Trial Outcomes & Findings for Bortezomib With Melphalan and Prednisone for Multiple Myeloma (NCT NCT00734149)

Last Updated: 2023-11-07

Results Overview

Overall response rate equals complete response and partial response per Southwest Oncology Group Criteria. Measurable, quantifiable protein criteria must be present. Acceptable protein criteria are quantitative immunoglobulin IgG, IgA, IgD, IgE or IgM and/or urine M-component (Bence-Jones protein). If both are present, the quantitative immunoglobulin will be followed for response. Complete Remission: The absence of bone marrow or blood findings of multiple myeloma. This includes disappearance of all evidence of serum and urine M-components on electrophoresis as by immunofixation studies. There must also be no evidence of increasing anemia. Partial Remission: A 50-74% reduction in the quantitative immunoglobulin, and if present, a 50-89% reduction in the urine M-component (Bence-Jones protein). Stable/No Remission): A \<50% reduction I nthe quantitative immunoglobulin, or if the patient has light-chain disease only, a \<50% reduction in the urine M-component (Bence-Jones protein.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

45 participants

Primary outcome timeframe

6 weeks following completion of treatment

Results posted on

2023-11-07

Participant Flow

Recruitment period occurred from July 2004 to December 2007 at Duke University Medical Center.

Participant milestones

Participant milestones
Measure	Bortezomib+Melphalan+Prednisone Bortezomib 1.3 mg/m2 is administered intravenously in a 3-5 second bolus on days 1, 4, 8, and 11 of a 28 day cycle. Six cycles are planned. On days when both melphalan and bortezomib are given, melphalan is given at least one hour prior to bortezomib. Melphalan 6 mg/m2 is administered orally on an empty stomach daily on days 1-7 of each cycle. Prednisone 60 mg/m2 is administered orally daily on days 1-7 of each cycle.
Overall Study STARTED	45
Overall Study COMPLETED	44
Overall Study NOT COMPLETED	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Bortezomib+Melphalan+Prednisone Bortezomib 1.3 mg/m2 is administered intravenously in a 3-5 second bolus on days 1, 4, 8, and 11 of a 28 day cycle. Six cycles are planned. On days when both melphalan and bortezomib are given, melphalan is given at least one hour prior to bortezomib. Melphalan 6 mg/m2 is administered orally on an empty stomach daily on days 1-7 of each cycle. Prednisone 60 mg/m2 is administered orally daily on days 1-7 of each cycle.
Overall Study Withdrawal by Subject	1

Baseline Characteristics

Bortezomib With Melphalan and Prednisone for Multiple Myeloma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Bortezomib+Melphalan+Prednisone n=45 Participants Bortezomib 1.3 mg/m2 is administered intravenously in a 3-5 second bolus on days 1, 4, 8, and 11 of a 28 day cycle. Six cycles are planned. On days when both melphalan and bortezomib are given, melphalan is given at least one hour prior to bortezomib. Melphalan 6 mg/m2 is administered orally on an empty stomach daily on days 1-7 of each cycle. Prednisone 60 mg/m2 is administered orally daily on days 1-7 of each cycle.
Age, Categorical <=18 years	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	27 Participants n=5 Participants
Age, Categorical >=65 years	18 Participants n=5 Participants
Sex: Female, Male Female	19 Participants n=5 Participants
Sex: Female, Male Male	26 Participants n=5 Participants

PRIMARY outcome

Timeframe: 6 weeks following completion of treatment

Outcome measures

Outcome measures
Measure	Bortezomib+Melphalan+Prednisone n=44 Participants Bortezomib 1.3 mg/m2 is administered intravenously in a 3-5 second bolus on days 1, 4, 8, and 11 of a 28 day cycle. Six cycles are planned. On days when both melphalan and bortezomib are given, melphalan is given at least one hour prior to bortezomib. Melphalan 6 mg/m2 is administered orally on an empty stomach daily on days 1-7 of each cycle. Prednisone 60 mg/m2 is administered orally daily on days 1-7 of each cycle.	Bortezomib+Melphalan+Prednisone: ASCT Bortezomib 1.3 mg/m2 is administered intravenously in a 3-5 second bolus on days 1, 4, 8, and 11 of a 28 day cycle. Six cycles are planned. On days when both melphalan and bortezomib are given, melphalan is given at least one hour prior to bortezomib. Melphalan 6 mg/m2 is administered orally on an empty stomach daily on days 1-7 of each cycle. Prednisone 60 mg/m2 is administered orally daily on days 1-7 of each cycle. Patients proceeded to autologous stem cell transplant (ASCT).
Response	42 participants	—

SECONDARY outcome

Timeframe: At any time during the study and up to 30 days after stopping the study drug

Number of patients with any grade or severe, defined as ≥ grade 3 by Common Terminology Criteria for Adverse Events (CTCAE) v4.0, adverse events as a measure of safety

