safety population. This trial (NCT03158688) is registered with ClinicalTrials.gov, and is active but not recruiting. Between June 13, 2017, and June 25, 2018, 466 patients of 569 assessed for eligibility were enrolled. After median follow-up of approximately 17 months, median progression-free survival was not reached in the KdD group versus 15·8 months in the Kd group (hazard ratio 0·63; 95% CI 0·46-0·85; p=0·0027). Median treatment duration was longer in the KdD versus the Kd group (70·1 vs 40·3 weeks). Grade 3 or higher adverse events were reported in 253 (82%) patients in the KdD group and 113 (74%) patients in the Kd group. The frequency of adverse events leading to treatment discontinuation was similar in both groups (KdD, 69 [22%]; Kd, 38 [25%]). KdD significantly prolonged progression-free survival versus Kd in patients with relapsed or refractory multiple myeloma and was associated with a favourable benefit-risk profile. Amgen.

Efficacy and safety of carfilzomib, dexamethasone, daratumumab (KdD) twice-weekly at 56 mg/m2 and once-weekly at 70 mg/m2 in relapsed or refractory multiple myeloma (RRMM): Cross-study comparison of candor and MMY1001.

8526 Background: CANDOR, a randomized phase 3 study, showed significantly improved progression-free survival (PFS) and overall response rate (ORR) for twice-weekly KdD 56 mg/m2(TW KdD56) vs Kd in RRMM, with a 37% risk reduction in disease progression or death (Usmani, 2019). The benefit of once-weekly carfilzomib (K) at 70mg/m2 for the same triplet, KdD (OW KdD70), in RRMM was shown in the nonrandomized MMY1001 study. We performed robust cross-study comparisons to investigate how TW KdD56 compares to OW KdD70. Methods: For alignment of inclusion criteria, the primary analysis set for this cross-study comparison included individual data from CANDOR pts with prior exposure to bortezomib and immunomodulatory drug, and all pts in MMY1001. Propensity score method (Rambaldi, 2019; Kumar, 2019) allowed reliable cross-study comparison, controlling for baseline prespecified covariates such as age, creatinine clearance, performance status, prior treatment exposure/refractoriness, and time from initial diagnosis and relapse. Propensity score adjustment based on inverse probability of treatment weighting (IPTW) was implemented on efficacy endpoints, while safety was evaluated side-by-side. Results: The unadjusted and adjusted propensity score comparison of CANDOR and MMY1001 showed similar efficacy in terms of ORR and PFS in the TW KdD56 and OW KdD70 groups (Table). As propensity score comparisons were for efficacy only, safety comparisons between CANDOR and MMY1001 included differing sample sizes and treatment duration (Table). The safety of KdD56 and KdD70 was consistent with the known safety profiles of individual study treatments. Conclusions: OW KdD70 is an efficacious dosing option with favorable benefit-risk, comparable to TW KdD56. The OW KdD70 dosing option represents a more convenient regimen that might encourage adherence and potentially lead to better outcomes for RRMM pts. Clinical trial information: NCT03158688 . [Table: see text]

Carfilzomib Based Treatment Strategies in the Management of Relapsed/Refractory Multiple Myeloma with Extramedullary Disease.

Published experience with carfilzomib in patients with relapsed/refractory multiple myeloma (RRMM) and extramedullary disease (EMD) is still limited. The current study aimed to assess the efficacy and safety of carfilzomib containing therapy regimens in EMD. We retrospectively analyzed 45 patients with extramedullary RRMM treated with carfilzomib from June 2013 to September 2019. The median age at the start of carfilzomib was 64 (range 40–80) years. Twenty (44%) and 25 (56%) patients had paraosseous manifestation and EMD without adjacency to bone, respectively. The serological overall response rate (ORR) was 59%. Extramedullary response was evaluable in 33 patients, nine (27%) of them achieved partial remission (PR) (ORR = 27%). In 15 (33%) patients, we observed no extramedullary response despite serological response. The median progression-free survival (PFS) and overall survival (OS) were five (95% CI, 3.5–6.5) and ten (95% CI, 7.5–12.5) months, respectively. EMD without adjacency to bone was associated with a significantly inferior PFS (p = 0.004) and OS (p = 0.04) compared to paraosseous lesions. Carfilzomib based treatment strategies showed some efficacy in heavily pretreated patients with extramedullary RRMM but could not overcome the negative prognostic value of EMD. Due to the discrepancy between serological and extramedullary response, evaluation of extramedullary response using imaging is mandatory in these patients.

