CARFILZOMIB WEEKLY PLUS MELPHALAN AND PREDNISONE IN NEWLY DIAGNOSED ELDERLY MULTIPLE MYELOMA (IFM 2012-03)
Author(s): ,
Xavier Leleu
Affiliations:
Oncologie Hématologique et Thérapie Cellulaire,CHU Poitiers,POITIERS,France
,
Guillemette Fouquet
Affiliations:
CHU Lille,LILLE,France
,
Lionel Karlin
Affiliations:
CHU LYON SUD,LYON,France
,
Brigitte Kolb
Affiliations:
CHU REIMS,REIMS,France
,
Mourad Tiab
Affiliations:
CH LA ROCHE SUR YON,LA ROCHE SUR YON,France
,
Carla Araujo
Affiliations:
CH BAYONNE,BAYONNE,France
,
Nathalie Meuleman
Affiliations:
Institut Bordet,BRUXELLES,France
,
Thierry de Revel
Affiliations:
CH CLAMART,CLAMART,France
,
Pascal Bourquard
Affiliations:
CHU NIMES,NIMES,France
,
Pascal Lenain
Affiliations:
Centre Henri Becquerel,ROUEN,France
,
Murielle Roussel
Affiliations:
Cancer Research Center,TOULOUSE,France
,
Arnaud Jaccard
Affiliations:
CHU LIMOGES,LIMOGES,France
,
Marie-Odile Petillon
Affiliations:
CHU Lille,LILLE,France
,
Karim Belhadj-Merzoug
Affiliations:
CHU Henri Mondor,CRETEIL,France
,
Gérard Lepeu
Affiliations:
CH Avignon,AVIGNON,France
,
Marie-Lorraine Chretien
Affiliations:
CHU Dijon,DIJON,France
,
Jean Fontan
Affiliations:
CHU Besançon,BESANCON,France
,
Philippe Rodon
Affiliations:
CH Périgueux,PERIGUEUX,France
,
Anna Schmitt
Affiliations:
Institut Bergonié,BORDEAUX,France
,
Fritz Offner
Affiliations:
Universitair Ziekenhuis Gent,GENT,Belgium
,
Laurent Voillat
Affiliations:
CH CHALON SUR SAONE,CHALON SUR SAONE,France
,
Sophie Cerejat
Affiliations:
CH CORBEIL ESSONNES,CORBEIL ESSONNES,France
,
Frédérique Kuhnowsko
Affiliations:
Institut Curie,PARIS,France
,
Sophie Rigaudeau
Affiliations:
CHU Versailles,VERSAILLES,France
,
Olivier Decaux
Affiliations:
CHU de Rennes,RENNES,France
,
Catherine Humbrecht-Kraut
Affiliations:
CH Colmar,COLMAR,France
,
Jamile Frayfer
Affiliations:
CH Meaux,MEAUX,France
,
Olivier Fitoussi
Affiliations:
Polyclinique Bordeaux Nord,BORDEAUX,France
,
Damien Roos Weil
Affiliations:
Groupe Hospitalier Pitié Salpétrière,PARIS,France
,
Jean-Claude Eisenmann
Affiliations:
CH Mulhouse,MULHOUSE,France
,
Véronique Dorvaux
Affiliations:
CH Metz-Thionville,METZ-THIONVILLE,France
,
Eric G Voog
Affiliations:
Centre Jean Bernard,LE MANS,France
,
Cyrille Hulin
Affiliations:
CHRU Nancy,NANCY,France
,
Michel Attal
Affiliations:
CHU Toulouse,TOULOUSE,France
,
Philippe Moreau
Affiliations:
CHU Nantes,NANTES,France
Thierry Facon
Affiliations:
CHU Lille,LILLE,France
(Abstract release date: 05/19/16) EHA Library. Leleu X. 06/10/16; 135133; S100
Dr. Xavier Leleu
Dr. Xavier Leleu
Contributions
Abstract
Abstract: S100

Type: Oral Presentation

Presentation during EHA21: On Friday, June 10, 2016 from 11:30 - 11:45

Location: Hall A1

Background
Melphalan plus prednisone and bortezomib combination is the most frequent standard of care used upfront for newly diagnosed elderly myeloma (eNDMM). Despite significant improvements with bortezomib, such as sub-cutaneous administration and weekly schedule, safety profile issues remain with MPV, that only can be resolved with lowering the doses, albeit of the potential loss of efficacy.Carfilzomib, a novel generation proteasome inhibitor, has different safety profile with absence of neuropathy. Carmysap, a phase I/II trial of twice weekly Carfilzomib plus MP in eNDMM, demonstrated carfilzomib MTD at 36mg/m2. The safety profile appeared otherwise good for this frail population.

