MagnetisMM-4: Umbrella Study of Elranatamab (PF-06863135) in Combination With Anti-Cancer Treatments in Multiple Myeloma

An adverse event was any untoward medical occurrence in a participant temporally associated with the use of study intervention, whether or not considered related to the study intervention, including both serious and all non-serious adverse events. A serious adverse event (SAE): any untoward medical occurrence that, at any dose resulting in any of the following outcomes: death; life-threatening; required inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; or that was considered as an important medical event. Relatedness of any AE to treatment to be judged by investigator.

CRS: supraphysiologic response following any immune therapy that results in the activation or engagement of endogenous or infused T-cells and/or other immune effector cells. Symptoms must include fever at the onset, and may include hypotension, hypoxia and end organ dysfunction. As per ASTCT criteria, G1: fever (temperature >=38 degree Celsius), hypotension and/or hypoxia none; G2: fever, hypotension not requiring vasopressors, hypoxia requiring low-flow nasal cannula/facemask or blow-by; G3: fever, hypotension requiring a vasopressor with or without vasopressin, hypoxia requiring high-flow nasal cannula/facemask, nonrebreather mask, or Venturi mask; G4: fever, hypotension requiring multiple vasopressors (excluding vasopressin), hypoxia requiring positive pressure. Organ toxicities associated with CRS graded according to CTCAE v5.0. G1: mild, G2: moderate, G3: severe, G4: life-threatening consequences; urgent intervention indicated. G5: death related to AE.

ASTCT for ICANS [immune effector cell-associated encephalopathy (ICE, overall score range 0-10, higher score = better condition). G1: ICE score 7-9, awakens spontaneously; G2: ICE score 3-6, awakens to voice; G3: ICE score 0-2, awakens only to tactile stimulus, any clinical seizure that resolves rapidly or non-convulsive seizures on electroencephalography that resolve with intervention, focal/local oedema on neuroimaging; G4: ICE score 0 (unarousable and unable to perform ICE), unarousable or requires vigorous or repetitive tactile stimuli to arouse. Stupor or coma, life-threatening prolonged seizure (>5 min); or repetitive clinical or electrical seizures without return to baseline in between, deep focal motor weakness such as hemiparesis or paraparesis, diffuse cerebral oedema on neuroimaging; decerebrate or decorticate posturing; or cranial nerve VI (abducens nerve) palsy; or papilledema; or Cushing's triad; G5: death.

Number of participants with laboratory abnormalities will be reported in this outcome measure.

ORR: % of participants with objective response. Stringent complete response(sCR): CR \& normal serum free light chain (sFLC) ratio \&absence of clonal cells in BMB/BMA by immunohistochemistry or immunofluorescence. CR: negative immunofixation on serum \&urine, disappearance of soft tissue plasmacytomas \&<5% plasma cells in BMA. If disease measurable by sFLC only, preceding criteria \&normal sFLC ratio. VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis; or >=90% reduction in serum M-protein \& urine M-protein level <100 mg/24h; PR: >=50% reduction of serum M-protein \& reduction in 24h urinary M-protein by >=90% or to <200 mg/24 hours (If disease measurable by sFLC only: VGPR \& PR: >=90% \&>=50% decrease in difference respectively between involved \& uninvolved sFLC levels). In addition, if present at baseline, VGPR \& PR: >=90% \&>=50% reduction compared with baseline in soft tissue plasmacytomas' size.

CRR was defined as the percentage of participants with a Best Overall Response (BOR) of confirmed sCR/CR per IMWG response criteria as determined by investigator. sCR: i) CR; ii) normal serum FLC ratio and absence of clonal cells in BMB/BMA by immunohistochemistry or immunofluorescence (κ/λ ratio <=4:1 or >=1:2 for κ and λ participants, respectively, after counting >=100 plasma cells; iii) if the only measurable disease was by serum FLC levels, sCR was defined as normal serum FLC ratio of 0.26 to 1.65 plus absence of clonal cells in BMB/BMA b by immunohistochemistry or immunofluorescence (κ/λ ratio <=4:1 or >=1:2 for κ and λ participants, respectively, after counting >=100 plasma cells). CR: i) negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and <5% plasma cells in BMA; ii) if the only measurable disease was by serum FLC levels, CR was defined as normal serum FLC ratio of 0.26 to 1.65 plus criteria (i).

