PF-06863135 As Single Agent And In Combination With Immunomodulatory Agents In Relapse/Refractory Multiple Myeloma

Hematological: Grade 4 neutropenia lasting >5 days; Febrile neutropenia <1000/mm^3 with a single temperature of >38.3 degree Celsius (C) or a sustained temperature of >=38 degree C for more than one hour; grade >=3 neutropenia with infection; grade 4 thrombocytopenia; grade 3 thrombocytopenia with >= Grade 2 bleeding. Non-hematological: grade 4 adverse events (AEs); Grade 3 AE lasting >=5 days despite optimal supportive care, with exception of AE attributed to cytokine release syndrome (CRS) event; grade 3 CRS, except those CRS that had a) not been maximally treated or b) improved to <=grade 1 within 48 hours; grade 4 CRS; confirmed drug-induced liver injury (DILI) meeting Hy's law criteria; grade 4 laboratory abnormalities deemed clinically significant by the investigator reported Grade 4 AE; clinically important or persistent toxicities that were not included in above criteria were also be considered a DLT following review by the investigators and the sponsor.

ORR per IMWG criteria: percentage of participants with best overall response (BOR) of stringent complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR). sCR: complete response plus normal free light chain (FLC) ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry; CR: negative immunofixation on serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow aspirates. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis or >=90% reduction in serum M-protein plus urine M-protein level <100 mg/24 hr. PR: >=50% reduction of serum M-protein and reduction in 24 hrs urinary M-protein by >=90% or to <200 mg/24 hr. If serum and urine M-protein were unmeasurable, >=50% decrease in difference between involved and uninvolved FLC levels required in place of the M-protein criteria.

DOR per IMWG criteria:time from first documentation of objective tumor (OT)response to first documentation of OTprogression or to death due to any cause, whichever occurred first.sCR: CR plus normal FLC ratio & absence of clonal cells in bone marrow biopsy by immunohistochemistry;CR:Negative immunofixation on serum & urine & disappearance of any soft tissue plasmacytomas&<5% plasma cells in bone marrow aspirates.VGPR: serum & urine M-protein(Mp) detectable by immunofixation but not on electrophoresis or >=90% reduction in serum Mp plus urine Mp level <100 mg/24 hr. PR: >=50% reduction of serum Mp & reduction in 24 hrs urinary Mp by >=90% or to <200 mg/24 hr.If serum & urine Mp were unmeasurable, >=50% decrease in difference between involved & uninvolved FLC levels required in place of Mp criteria. Progression: appearance of local, regional or distant disease of same type after CR or progression of pre-existing lesions. It did not include second primary malignancies of unrelated types.

AE: any untoward medical occurrence in clinical study participant, temporally associated with use of study intervention, whether or not considered related to intervention. TEAE: any event increasing in severity from baseline or event started during PF-06863135 therapy or within 30 days of last dose of drug. SAE: any untoward medical occurrence at any dose that resulted in either: death; life-threatening; required inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; suspected transmission via Pfizer product of infectious agent, pathogenic or non-pathogenic; or considered as important event. Treatment-related AE: AEs attributed to drug in participants who received drug. Relatedness was judged by investigator. NCI CTCAE v4.03, Grade 3= severe AE, Grade 4= life-threatening, urgent intervention indicated, Grade 5= death related to AE. AEs included SAEs and all non-SAEs.

Hematology parameters included: activated partial thromboplastin time prolonged, anemia, hemoglobin increased, international normalized ratio (INR) increased, leukocytosis, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased and, white blood cell decreased. According to NCI CTCAE version 4.03: Grade 1= mild, Gade 2= moderate, Grade 3= severe AE, Grade 4= life-threatening, urgent intervention indicated, Grade 5= death related to AE. In this outcome measure number of participants with shifts from grade 2 at baseline to grade 3 or 4 post-baseline in any of hematology parameters are reported.