Efficacy and Safety of Carfilzomib in the Treatment of Multiple Myeloma：A Systematic Evaluation

To evaluate the efficacy and safety of carfilzomib in the treatment of multiple myeloma (MM). Computer was used to search PubMed, EMbase, Cochrane library and MEDLINE databases for carfilzomib treatment of MM. Clinical features and results were extracted and meta-analysis was performed using Stata12.0 software. Twelve eligible Phase I/II, II and III clinical trials of carfilzomib were extracted and 2 487 MM patients involved in evaluable. The summary analysis showed that the rate of complete response (CR) of carfilzomib treatment was 28%, the rate of ≥very good partial response (VGPR) was 73%, and the rate of overall response rate (0RR) was 93%; the 1-year progression-free survival (PFS) rate of MM patients was 93%, the 2-year PFS rate was 85%, and the 3-year PFS rate was 74%. Three randomized controlled trials showed a significant improvement in ORR [OR=1.644, 95% CI=(1.056, 2.560) ] (P＜0.05) and clinical benefit rate (CBR) in MM patients [OR=1.595, 95%) CI=(1.044, 2.435) ] (P＜0.05). Compared with the control group, the OR of cardiotoxicity (P＜0.05) was significantly increased, while that of peripheral neuropathy (P＞0.05) was not significantly changed. Compared with traditional treatments, carfilzomib significantly improves survival in the patients with multiple myeloma without increasing the incidence of peripheral neuropathy, but the incidence of cardiotoxicity seems higher.

Efficacy and Safety of Carfilzomib in the Treatment of Multiple Myeloma：A Systematic Evaluation

To evaluate the efficacy and safety of carfilzomib in the treatment of multiple myeloma (MM). Computer was used to search PubMed, EMbase, Cochrane library and MEDLINE databases for carfilzomib treatment of MM. Clinical features and results were extracted and meta-analysis was performed using Stata12.0 software. Twelve eligible Phase I/II, II and III clinical trials of carfilzomib were extracted and 2 487 MM patients involved in evaluable. The summary analysis showed that the rate of complete response (CR) of carfilzomib treatment was 28%, the rate of ≥very good partial response (VGPR) was 73%, and the rate of overall response rate (0RR) was 93%; the 1-year progression-free survival (PFS) rate of MM patients was 93%, the 2-year PFS rate was 85%, and the 3-year PFS rate was 74%. Three randomized controlled trials showed a significant improvement in ORR [OR=1.644, 95% CI=(1.056, 2.560) ] (P＜0.05) and clinical benefit rate (CBR) in MM patients [OR=1.595, 95%) CI=(1.044, 2.435) ] (P＜0.05). Compared with the control group, the OR of cardiotoxicity (P＜0.05) was significantly increased, while that of peripheral neuropathy (P＞0.05) was not significantly changed. Compared with traditional treatments, carfilzomib significantly improves survival in the patients with multiple myeloma without increasing the incidence of peripheral neuropathy, but the incidence of cardiotoxicity seems higher.

A Randomized Phase 2 Trial Comparing Carfilzomib-Dexamethasone Vs Observation As Maintenance after Induction with Carfilzomib-Cyclophosphamide-Dexamethasone in Salvage ASCT in Multiple Myeloma: A Trial By the Nordic Myeloma Study Group

A Randomized Phase 2 Trial Comparing Carfilzomib-Dexamethasone Vs Observation As Maintenance after Induction with Carfilzomib-Cyclophosphamide-Dexamethasone in Salvage ASCT in Multiple Myeloma: A Trial By the Nordic Myeloma Study Group

Comparative Efficacy and Safety of Once Versus Twice Weekly Carfilzomib Based Therapies in Relapsed Refractory Multiple Myeloma- a Systematic Review

