Panobinostat/Bortezomib/Dexamethasone in Relapsed or Relapsed-and-refractory Multiple Myeloma

ORR is defined as the percentage of participants with a confirmed partial response (PR) or better (immunophenotypic complete response \[iCR\] or stringent complete response \[sCR\] or complete response \[CR\] or very good partial response \[VGPR\]) as their best overall response after completion of up to 8 cycles of assigned study regimen. Each cycle was 21 days long. Best overall response was the best post-baseline confirmed overall response observed in a given participant and was determined based on overall responses observed at all post-baseline response assessments, recorded from randomization until progressive disease (PD), death, start of new therapy, withdrawal of consent, or end of study, whatever came first. ORR was assessed blindly per independent review committee (IRC) according to International Myeloma Working Group (IMWG) criteria.

Time frame: Up to 168 days

Population: Full analysis set (FAS): all participants to whom study treatment was assigned by randomization.

Health-related quality of life (HRQoL) was assessed by the EORTC QLQ-C30, which is frequently employed in clinical oncology trials and is recognized as reliable and valid. The EORTC QLQ-C30 measures functional dimensions (physical, role, emotional, cognitive, and social), 3 symptom items (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea and financial impact), and a global health scale (GHS) and quality-of-life scale. For each domain and item, a linear transformation is applied to standardize the score between 0 and 100. Results are presented specifically for the GHS score. A higher GHS score indicates a higher HRQoL. Each cycle was 21 days long.

Time frame: Cycle 15 Day 1, at approximately 295 days

Population: Full analysis set (FAS): all participants to whom study treatment was assigned by randomization and who had a valid baseline HRQoL assessment and at least 1 post-baseline assessment. Here, 'Overall Number of Participants Analyzed' refers to the number of evaluable participants analyzed.

HRQoL was assessed by the FACT/GOG-Ntx, a 38-item questionnaire designed to assess general quality of life and severity and impact of neurotoxicity from systemic chemotherapy. It is frequently employed in clinical oncology trials and is recognized as a reliable and valid measure to assess symptoms associated with neurotoxicity. It focuses on 4 general quality of life domains for physical well-being, functional well-being, social/family well-being, and emotional well-being, and includes the neurotoxicity subscale domain to characterize treatment-related neurotoxicity. Results are presented specifically for the 11-item neurotoxicity subscale, which uses a 5-point rating scale (0=not at all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much). Each item is scored from 0-4, with the severity of neurotoxicity measured as the sum of the 11 items, ranging from 0 to 44. Lower scores indicate lower neurotoxicity and higher HRQoL. Each cycle was 21 days long.

Time frame: Cycle 15 Day 1, at approximately 295 days

Population: Full analysis set (FAS): all participants to whom study treatment was assigned by randomization and who had a valid baseline HRQoL assessment and at least 1 post-baseline assessment. Here, 'Overall Number of Participants Analyzed' refers to the number of evaluable participants analyzed.

Serial blood samples were collected for bortezomib Cmax analysis. Results are reported in ng/mL.

Time frame: Cycle 1 Day 1 (Pre-dose, up to 8 hours post dose)

Population: Pharmacokinetics Analysis Set (PAS): all participants with at least 1 evaluable pharmacokinetics concentration of bortezomib after dosing on Day 1. Here, 'Overall Number of Participants Analyzed' refers to the number of evaluable participants analyzed.

CR, based on IMWG criteria per blinded IRC assessment, is defined as: negative immunofixation of serum and urine; disappearance of any soft tissue plasmacytoma(s), in the case of any presence of soft tissue plasmacytoma(s) at baseline; less than 5% plasma cells in bone marrow; in case the only measurable disease at baseline is the serum FLC assessment, a normal FLC ratio of 0.26 to 1.65 is required additionally to qualify for CR. Results reported as percentage of participants achieving CR.

Time frame: Up to 5.2 years

Population: Full analysis set (FAS): all participants to whom study treatment was assigned by randomization.

DOR, based on IMWG criteria per blinded IRC assessment, is defined as the duration from the first documented onset of PR or better (iCR or sCR or CR or VGPR) to the date of first documented disease progression or death due to multiple myeloma.

Time frame: Up to 5.2 years

Population: Full analysis set (FAS): all participants to whom study treatment was assigned by randomization.

The exposure-response relationship was assessed utilizing Cmax (Cycle 1 Day 1) for panobinostat versus the outcomes of ORR, grade 3/4 thrombocytopenia, and grade 3/4 diarrhea. Two statistical models were used: logistic regression models, in which these 3 outcomes were treated in a binary fashion according to their occurrence; Cox regression models, with the relevant outcomes being the time to occurrence of grade 3/4 thrombocytopenia and the time to occurrence of grade 3/4 diarrhea. Results are reported as model-based probability. An increase in the model-based probability indicates an increase in the occurrence of the outcomes (ORR, grade 3/4 thrombocytopenia, 3/4 diarrhea) with increasing values of Cmax (that is, with increasing dose of panobinostat).