Outcome measures

Outcome measures
Measure	Bortezomib+Melphalan+Prednisone n=45 Participants Bortezomib 1.3 mg/m2 is administered intravenously in a 3-5 second bolus on days 1, 4, 8, and 11 of a 28 day cycle. Six cycles are planned. On days when both melphalan and bortezomib are given, melphalan is given at least one hour prior to bortezomib. Melphalan 6 mg/m2 is administered orally on an empty stomach daily on days 1-7 of each cycle. Prednisone 60 mg/m2 is administered orally daily on days 1-7 of each cycle.	Bortezomib+Melphalan+Prednisone: ASCT Bortezomib 1.3 mg/m2 is administered intravenously in a 3-5 second bolus on days 1, 4, 8, and 11 of a 28 day cycle. Six cycles are planned. On days when both melphalan and bortezomib are given, melphalan is given at least one hour prior to bortezomib. Melphalan 6 mg/m2 is administered orally on an empty stomach daily on days 1-7 of each cycle. Prednisone 60 mg/m2 is administered orally daily on days 1-7 of each cycle. Patients proceeded to autologous stem cell transplant (ASCT).
Number of Patients With Any Grade or Severe Adverse Event	34 participants	—

SECONDARY outcome

Timeframe: up to 4 years

Duration of response is measured from date of first confirmed response until date of disease progression.

Outcome measures

Outcome measures
Measure	Bortezomib+Melphalan+Prednisone n=24 Participants Bortezomib 1.3 mg/m2 is administered intravenously in a 3-5 second bolus on days 1, 4, 8, and 11 of a 28 day cycle. Six cycles are planned. On days when both melphalan and bortezomib are given, melphalan is given at least one hour prior to bortezomib. Melphalan 6 mg/m2 is administered orally on an empty stomach daily on days 1-7 of each cycle. Prednisone 60 mg/m2 is administered orally daily on days 1-7 of each cycle.	Bortezomib+Melphalan+Prednisone: ASCT n=20 Participants Bortezomib 1.3 mg/m2 is administered intravenously in a 3-5 second bolus on days 1, 4, 8, and 11 of a 28 day cycle. Six cycles are planned. On days when both melphalan and bortezomib are given, melphalan is given at least one hour prior to bortezomib. Melphalan 6 mg/m2 is administered orally on an empty stomach daily on days 1-7 of each cycle. Prednisone 60 mg/m2 is administered orally daily on days 1-7 of each cycle. Patients proceeded to autologous stem cell transplant (ASCT).
Median Duration of Response	19.8 months Interval 14.3 to NA = many patients were censored at the time of last assessment, and therefore upper bound was not estimable- confidence intervals are extremely wide.	27.9 months Interval 14.6 to NA = many patients were censored at the time of last assessment, and therefore upper bound was not estimable- confidence intervals are extremely wide.

Adverse Events

Bortezomib+Melphalan+Prednisone

Serious events: 6 serious events

Other events: 30 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Bortezomib+Melphalan+Prednisone n=45 participants at risk Bortezomib 1.3 mg/m2 is administered intravenously in a 3-5 second bolus on days 1, 4, 8, and 11 of a 28 day cycle. Six cycles are planned. On days when both melphalan and bortezomib are given, melphalan is given at least one hour prior to bortezomib. Melphalan 6 mg/m2 is administered orally on an empty stomach daily on days 1-7 of each cycle. Prednisone 60 mg/m2 is administered orally daily on days 1-7 of each cycle.
Gastrointestinal disorders Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation)	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Infections and infestations Infection with unknown ANC - Lung (pneumonia)	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Nervous system disorders Neuropathy: sensory	4.4% 2/45 • Number of events 2 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Nervous system disorders Seizure	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
General disorders Death Not Associated with CTCAE term - Disease Progression NOS	4.4% 2/45 • Number of events 2 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Secondary Malignancy - possibly related to cancer treatment	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.