Introduction: Carfilzomib use as a single agent or in combination has been shown to improve outcomes in relapsed refractory multiple myeloma (RRMM). Traditionally, carfilzomib has been administered in twice-weekly dosage schemes as compared to the newly approved once-weekly dosage scheme. The once-weekly dosing of carfilzomib is thought to provide same efficacy and has been evaluated in many clinical trials. We have performed a systematic review of comparative efficacy and toxicity profiles of once and twice-weekly carfilzomib dosing schemes in RRMM. Materials and methods: Systematic review was done according to PRISMA statement. PubMed, Embase, AdisInsight, &amp; Clinicaltrials.gov databases were searched, without any filters, using the search terms "Multiple Myeloma" AND "Kyprolis" OR "Carfilzomib". Most recent reports of phase I/II/III clinical trials reporting the clinical efficacy and/or safety of carfilzomib in RRMM were considered for inclusion. After screening of 267 articles, 16 clinical trials (N=2393) evaluating twice-weekly carfilzomib and 4 trials (N=418) evaluating once-weekly dosing schedule were considered for inclusion. Results Once versus (vs.) twice-weekly carfilzomib regimens were evaluated in a total of 406 and 1869 patients, respectively. In our discussion, group-1 refers to patients receiving once weekly carfilzomib while group-2 refers to twice weekly dosing schedule group. For the evaluated population, high risk cytogenetics were reported in 15% (n=60) patients in group-1 and in 17% (n= 317) patients in group-2. The median no. of prior lines of therapy ranged 1-8 in group-1 as compared to 1-20 in group-2. All studies reported the patient responses according to International Myeloma Working Group (IWMG) response criteria. The cumulative overall response rate (ORR) was better in group 1: 70.4% (n= 286) vs. 48% (n= 896). Similarly, more patients in group-1 achieved stringent complete response (sCR) or complete response (CR): 11.5% (n= 47) patients in group 1 vs. 5.2% (n= 99) patients in group 2. The response rates were also non-inferior in group-1 for other responses as overall. In group-1, 30% (n= 123) patients achieved very good partial response (VGPR) compared to 21% (n=389) patients in group-2. The partial response (PR) rate was 28.5% (n= 116) vs. 22% (n= 412) in groups 1 and 2 respectively The rate of minimal response (MR) achievement was comparable in both groups: 5% (n= 21) in group-1 vs. 8% (n= 154) patients in group-2. But lesser proportion of patients in group-1 went on to develop progression of myeloma disease [5.6% (n= 23) vs. 15.6% (n= 293)]. Stable disease (SD) state was achieved by 12.3% (n=50) patients in group-1 compared to 20% (n= 379) patients in group-2. Owing to phase-1 design of most clinical trials evaluating the once-weekly dosing schedule, the survival data is immature at present, but the median progression free survival (PFS) ranged from 1 day to 12.6 months in group-1 while in group 2 it ranged from 3.7-44.4 months. (Table-1) The toxicity profiles were also comparable for both dosing schedules. The most common hematological adverse events (AEs) were anemia and thrombocytopenia and their incidences were 15.7% (n= 64) vs. 25.5% (n= 477) and 13.3% (n= 54) vs. 23.1% (n= 432) in groups 1 and 2 respectively. The most common non-hematological AEs were infections, fatigue, and nausea that were reported in 22% (n= 89), 19% (n= 77), and 17.4% (n= 71) patients in group 1, and 14.5% (n= 272), 19.3% (n= 362), and 19.1% (n= 357) patients in group 2, respectively. Overall, grade 3 or above cardiac AEs were reported in 3.4% (n= 14) patients in group 1 and 3.3% (63/1869) patients in group 2. The most common cardiac AE was hypertension which constituted 50% (n= 7) and 64% (n= 40) of all grade 3 or more cardiac AEs in groups 1 and 2, respectively. Conclusion Achievement of objective response rates for once-weekly carfilzomib appears to be better or at-least similar to twice-weekly carfilzomib regimens. There is paucity of prospective studies comparing once vs. twice-weekly carfilzomib in RRMM which highlights the need for more clinical trials evaluating this regimen. Apart from efficacy and safety profile, once-weekly carfilzomib dosing also carries the potential of becoming a preferred option in terms of lesser financial burden and number of patient visits to the infusion centers. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Efficacy and Safety of Carfilzomib at 56mg/m2 with Cyclophosphamide and Dexamethasone (K56Cd) in Newly Diagnosed Multiple Myeloma Patients Followed By ASCT or K56Cd Consolidation: Initial Results of the Phase 2 Cardamon Study