Time frame: Up to 5.2 Years

Population: Full analysis set (FAS): all participants to whom study treatment was assigned by randomization. Here, 'Overall Number of Participants Analyzed' refers to the number of evaluable participants analyzed.

iCR, based on IMWG criteria per blinded IRC assessment, is defined as: negative immunofixation of serum and urine; disappearance of any soft tissue plasmacytoma(s), in the case of any presence of soft tissue plasmacytoma(s) at baseline; less than 5% plasma cells in bone marrow; normal free light chain (FLC) ratio; absence of clonal plasma cells in bone marrow analyzed by immunohistochemistry or 2- to 4-color flow cytometry; absence of phenotypically aberrant plasma cells (clonal) in bone marrow (BM) with a minimum of 1 million total BM cells analyzed by multiparametric flow cytometry (\>4 colors). Results reported as percentage of participants achieving iCR.

Time frame: Up to 5.2 years

Population: Full analysis set (FAS): all participants to whom study treatment was assigned by randomization.

Serial blood samples were collected for panobinostat Cmax analysis. Results are reported in nanograms/milliliter (ng/mL).

Time frame: Cycle 1 Day 1 (Pre-dose, up to 8 hours post dose)

Population: Pharmacokinetics Analysis Set (PAS): all participants with at least 1 evaluable pharmacokinetics concentration of panobinostat after dosing on Day 1. Here, 'Overall Number of Participants Analyzed' refers to the number of evaluable participants analyzed.

ORR is defined as the percentage of participants with a confirmed PR or better (iCR or sCR or CR or VGPR) as their best overall response throughout the entire study. Best overall response was the best post-baseline confirmed overall response observed in a given participant and was determined based on overall responses observed at all post-baseline response assessments, recorded from randomization until PD, death, start of new therapy, withdrawal of consent or end of study, whatever came first. ORR was assessed blindly per IRC according to IMWG criteria.

Time frame: Up to 5.2 years

Population: Full analysis set (FAS): all participants to whom study treatment was assigned by randomization.

OS is defined as the time from date of randomization to the date of death due to any cause.

Time frame: Up to 5.2 years

Population: Full analysis set (FAS): all participants to whom study treatment was assigned by randomization.

PFS, assessed based on IMWG criteria per blind IRC assessment, is defined as the time from date of randomization to date of first documented disease progression or death (regardless of cause of death).

Time frame: Up to 5.2 years

Population: Full analysis set (FAS): all participants to whom study treatment was assigned by randomization.

sCR, based on IMWG criteria per blinded IRC assessment, is defined as: negative immunofixation of serum and urine; disappearance of any soft tissue plasmacytoma(s), in the case of any presence of soft tissue plasmacytoma(s) at baseline; less than 5% plasma cells in bone marrow; normal FLC ratio; absence of clonal plasma cells in bone marrow analyzed by immunohistochemistry or 2- to 4-color flow cytometry. Results reported as percentage of participants achieving sCR.

Time frame: Up to 5.2 years

Population: Full analysis set (FAS): all participants to whom study treatment was assigned by randomization.

TTP, based on IMWG criteria per blinded IRC assessment, is defined as the time from the date of randomization to the date of the first documented disease progression or death due to multiple myeloma.

Time frame: Up to 5.2 years

Population: Full analysis set (FAS): all participants to whom study treatment was assigned by randomization.

Serial blood samples were collected for panobinostat Tmax analysis. Results are reported in hours.

Time frame: Cycle 1 Day 1 (Pre-dose, up to 8 hours post dose)

Population: Pharmacokinetics Analysis Set (PAS): all participants with at least 1 evaluable pharmacokinetics concentration of panobinostat after dosing on Day 1. Here, 'Overall Number of Participants Analyzed' refers to the number of evaluable participants analyzed.

TTR, based on IMWG criteria per blinded IRC assessment, is the time between date of randomization to the date of first onset of PR or better response (iCR or sCR or CR or VGPR).

Time frame: Up to 5.2 years

Population: Full analysis set (FAS): all participants to whom study treatment was assigned by randomization.

Serial blood samples were collected for bortezomib Tmax analysis. Results are reported in hours.

Time frame: Cycle 1 Day 1 (Pre-dose, up to 8 hours post dose)

Population: Pharmacokinetics Analysis Set (PAS): all participants with at least 1 evaluable pharmacokinetics concentration of bortezomib after dosing on Day 1. Here, 'Overall Number of Participants Analyzed' refers to the number of evaluable participants analyzed.

VGPR, based on IMWG criteria per blinded IRC assessment, is defined as: serum and/or urine M protein detectable by immunofixation but not on protein electrophoresis, or ≥90% reduction from baseline in serum) and urine M protein \<100 milligrams/24 hours); in the case of the presence of any soft tissue plasmacytoma(s) at baseline, a reduction in the sum of the products of the cross-diameters by ≥50% from baseline is required; in case the only measurable disease in a participant at baseline is the serum FLC level (that is, no measurable disease in serum and urine PEP), a decrease of \>90% in the difference between involved and uninvolved FLC levels from baseline is required. Results reported as percentage of participants achieving VGPR.

Time frame: Up to 5.2 years

Population: Full analysis set (FAS): all participants to whom study treatment was assigned by randomization.