Clinical chemistry parameters included: alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, creatinine increased, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia and hypophosphatemia. According to NCI CTCAE version 4.03: Grade 1= mild, Gade 2= moderate, Grade 3= severe AE, Grade 4= life-threatening, urgent intervention indicated, Grade 5= death related to AE. In this outcome measure number of participants with shifts from grade 2 at baseline to grade 3 or 4 post-baseline in any of clinical chemistry parameters are reported.

Proteinuria was estimated in urinalysis. According to NCI CTCAE version 4.03: Grade 1= mild, Gade 2= moderate, Grade 3= severe AE, Grade 4= life-threatening, urgent intervention indicated, Grade 5= death related to AE. In this outcome measure number of participants with shifts from grade 2 at baseline to grade 3 or 4 post-baseline in any of urinalysis parameters are reported.

ORR per IMWG criteria: percentage of participants with best overall response (BOR) of stringent complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR). sCR: complete response plus normal free light chain (FLC) ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry; CR: negative immunofixation on serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow aspirates. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis or >=90% reduction in serum M-protein plus urine M-protein level <100 mg/24 hr. PR: >=50% reduction of serum M-protein and reduction in 24 hrs urinary M-protein by >=90% or to <200 mg/24 hr. If serum and urine M-protein were unmeasurable, >=50% decrease in difference between involved and uninvolved FLC levels required in place of the M-protein criteria.

TTR: Defined for participants with confirmed objective response as time from first dose to first documentation of objective tumor response. sCR: complete response + normal FLC ratio & absence of clonal cells in bone marrow biopsy by immunohistochemistry; CR: Negative immunofixation on serum& urine & disappearance of soft tissue plasmacytomas & <5% plasma cells in bone marrow aspirates. VGPR: serum& urine M-protein detectable by immunofixation but not on electrophoresis or >=90% reduction in serum M-protein plus urine M-protein level <100 mg/24 hr. PR: >=50% reduction of serum M-protein& reduction in 24hrs urinary M-protein by >=90% or <200 mg/24hr. If serum & urine M-protein unmeasurable, >=50% decrease in difference between involved & uninvolved FLC levels required in place of M-protein criteria. Progression: Appearance of local, regional, distant disease of same type after CR or progression of pre-existing lesions. It didn't include second primary malignancies of unrelated types.

CRR: percentage of participants with complete response (sCR or CR). sCR: complete response plus normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry; CR: negative immunofixation on serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow aspirates.

DOR per IMWG criteria:time from first documentation of objective tumor (OT)response to first documentation of OTprogression or to death due to any cause, whichever occurred first.sCR: CR plus normal FLC ratio & absence of clonal cells in bone marrow biopsy by immunohistochemistry;CR:Negative immunofixation on serum & urine & disappearance of any soft tissue plasmacytomas&<5% plasma cells in bone marrow aspirates.VGPR: serum & urine M-protein(Mp) detectable by immunofixation but not on electrophoresis or >=90% reduction in serum Mp plus urine Mp level <100 mg/24 hr. PR: >=50% reduction of serum Mp & reduction in 24 hrs urinary Mp by >=90% or to <200 mg/24 hr.If serum & urine Mp were unmeasurable, >=50% decrease in difference between involved & uninvolved FLC levels required in place of Mp criteria. Progression: appearance of local, regional or distant disease of same type after CR or progression of pre-existing lesions. It did not include second primary malignancies of unrelated types.

DoCR was defined for participants with confirmed complete response (sCR or CR) as the time from the first documentation of complete response to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. sCR: complete response plus normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry; CR: Negative immunofixation on serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow aspirates. Progression was defined as appearance of local, regional or distant disease of same type after CR or progression of pre-existing lesions. It didn't include second primary malignancies of unrelated types.