Introduction: Carfilzomib (20/36mg/m2) triplets with Lenalidomide-Dexamethasone (KRd), or Cyclophosphamide-Dexamethasone (KCd) are safe and effective in patients with newly diagnosed multiple myeloma(NDMM). The higher dose of 56mg/m2 is effective as a doublet with Dexamethasone in the relapsed setting, but there is limited data on this dose in triplet combinations in the frontline setting. Aim: The CARDAMON study evaluated KCd with bi-weekly carfilzomib (56mg/m2) as induction in NDMM patients, and the benefit of ASCT versus K56Cd consolidation followed by carfilzomib maintenance. Co-primary endpoints were major response (≥VGPR rate) to 4 induction cycles of K56Cd, and 2-year PFS for ASCT versus K56Cd consolidation. Here we report interim analysis of the first primary endpoint of ≥VGPR rate to K56Cd induction. Methods: Transplant eligible ND patients received 4 x 28d cycles of K56Cd (carfilzomib:20/56mg/m2, IV d1, 2, 8, 9, 15, 16, cyclophosphamide 500mg orally d1, 8, 15 and dexamethasone 20mg d1, 2, 8, 9, 15, 16). Responding patients with a successful stem cell harvest (PBSCH) were randomised to autologous stem cell transplant (ASCT) or 4 more cycles of K56Cd as consolidation, followed by 18 months carfilzomib maintenance (K56 days 1, 8, 15) for both arms. Trial recruitment completed in July 2019. Response was assessed by IMWG criteria; all patients had MRD testing by multi-parameter flow cytometry (10-5) after PBSCH. Adverse risk genetics was any one of t(4;14), t(14;16), t(14,20) or del(17p). Results: 281 pts were registered between 06/2015 and 07/2019; we report outcomes for 252 patients who either completed induction or came off study before end of induction. Median age was 58yrs(33-74), 91% ECOG 0-1, 45.2% ISS I, 24.7% adverse risk (48.5% when including 1p/1q+). Best response at end of induction or after PBSCH (n=250) was: ≥VGPR 59.2%, ORR 87.6%. ≥VGPR rate in adverse risk patients was 53.4% vs 61.9% in standard risk(SR), (p=0.25), ORR was similar: adverse risk, 87.9% vs standard risk, 88.1%. Post-PBSCH, 24.1% of patients were MRD-negative (patients who were withdrawn due to insufficient induction response or toxicity and those with an inconclusive result were grouped with the MRD-positive). Of 19 patients in sCR/CR, 9 were MRD-negative(47.4%) while 40/110 (36.4%) of VGPR patients were MRD-negative. MRD-negative rates in adverse and standard risk patients were 22.8% and 24.7% respectively. 10 patients progressed during or at end of induction, and 12 were withdrawn for toxicity. There were 4 deaths during induction, one from myocardial infarction, the other 3 from cardiac arrest, associated with bronchopneumonia and sepsis. During induction, 114 serious adverse events (SAEs) were reported in 72/252 patients, notable ones were thrombotic microangiopathy (2), grade 3 cardiac ischaemia (4), infection (16.3%, mainly lung), renal impairment (6), G3 hypertension (3), thromboembolism(2). Specific guidance for hypertension management was incorporated. 25% of patients are currently reported to have received a dose modification during induction. Full details of adverse events and dose intensity will be presented at the meeting. Conclusion: K56Cd is an effective induction regimen in NDMM patients, and has equivalent MRD negative rates in adverse and standard risk disease. The SAE profile is in keeping with published safety data with carfilzomib. Disclosures Yong: Sanofi: Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Autolus: Consultancy; Janssen: Speakers Bureau; Takeda: Research Funding, Speakers Bureau. Popat:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses; Janssen: Honoraria, Other: travel support to meetings; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria; Takeda: Honoraria, Other: travel, accommodations, expenses. Ramasamy:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; NAPP Pharmaceuticals Ltd.: Research Funding; Janssen-Cilag Ltd.: Research Funding; Oncopeptides and Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Chapman:Takeda: Honoraria. Benjamin:Allogene: Research Funding; Gilead: Honoraria; Novartis: Honoraria; Pfizer: Research Funding; Amgen: Honoraria; Takeda: Honoraria; Servier: Research Funding; Eusapharm: Consultancy. Owen:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel/ meeting support. OffLabel Disclosure: Carfilzomib is used with cyclophosphamide as 1st line treatment for myeloma