Aims
We hypothesized that Carfilzomib can be used on a weekly schedule allowing to increase the dose of Carfilzomib given its positive safety profile.

Methods
IFM2012-03 (carmysap weekly) is a phase 1/2 multicenter open label single arm study to determine MTD during the phase 1 part and VGPR+CR rate (IMWG criteria) during the phase 2 part of KMP (Carfilzomib Weekly Plus Melphalan and Prednisone) regimen.The inclusion/exclusion criteria of interest were eNDMM (65 and older), with CRAB and measurable disease, with absolute neutrophils ≥1G/L, untransfused platelet count ≥75G/L, hemoglobine ≥8.5g/dL and clairance creatinine ≥30ml/min.Induction comprised nine 5 weeks cycles. Carfilzomib is given 36, 45, 56 and 70 mg/m2 on days 1, 8, 15, 22 IV route in combination to oral Melphalan 0.25mg/kg/j and oral prednisone 60mg/m2, both on days 1 to 4. Maintenance. Carfilzomib. 36 mg/m2 weekly, every two weeks IV route for 1 year. Melphalan and Prednisone is not pursued at maintenance. Analysis is done on an Intent to Treat. Recruitment was 6 patients per cohort, 3 DLTs meant MTD at the lower N-1 dose. The following are defined as DLTs: Any hematologic toxicity of grade 4 intensity or preventing administration of 2 or more of the 4 carfilzomib doses of the first treatment cycle; Grade ≥3 febrile neutropenia; Grade ≥3 gastrointestinal toxicities; Any other grade ≥3 nonhematologic toxicity considered related to CMP by the principal investigator; Grade ≥3 peripheral neuropathy persisting for more than 3 weeks after discontinuation of study drugs. We report herein the phase 1 part of the study with the 2 cohorts at 70mg/m2.

Results
32 NDMM recruited, 30 treated in the study, 6 per cohort at 36 mg/m² carfilzomib +MP, then 45, 56, and finally at 70mg/m². At the end of the first 70 cohort, the DSMB decided to add a second 70 cohort. The median age was 76 with 15 patients older than 75, sex ratio M/F 1.2, R-ISS 2 and 3 in 80%. There was one DLT at 36 mg/m² carfilzomib (grade 4 lymphopenia), one at 45 (lysis syndrome complicated with grade 4 renal insufficiency, two at 56 (cardiac insufficiency grade 3 and febrile neutropenia grade 3) and 2 at 70 (vomiting grade 3 and liver cholestase enzyme grade 3).As a whole for the study, the ORR is 87.5%, with 33% at least in CR. At data cut-off, with a median follow-up at 12 months, one patient had progressed and one patients had died of cardiac dysfunction considered related to Carfilzomib at the dose of 56mg/m2. Along with the previous 2 patients, 2 other patients have stopped treatment for lysis syndrome (at 45) and pulmonary hypertension later in the disease course on cycle 5 at 56. Overall, there are 22 SAE reported for a total of greater than 200 cycles administered of KMP. An extra 3 patients have had Carfilzomib dose reduction, 2 patients at 36 from 45 and one at 45 from 56, for neutropenia grade 4,  thrombocytopenia grade 4, and dyspnea grade 3, respectively.

Conclusion
IFM2012-03, the study of KMP, Carfilzomib (Kyprolis) plus Melphalan and Prednisone in elderly NDMM has not reached MTD up to 70mg/m2 of carfilzomib. The RP2D could then be at 70 for carfilzomib. KMP appears feasible and manageable, the primary cause of AEs coming from dose adaptation of Melphalan in very elderly NDMM. Updated data will be presented at ASCO.