DOSD per IMWG criteria: participants with confirmed stable disease (SD): time from first documentation (doc) of objective SD to first doc of objective tumor progression (P)/death by any cause, whichever occurred first. SD: not meeting criteria for CR,VGPR, PR, MR or PD. CR: Negative immunofixation on serum & urine &disappearance of any soft tissue plasmacytomas &<5% plasma cells in bone marrow aspirates. VGPR: serum & urine M-protein (Mp) detectable by immunofixation but not on electrophoresis or >=90% reduction in serum Mp plus urine Mp level <100 mg/24 hr. PR: >=50% reduction of serum Mp & reduction in 24 hours urinary Mp by >=90% or<200 mg/24 hr. If serum & urine Mp were unmeasurable, >=50% decrease in difference between involved & uninvolved FLC levels required in place of Mp criteria. Progression: appearance of local, regional, distant disease of same type after CR or progression of pre-existing lesions. It didn't include second primary malignancies of unrelated types.

PFS as per IMWG criteria was the time from start date of study treatment to date of first documentation of progression, or death due to any cause. Progression was defined as the appearance of local, regional or distant disease of the same type after CR or progression of pre-existing lesions. It does not include second primary malignancies of unrelated types. CR: Negative immunofixation on serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow aspirates.

OS was defined as the time from start date of study treatment to date of death due to any cause. OS for participants not known to had died were censored on the date of last known alive.

MRD negativity rate: percentage of participants with negative MRD (assessed by central laboratory) per IMWG criteria at any time from date of first dose until first documentation of confirmed progression, death or start of new anticancer therapy, whichever occurred first. Progression was defined as appearance of local, regional, distant disease of same type after CR or progression of pre-existing lesions. It didn't include second primary malignancies of unrelated types. MRD negativity was defined by two thresholds, 10^-5 and 10^-6.

Cmax of PF-06863135 was measured in this outcome measure. Total is free and bound drug in the body.

Area under the concentration curve from time 0 to end of dosing interval (AUCtau) was measured in this outcome measure. Total is free and bound drug in the body.

Plasma concentration of lenalidomide and pomalidomide was measured in this outcome measure.

Number of participants with ADA and NAb against PF-06863135 were reported in this outcome measure. A participant was ADA (or NAb) positive if: (1) baseline titer was missing or negative and participant had >= 1 post-treatment positive titer (treatment-induced), or (2) positive titer at baseline and had a >= 4-folder dilution increase in titer from baseline in >= 1 post-treatment sample (treatment-boosted).

The concentration of Interleukin-2, Interleukin-6, Interferon-gamma and tumor necrosis factor-alpha were measured in this outcome measure. Cycle = C.

AE: any untoward medical occurrence in clinical study participant, temporally associated with use of study intervention, whether or not considered related to intervention. TEAE: any event increasing in severity from baseline or event started during PF-06863135 therapy or within 30 days of last dose of drug. SAE: any untoward medical occurrence at any dose that resulted in either: death; life-threatening; required inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; suspected transmission via Pfizer product of infectious agent, pathogenic or non-pathogenic; or considered as important event. Treatment-related AE: AEs attributed to drug in participants who received drug. Relatedness was judged by investigator. NCI CTCAE v4.03, Grade 3= severe AE, Grade 4= life-threatening, urgent intervention indicated, Grade 5= death related to AE. AEs included SAEs and all non-SAEs.

Hematology parameters included: activated partial thromboplastin time prolonged, anemia, hemoglobin increased, international normalized ratio (INR) increased, leukocytosis, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased and, white blood cell decreased. According to NCI CTCAE version 4.03: Grade 1= mild, Gade 2= moderate, Grade 3= severe AE, Grade 4= life-threatening, urgent intervention indicated, Grade 5= death related to AE. In this outcome measure number of participants with shifts from grade 2 at baseline to grade 3 or 4 post-baseline in any of hematology parameters are reported.

Clinical chemistry parameters included: alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, creatinine increased, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia and hypophosphatemia. According to NCI CTCAE version 4.03: Grade 1= mild, Gade 2= moderate, Grade 3= severe AE, Grade 4= life-threatening, urgent intervention indicated, Grade 5= death related to AE. In this outcome measure number of participants with shifts from grade 2 at baseline to grade 3 or 4 post-baseline in any of clinical chemistry parameters are reported.