Carfilzomib-Lenalidomide-Dexamethasone in the Management of Lenalidomide-Refractory Multiple Myeloma

Carfilzomib is an epoxyketone proteasome inhibitor of second generation, proved to be effective and safe in relapsed and refractory Multiple Myeloma (rrMM), in combination with dexamethasone or lenalidomide and dexamethasone. In this retrospective observational trial, it has been evaluated efficacy and safety of carfilzomib, in combination with lenalidomide-dexamethasone (KRD) as salvage regimen in patients with rrMM, refractory to lenalidomide, whose prognosis is particularly severe. 41 patients (23 M/18 F), with rrMM, median age at diagnosis 63.7 years (r.

S1602 CARFILZOMIB AND DEXAMETHASONE MAINTENANCE PROLONG TIME TO PROGRESSION

Background:Salvage autologous stem cell transplantation (ASCT) is used in selected patients with relapsed multiple myeloma after up‐front ASCT. There is strong support for the use of maintenance therapy after upfront ASCT in newly diagnosed multiple myeloma whereas data on maintenance therapy after salvage ASCT are sparse.The Nordic Myeloma Study Group (NMSG) initiated the CARFI trial (NCT02572492), an open randomized phase II study, to investigate the efficacy and safety of carfilzomib as part of induction and conditioning in salvage ASCT and to evaluate the role of carfilzomib/dexamethasone maintenance after salvage ASCT. We report here response and safety data on 168 patients randomized to maintenance treatment with carfilzomib and dexamethasone or to observation.Aims:To report response and safety data in 168 patients randomized to maintenance with carfilzomib‐dexamethasone or observation following salvage ASCT.Methods:Patients with first relapse after up‐front ASCT were treated with an induction regime containing four cycles of CAR‐CY‐DEX (iv carfilzomib 20 mg/sqm → 36 mg/sqm on days 1, 2, 8, 9, 15 and 16, tablet cyclophosphamide 300 mg/sqm on days 1, 8 and 15 and tablet dexamethasone 20 mg on days 1, 2, 8, 9, 15 and 16 in each 28‐days cycle). The subsequent conditioning regimen contained iv carfilzomib 27 mg/sqm on day –2 and –1, and iv melphalan 200 mg/sqm on day –2. The patients had not received any maintenance therapy after upfront ASCT. Two months after ASCT patients were randomized (1:1) to observation or maintenance therapy with iv carfilzomib 27 mg/sqm → 56 mg/sqm every second week and tablet dexamethasone 20 mg every second week. The randomization was stratified according to relapse 1 – 2 year or &gt; 2 years after up‐front ASCT, ISS stage and standard versus high‐risk cytogenetics. Primary end‐point was to compare time to progression between carfilzomib‐dexamethasone maintenance and observation in patients treated with salvage ASCT.Results:200 patients were enrolled in the study and 32 of these went off study during the induction and after ASCT. The remaining 168 patients were randomized to carfilzomib‐dexamethasone (82 patients) or observation (86 patients). The median age was 62 (interquartile range: 56; 66) years and the median follow‐up from randomization was 10.7 (5.5 ‐ 18.6) months. The two groups were balanced regarding age, time from myeloma diagnosis, treatment at diagnosis, performance status, ISS stage and high‐risk cytogenetics. The median time to progression was 25.1 (95% CI: 24.4‐NR) months in the maintenance group and 18.9 (95% CI: 14.3–23.7) months in the observation group (hazard ratio 0.5 (95% CI: 0.3–0.8, P = 0.006)) (Figure I). A total of 47 serious adverse events (SAE) were reported in 24 patients on carfilzomib‐dexamethasone maintenance and 26 SAEs in 18 patients in the observation group. The majority of the SAEs were infections; 35 in the maintenance group and 21 in the observation group, divided into viral infection (10 versus 2), septicemia (2 versus 0) and pneumonia (10 versus 6). Three SAEs classified as cardiac related were observed in the maintenance group (syncope, atrial fibrillation and pulmonary embolism) in contrast to one in the observation group (dyspnea).Summary/Conclusion:Maintenance therapy with carfilzomib and dexamethasone maintenance prolongs median time to progression with approximately 6 months following salvage ASCT in multiple myeloma.image