TTR was defined, for participants with an objective response per IMWG criteria, as the time from the date of first dose to the first documentation of objective response that is subsequently confirmed.

DOR (for participants (pts) with objective response (OR) per IMWG)=time from the first OR that is confirmed (conf), until conf PD per IMWG, or death due to any cause, whichever occurred first. PD=any of: (i)Increase (inc) >=25% from lowest conf response value of (a)Serum M-component (absolute (abs) inc >=0.5 g/dL) (b)Serum M-protein inc >=1 g/dL if lowest M component >=5 g/dL (c)Urine M-protein (abs inc >=200 mg/24 h) (d)in pts without measurable (meas) serum and urine M-protein levels, difference between involved and uninvolved serum FLC levels (abs inc >10 mg/dL) (e)in pts without meas serum and urine M-protein levels and without meas involved serum FLC, bone marrow plasma-cell (PC) percentage irrespective of baseline status (abs inc >=10%) (ii)appearance of new lesion(s), >=50% inc from nadir in SPD of >1 lesion, or >= 50% inc in longest diameter of a prior lesion >1 cm in short axis (iii)>=50% inc in circulating PC (minimum 200 cells per microliter) if the only measure of disease.

DOCR (for participants (pts) with CR/sCR per IMWG)= time from the first CR/sCR that is confirmed (conf), until conf PD per IMWG, or death due to any cause, whichever occurred first. PD=any of: (i)Increase (inc) >=25% from lowest conf response value of (a)Serum M-component (absolute (abs) inc >=0.5 g/dL) (b)Serum M-protein inc >=1 g/dL if lowest M component >=5 g/dL (c)Urine M-protein (abs inc >=200 mg/24 h) (d)in pts without measurable (meas) serum and urine M-protein levels, difference between involved and uninvolved serum FLC levels (abs inc >10 mg/dL) (e)in pts without meas serum and urine M-protein levels and without meas involved serum FLC, bone marrow plasma-cell (PC) percentage irrespective of baseline status (abs inc >=10%) (ii)appearance of new lesion(s), >=50% inc from nadir in SPD of >1 lesion, or >= 50% inc in longest diameter of a prior lesion >1 cm in short axis (iii)>=50% inc in circulating PC (minimum 200 cells per microliter) if the only measure of disease.

PFS=time from date of first dose until confirmed PD per IMWG criteria or death due to any cause, whichever occurred first. PD=any of: (i)Increase (inc) >=25% from lowest confirmed response value of (a)Serum M-component (absolute (abs) inc >=0.5 g/dL) (b)Serum M-protein inc >=1 g/dL if lowest M component >=5 g/dL (c)Urine M-protein (abs inc >=200 mg/24 h) (d)in pts without measurable (meas) serum and urine M-protein levels, difference between involved and uninvolved serum FLC levels (abs inc >10 mg/dL) (e)in pts without meas serum and urine M-protein levels and without meas involved serum FLC, bone marrow plasma-cell (PC) percentage irrespective of baseline status (abs inc >=10%) (ii)appearance of new lesion(s), >=50% inc from nadir in SPD of >1 lesion, or >= 50% inc in longest diameter of a previous lesion >1 cm in short axis (iii)>=50% inc in circulating PC (minimum 200 cells per microliter) if the only measure of disease.

OS was defined as the time from the first date of the study intervention to the date of death due to any cause. Participants not known to have died are censored on the date of last known alive.

MRD negativity rate is defined as the proportion of participants with CR or better by investigator and negative MRD (assessed by central lab) per IMWG sequencing criteria at any time from the date of first dose until the first documentation of confirmed PD, death or start of new anticancer therapy, whichever occurs first. 1) CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and <5% plasma cells in BMA. If the only measurable disease is by serum FLC levels, CR was defined as normal serum FLC ratio of 0.26 to 1.65; 2) Sequencing MRD-negative: Absence of clonal plasma cells by next generation sequencing (NGS) on BMA in which presence of a clone was defined as <2 identical sequencing reads obtained after DNA sequencing of BMA using the LymphoSIGHT platform (or validated equivalent method) with a minimum sensitivity of 1 in 10^5 nucleated cells.