Proteinuria was estimated in urinalysis. According to NCI CTCAE version 4.03: Grade 1= mild, Gade 2= moderate, Grade 3= severe AE, Grade 4= life-threatening, urgent intervention indicated, Grade 5= death related to AE. In this outcome measure number of participants with shifts from grade 2 at baseline to grade 3 or 4 post-baseline in any of urinalysis parameters are reported.

CRR: percentage of participants with complete response (sCR or CR). sCR: complete response plus normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry; CR: negative immunofixation on serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow aspirates.

DoCR was defined for participants with confirmed complete response (sCR or CR) as the time from the first documentation of complete response to the first documentation of objective tumor progression or to death due to any cause, whichever occured first. sCR: complete response plus normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry; CR: Negative immunofixation on serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow aspirates. Progression was defined as appearance of local, regional or distant disease of same type after CR or progression of pre-existing lesions. It didn't include second primary malignancies of unrelated types.

TTR: Defined for participants with confirmed objective response as time from first dose to first documentation of objective tumor response. sCR: complete response + normal FLC ratio & absence of clonal cells in bone marrow biopsy by immunohistochemistry; CR: Negative immunofixation on serum& urine & disappearance of soft tissue plasmacytomas & <5% plasma cells in bone marrow aspirates. VGPR: serum& urine M-protein detectable by immunofixation but not on electrophoresis or >=90% reduction in serum M-protein plus urine M-protein level <100 mg/24 hr. PR: >=50% reduction of serum M-protein& reduction in 24hrs urinary M-protein by >=90% or <200 mg/24hr. If serum & urine M-protein unmeasurable, >=50% decrease in difference between involved & uninvolved FLC levels required in place of M-protein criteria. Progression: Appearance of local, regional, distant disease of same type after CR or progression of pre-existing lesions. It didn't include second primary malignancies of unrelated types.

DOSD per IMWG criteria: participants with confirmed stable disease (SD): time from first documentation (doc) of objective SD to first doc of objective tumor progression (P)/death by any cause, whichever occurred first. SD: not meeting criteria for CR,VGPR, PR, MR or PD. CR: Negative immunofixation on serum & urine &disappearance of any soft tissue plasmacytomas &<5% plasma cells in bone marrow aspirates. VGPR: serum & urine M-protein (Mp) detectable by immunofixation but not on electrophoresis or >=90% reduction in serum Mp plus urine Mp level <100 mg/24 hr. PR: >=50% reduction of serum Mp & reduction in 24 hours urinary Mp by >=90% or<200 mg/24 hr. If serum & urine Mp were unmeasurable, >=50% decrease in difference between involved & uninvolved FLC levels required in place of Mp criteria. Progression: appearance of local, regional, distant disease of same type after CR or progression of pre-existing lesions. It didn't include second primary malignancies of unrelated types.

PFS as per IMWG criteria was the time from start date of study treatment to date of first documentation of progression, or death due to any cause. Progression was defined as the appearance of local, regional or distant disease of the same type after CR or progression of pre-existing lesions. It does not include second primary malignancies of unrelated types. CR: Negative immunofixation on serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow aspirates.

OS was defined as the time from start date of study treatment to date of death due to any cause. OS for participants not known to had died were censored on the date of last known alive.

MRD negativity rate: percentage of participants with negative MRD (assessed by central laboratory) per IMWG criteria at any time from date of first dose until first documentation of confirmed progression, death or start of new anticancer therapy, whichever occurred first. Progression was defined as appearance of local, regional, distant disease of same type after CR or progression of pre-existing lesions. It didn't include second primary malignancies of unrelated types. MRD negativity was defined by two thresholds, 10^-5 and 10^-6.

Number of participants with ADA and NAb against PF-06863135 were reported in this outcome measure. A participant was ADA (or NAb) positive if: (1) baseline titer was missing or negative and participant had >= 1 post-treatment positive titer (treatment-induced), or (2) positive titer at baseline and had a >= 4-folder dilution increase in titer from baseline in >= 1 post-treatment sample (treatment-boosted).

The concentration of Interleukin-2, Interleukin-6, Interferon-gamma and tumor necrosis factor-alpha were measured in this outcome measure.