Other adverse events

Other adverse events
Measure	Bortezomib+Melphalan+Prednisone n=45 participants at risk Bortezomib 1.3 mg/m2 is administered intravenously in a 3-5 second bolus on days 1, 4, 8, and 11 of a 28 day cycle. Six cycles are planned. On days when both melphalan and bortezomib are given, melphalan is given at least one hour prior to bortezomib. Melphalan 6 mg/m2 is administered orally on an empty stomach daily on days 1-7 of each cycle. Prednisone 60 mg/m2 is administered orally daily on days 1-7 of each cycle.
Investigations Leukocytes (total WBC)	6.7% 3/45 • Number of events 5 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Ear and labyrinth disorders Auditory/Ear - Other	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Investigations Haptoglobin	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Blood and lymphatic system disorders Hemoglobin	15.6% 7/45 • Number of events 8 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Investigations Neutrophils / granulocytes (ANC / AGC)	8.9% 4/45 • Number of events 4 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Investigations Platelets	15.6% 7/45 • Number of events 10 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Blood and lymphatic system disorders Splenic function	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Cardiac disorders Supraventricular and nodal arrhythmia - sinus bradycardia	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Vascular disorders Hypertension	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Vascular disorders Hypotension	2.2% 1/45 • Number of events 4 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
General disorders Fatigue (asthenia, lethargy, malaise)	28.9% 13/45 • Number of events 19 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
General disorders Fever (in the absence of neutropenia, defined as ANC <1.0 x 10e9/L)	15.6% 7/45 • Number of events 7 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
General disorders Rigors/chills	8.9% 4/45 • Number of events 4 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Investigations Weight loss	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Skin and subcutaneous tissue disorders Dermatology/Skin - Other	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Skin and subcutaneous tissue disorders Dry skin	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
General disorders Injection site reaction/extravasation changes	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Skin and subcutaneous tissue disorders Rash/desquamation	6.7% 3/45 • Number of events 3 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Skin and subcutaneous tissue disorders Ulceration	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Vascular disorders Hot flashes/flushes	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Metabolism and nutrition disorders Anorexia	6.7% 3/45 • Number of events 4 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Gastrointestinal disorders Constipation	6.7% 3/45 • Number of events 4 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Metabolism and nutrition disorders Dehydration	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Gastrointestinal disorders Dental: periodontal disease	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Gastrointestinal disorders Diarrhea	4.4% 2/45 • Number of events 2 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Gastrointestinal disorders Dysphagia (difficulty swallowing)	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Gastrointestinal disorders Flatulence	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Gastrointestinal disorders Gastrointestinal - other	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Gastrointestinal disorders Mucositis / stomatitis (clinical exam) - Oral cavity	4.4% 2/45 • Number of events 4 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Gastrointestinal disorders Nausea	15.6% 7/45 • Number of events 8 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Gastrointestinal disorders Heartburn / dyspepsia	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Nervous system disorders Taste Alteration (dysgeusia)	4.4% 2/45 • Number of events 2 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Gastrointestinal disorders Vomiting	6.7% 3/45 • Number of events 3 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Blood and lymphatic system disorders Febrile neutropenia - fever of unknown origin (ANC <1.0 x 10e9/L, fever >=38.5 degrees C)	6.7% 3/45 • Number of events 3 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Infections and infestations Infection with Grade 3 or 4 neutrophils (ANC <1.0 x 10e9/L)	6.7% 3/45 • Number of events 3 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Infections and infestations Infection with Grade 3 or 4 neutrophils (ANC <1.0 x 10e9/L) - lung (pneumonia)	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Infections and infestations Infection with normal ANC or Grade 1 or 2 neutrophils	2.2% 1/45 • Number of events 2 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Infections and infestations Infection with unknown ANC - Urinary tract NOS	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
General disorders Edema: limb	4.4% 2/45 • Number of events 2 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
General disorders Edema: other	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Investigations ALT, SGPT (serum glutamic pyruvic transaminase)	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Investigations AST, SGOT (serum glutamic oxaloacetic transaminase)	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Metabolism and nutrition disorders Potassium, serum-low (hypokalemia)	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Metabolism and nutrition disorders Sodium, serum-low (hyponatremia)	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Injury, poisoning and procedural complications Fracture	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Musculoskeletal and connective tissue disorders Joint-function	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Psychiatric disorders Mood Alteration - Anxiety	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Psychiatric disorders Mood Alteration - Depression	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
General disorders Other	6.7% 3/45 • Number of events 4 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Gastrointestinal disorders Pain - abdomen not otherwise specified	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Musculoskeletal and connective tissue disorders Pain - back	11.1% 5/45 • Number of events 8 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
General disorders Pain - Chest / thorax not otherwise specified	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Musculoskeletal and connective tissue disorders Pain - extremity - limb	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Nervous system disorders Pain - head/headache	4.4% 2/45 • Number of events 2 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
General disorders Pain - other	6.7% 3/45 • Number of events 4 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Respiratory, thoracic and mediastinal disorders Cough	11.1% 5/45 • Number of events 8 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Respiratory, thoracic and mediastinal disorders Dyspnea (shortness of breath)	15.6% 7/45 • Number of events 10 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Respiratory, thoracic and mediastinal disorders Pneumonitis / pulmonary infiltrates	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Respiratory, thoracic and mediastinal disorders Pulmonary/upper respiratory - other	4.4% 2/45 • Number of events 2 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Renal and urinary disorders Renal failure	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Renal and urinary disorders Urinary frequency / urgency	6.7% 3/45 • Number of events 3 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Reproductive system and breast disorders Erectile dysfunction	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Vascular disorders Thrombosis / thrombus / embolism	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Renal and urinary disorders Proteinuria	2.2% 1/45 • Number of events 1 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.
Nervous system disorders Neuropathy: sensory	28.9% 13/45 • Number of events 17 • From first dose of study drug to 30 days after the last dose of study drug All adverse events are reported whether or not they are considered attributable to the study treatment.

Additional Information

Cristina Gasparetto, MD

Duke University Medical Center

Phone: 919-668-1017

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place