AE: any untoward medical occurrence in a participant temporally associated with the use of study intervention, whether or not considered related to the study intervention, including both serious and all non-serious adverse events. A SAE: any untoward medical occurrence that, at any dose resulting in any of the following outcomes: death; life-threatening; required inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; or that was considered as an important medical event. Relatedness of any AE to treatment to be judged by investigator.

CRS: supraphysiologic response following any immune therapy that results in the activation or engagement of endogenous or infused T-cells and/or other immune effector cells. Symptoms must include fever at the onset, and may include hypotension, hypoxia and end organ dysfunction. As per ASTCT criteria, G1: fever (temperature >=38 degree Celsius), hypotension and/or hypoxia none; G2: fever, hypotension not requiring vasopressors, hypoxia requiring low-flow nasal cannula/facemask or blow-by; G3: fever, hypotension requiring a vasopressor with or without vasopressin, hypoxia requiring high-flow nasal cannula/facemask, nonrebreather mask, or Venturi mask; G4: fever, hypotension requiring multiple vasopressors (excluding vasopressin), hypoxia requiring positive pressure. Organ toxicities associated with CRS graded according to CTCAE v5.0. G1: mild, G2: moderate, G3: severe, G4: life-threatening consequences; urgent intervention indicated. G5: death related to AE.

ASTCT for ICANS (ICE, overall score range 0-10, higher score = better condition). G1: ICE score 7-9, awakens spontaneously; G2: ICE score 3-6, awakens to voice; G3: ICE score 0-2, awakens only to tactile stimulus, any clinical seizure that resolves rapidly or non-convulsive seizures on electroencephalography that resolve with intervention, focal/local oedema on neuroimaging; G4: ICE score 0 (unarousable and unable to perform ICE), unarousable or requires vigorous or repetitive tactile stimuli to arouse. Stupor or coma, life-threatening prolonged seizure (>5 min); or repetitive clinical or electrical seizures without return to baseline in between, deep focal motor weakness such as hemiparesis or paraparesis, diffuse cerebral oedema on neuroimaging; decerebrate or decorticate posturing; or cranial nerve VI (abducens nerve) palsy; or papilledema; or Cushing's triad; G5: death.

Number of participants with laboratory abnormalities will be reported in this outcome measure.

ORR: % of participants with objective response. sCR: CR \& normal sFLC ratio and absence of clonal cells in BMB/BMA by immunohistochemistry or immunofluorescence. CR: negative immunofixation on serum and urine, disappearance of soft tissue plasmacytomas \&<5% plasma cells in BMA. If disease measurable by sFLC only, preceding criteria \&normal sFLC ratio. VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis; or >=90% reduction in serum M-protein \& urine M-protein level <100 mg/24h; PR: >=50% reduction of serum M-protein \& reduction in 24h urinary M-protein by >=90% or to <200 mg/24 hours (If disease measurable by sFLC only: VGPR \& PR: >=90% \&>=50% decrease in difference respectively between involved \& uninvolved sFLC levels). In addition, if present at baseline, VGPR \& PR: >=90% \&>=50% reduction compared with baseline in soft tissue plasmacytomas' size.

CRR was defined as the percentage of participants with a BOR of confirmed sCR/CR per IMWG response criteria as determined by investigator. sCR: i) CR; ii) normal serum FLC ratio and absence of clonal cells in BMB/BMA by immunohistochemistry or immunofluorescence (κ/λ ratio <=4:1 or >=1:2 for κ and λ participants, respectively, after counting >=100 plasma cells; iii) if the only measurable disease was by serum FLC levels, sCR was defined as normal serum FLC ratio of 0.26 to 1.65 plus absence of clonal cells in BMB/BMA b by immunohistochemistry or immunofluorescence (κ/λ ratio <=4:1 or >=1:2 for κ and λ participants, respectively, after counting >=100 plasma cells). CR: i) negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and <5% plasma cells in BMA; ii) if the only measurable disease was by serum FLC levels, CR was defined as normal serum FLC ratio of 0.26 to 1.65 plus criteria (i).