Session topic: New agents for Myeloma treatment

Keyword(s): Elderly, Myeloma, Treatment
Abstract: S100

Type: Oral Presentation

Presentation during EHA21: On Friday, June 10, 2016 from 11:30 - 11:45

Location: Hall A1

Background
Melphalan plus prednisone and bortezomib combination is the most frequent standard of care used upfront for newly diagnosed elderly myeloma (eNDMM). Despite significant improvements with bortezomib, such as sub-cutaneous administration and weekly schedule, safety profile issues remain with MPV, that only can be resolved with lowering the doses, albeit of the potential loss of efficacy.Carfilzomib, a novel generation proteasome inhibitor, has different safety profile with absence of neuropathy. Carmysap, a phase I/II trial of twice weekly Carfilzomib plus MP in eNDMM, demonstrated carfilzomib MTD at 36mg/m2. The safety profile appeared otherwise good for this frail population.

Aims
We hypothesized that Carfilzomib can be used on a weekly schedule allowing to increase the dose of Carfilzomib given its positive safety profile.

Methods
IFM2012-03 (carmysap weekly) is a phase 1/2 multicenter open label single arm study to determine MTD during the phase 1 part and VGPR+CR rate (IMWG criteria) during the phase 2 part of KMP (Carfilzomib Weekly Plus Melphalan and Prednisone) regimen.The inclusion/exclusion criteria of interest were eNDMM (65 and older), with CRAB and measurable disease, with absolute neutrophils ≥1G/L, untransfused platelet count ≥75G/L, hemoglobine ≥8.5g/dL and clairance creatinine ≥30ml/min.Induction comprised nine 5 weeks cycles. Carfilzomib is given 36, 45, 56 and 70 mg/m2 on days 1, 8, 15, 22 IV route in combination to oral Melphalan 0.25mg/kg/j and oral prednisone 60mg/m2, both on days 1 to 4. Maintenance. Carfilzomib. 36 mg/m2 weekly, every two weeks IV route for 1 year. Melphalan and Prednisone is not pursued at maintenance. Analysis is done on an Intent to Treat. Recruitment was 6 patients per cohort, 3 DLTs meant MTD at the lower N-1 dose. The following are defined as DLTs: Any hematologic toxicity of grade 4 intensity or preventing administration of 2 or more of the 4 carfilzomib doses of the first treatment cycle; Grade ≥3 febrile neutropenia; Grade ≥3 gastrointestinal toxicities; Any other grade ≥3 nonhematologic toxicity considered related to CMP by the principal investigator; Grade ≥3 peripheral neuropathy persisting for more than 3 weeks after discontinuation of study drugs. We report herein the phase 1 part of the study with the 2 cohorts at 70mg/m2.

Results
32 NDMM recruited, 30 treated in the study, 6 per cohort at 36 mg/m² carfilzomib +MP, then 45, 56, and finally at 70mg/m². At the end of the first 70 cohort, the DSMB decided to add a second 70 cohort. The median age was 76 with 15 patients older than 75, sex ratio M/F 1.2, R-ISS 2 and 3 in 80%. There was one DLT at 36 mg/m² carfilzomib (grade 4 lymphopenia), one at 45 (lysis syndrome complicated with grade 4 renal insufficiency, two at 56 (cardiac insufficiency grade 3 and febrile neutropenia grade 3) and 2 at 70 (vomiting grade 3 and liver cholestase enzyme grade 3).As a whole for the study, the ORR is 87.5%, with 33% at least in CR. At data cut-off, with a median follow-up at 12 months, one patient had progressed and one patients had died of cardiac dysfunction considered related to Carfilzomib at the dose of 56mg/m2. Along with the previous 2 patients, 2 other patients have stopped treatment for lysis syndrome (at 45) and pulmonary hypertension later in the disease course on cycle 5 at 56. Overall, there are 22 SAE reported for a total of greater than 200 cycles administered of KMP. An extra 3 patients have had Carfilzomib dose reduction, 2 patients at 36 from 45 and one at 45 from 56, for neutropenia grade 4,  thrombocytopenia grade 4, and dyspnea grade 3, respectively.

Conclusion
IFM2012-03, the study of KMP, Carfilzomib (Kyprolis) plus Melphalan and Prednisone in elderly NDMM has not reached MTD up to 70mg/m2 of carfilzomib. The RP2D could then be at 70 for carfilzomib. KMP appears feasible and manageable, the primary cause of AEs coming from dose adaptation of Melphalan in very elderly NDMM. Updated data will be presented at ASCO.

Session topic: New agents for Myeloma treatment

Keyword(s): Elderly, Myeloma, Treatment

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