TTR was defined for participants with an objective response per IMWG criteria, as the time from the date of first dose to the first documentation of objective response that is subsequently confirmed.

DOR (for participants (pts) with objective response (OR) per IMWG)=time from the first OR that is confirmed (conf), until conf PD per IMWG, or death due to any cause, whichever occurred first. PD=any of: (i)Increase (inc) >=25% from lowest conf response value of (a)Serum M-component (absolute (abs) inc >=0.5 g/dL) (b)Serum M-protein inc >=1 g/dL if lowest M component >=5 g/dL (c)Urine M-protein (abs inc >=200 mg/24 h) (d)in pts without measurable (meas) serum and urine M-protein levels, difference between involved and uninvolved serum FLC levels (abs inc >10 mg/dL) (e)in pts without meas serum and urine M-protein levels and without meas involved serum FLC, bone marrow plasma-cell (PC) percentage irrespective of baseline status (abs inc >=10%) (ii)appearance of new lesion(s), >=50% inc from nadir in SPD of >1 lesion, or >= 50% inc in longest diameter of a prior lesion >1 cm in short axis (iii)>=50% inc in circulating PC (minimum 200 cells per microliter) if the only measure of disease.

DOCR (for participants (pts) with CR/sCR per IMWG)= time from the first CR/sCR that is confirmed (conf), until conf PD per IMWG, or death due to any cause, whichever occurred first. PD=any of: (i)Increase (inc) >=25% from lowest conf response value of (a)Serum M-component (absolute (abs) inc >=0.5 g/dL) (b)Serum M-protein inc >=1 g/dL if lowest M component >=5 g/dL (c)Urine M-protein (abs inc >=200 mg/24 h) (d)in pts without measurable (meas) serum and urine M-protein levels, difference between involved and uninvolved serum FLC levels (abs inc >10 mg/dL) (e)in pts without meas serum and urine M-protein levels and without meas involved serum FLC, bone marrow plasma-cell (PC) percentage irrespective of baseline status (abs inc >=10%) (ii)appearance of new lesion(s), >=50% inc from nadir in SPD of >1 lesion, or >= 50% inc in longest diameter of a prior lesion >1 cm in short axis (iii)>=50% inc in circulating PC (minimum 200 cells per microliter) if the only measure of disease.

PFS=time from date of first dose until confirmed PD per IMWG criteria or death due to any cause, whichever occurred first. PD=any of: (i)Increase (inc) >=25% from lowest confirmed response value of (a)Serum M-component (absolute (abs) inc >=0.5 g/dL) (b)Serum M-protein inc >=1 g/dL if lowest M component >=5 g/dL (c)Urine M-protein (abs inc >=200 mg/24 h) (d)in pts without measurable (meas) serum and urine M-protein levels, difference between involved and uninvolved serum FLC levels (abs inc >10 mg/dL) (e)in pts without meas serum and urine M-protein levels and without meas involved serum FLC, bone marrow plasma-cell (PC) percentage irrespective of baseline status (abs inc >=10%) (ii)appearance of new lesion(s), >=50% inc from nadir in SPD of >1 lesion, or >= 50% inc in longest diameter of a previous lesion >1 cm in short axis (iii)>=50% inc in circulating PC (minimum 200 cells per microliter) if the only measure of disease.

OS was defined as the time from the first date of the study intervention to the date of death due to any cause. Participants not known to have died are censored on the date of last known alive.

MRD negativity rate is defined as the proportion of participants with CR or better by investigator and negative MRD (assessed by central lab) per IMWG sequencing criteria at any time from the date of first dose until the first documentation of confirmed PD, death or start of new anticancer therapy, whichever occurs first. 1) CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and <5% plasma cells in BMA. If the only measurable disease is by serum FLC levels, CR was defined as normal serum FLC ratio of 0.26 to 1.65; 2) Sequencing MRD-negative: Absence of clonal plasma cells by next generation sequencing (NGS) on BMA in which presence of a clone was defined as <2 identical sequencing reads obtained after DNA sequencing of BMA using the LymphoSIGHT platform (or validated equivalent method) with a minimum sensitivity of 1 in 10^5 nucleated cells.