Study of Bortezomib and Dexamethasone With or Without Cyclophosphamide in Patients With Relapsed or Not Controllable Multiple Myeloma

• Sponsor: Janssen-Cilag G.m.b.H (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00813150
• Collaborator: (none)
• Enrollment: 96
• Locations: 40
• Arms: 2
• Duration (Months): 48
• Patients Per Site: 2.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to compare bortezomib, dexamethasone and cyclophosphamide to bortezomib and dexamethasone alone for primary refractory or relapsed multiple myeloma.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: Dexamethasone; Drug: Bortezomib; Drug: Cyclophosphamide	Phase 3

Detailed Description

This is a prospective, multi-centre, randomized (the study drug is assigned by chance), controlled, open-label (all people involved in the study know the identity of the assigned drug), parallel (each group of patients will be treated at the same time) group phase III study to determine the efficacy of the standard therapy of bortezomib and low dose dexamethasone in combination with or without continuous low dose oral cyclophosphamide for primary refractory or relapsed myeloma patients (1st - 3rd relapse). The study will consist of screening period, which may last from day -14 until day -1 before application of the first dose of bortezomib (on cycle 1, day 1), treatment phase begins on cycle 1 day 1 and continues until completion or discontinuation of all study drugs and follow-up phase. All patients will be followed up after end of treatment regardless of their response. Eligible patients will be randomized in 1:1 ratio to receive either treatment arms (Group A: receiving bortezomib plus dexamethasone or Group B receiving bortezomib plus dexamethasone plus cyclophosphamide). Patients will receive up to eight 3-weeks treatment cycles, unless they experience either unacceptable toxicity or if the patients request to withdraw from the study. The maximum number of cycles is dependent on patient response and investigator's discretion. It is recommended that patients with a confirmed complete response (CR) receive 2 additional cycles beyond a confirmation. Patients who do not achieve a CR but a partial response will receive a total of 8 cycles. For patients achieving stable disease it is within the investigator's discretion to continue study treatment beyond 6 cycles, after discussion with the sponsor. After completion of treatment the patients will be followed up every 12 weeks for up to 72 weeks. If the study is still ongoing a further follow up period will be done every 26 weeks until study end, or until the patient reaches progressive disease or start of alternative anti-myeloma therapy, if earlier. In case progressive disease (PD) has already been established during the treatment phase the patients will not enter the follow-up phase. In case of PD or start of alternative anti-myeloma treatment before the end of study the follow-up phase will be discontinued for the patient but the date of death of the patient will be documented (if applicable) before the end of study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 96 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized Phase III Study on Bortezomib and Low-Dose Dexamethasone With or Without Continuous Low-Dose Oral Cyclophosphamide for Primary Refractory or Relapsed Multiple Myeloma
• Study Start Date: Jan 1, 2009
• Actual Primary Completion Date: Jan 1, 2013
• Actual Study Completion Date: Jan 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Vd (bortezomib + dexamethasone) Participants received bortezomib at a dose of 1.3 mg/m² body surface area (BSA) for eight 3-week cycles. Within each cycle it was administered twice weekly (on Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12 through 21). They received single oral doses of 20 mg dexamethasone on Days 1 and 2, 4 and 5, 8 and 9, and 11 and 12 of each cycle.	Drug: Dexamethasone; Type=exact number, number=20, unit=mg, form=tablet, route=oral. The patients will receive 20 mg of dexamethasone on days 1+2,4+5,8+9,11+12 for 21 days for 8 cycles.; Drug: Bortezomib; Type=exact number, number=1.3, unit=mg, form=injection, route=intravenous. The patients will receive 1.3mg/m2 on days 1,4,8,11 for 21 days for 8 cycles.
Active Comparator: Vcd (bortezomib + low-dose dexamethasone + cyclophosphamide) Participants received bortezomib at a dose of 1.3 mg/m² body surface area (BSA) for eight 3-week cycles. Within each cycle it was administered twice weekly (on Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12 through 21). They received single oral doses of 20 mg dexamethasone on Days 1 and 2, 4 and 5, 8 and 9, and 11 and 12 of each cycle and single oral doses of 50 mg cyclophosphamide on a once daily basis from Day 1, Cycle 1 continuously until Day 21, Cycle 8.	Drug: Dexamethasone; Type=exact number, number=20, unit=mg, form=tablet, route=oral. The patients will receive 20 mg of dexamethasone on days 1+2,4+5,8+9,11+12 for 21 days for 8 cycles.; Drug: Bortezomib; Type=exact number, number=1.3, unit=mg, form=injection, route=intravenous. The patients will receive 1.3mg/m2 on days 1,4,8,11 for 21 days for 8 cycles.; Drug: Cyclophosphamide; Type=exact number, number=50, unit=mg, form=tablet, route=oral. The patients will receive 50 mg of cyclophosphamide once daily continuously from cycle 1 to 8.

Outcome Measures

Primary Outcome Measures

1. Time to Progression of Disease [From the date of randomization until the disease progression or participant's death from any cause whichever occurred first, as assessed up to 72 weeks after end of treatment visit (ie, 46 days after last dose of study medication)]

   'Median time to progression of disease is assessed according to International Myeloma Working Group (IMWG) criteria or death from any cause. IMWG criteria: increase of >=25% from lowest level in Serum M-component or (the absolute increase must be >=0.5 gram per deciliter [g/dL]); Urine M component or (the absolute increase must be >=200 milligram per 24 hour. Only in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain levels. The absolute increase >10 mg/dL. Bone marrow plasma cell percentage >=10%. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing. Development of hypercalcemia. Participants who died or dropped out due to any reason without progression will be censored with the day of death or drop-out, respectively and who are alive at the end of the study without any progression was censored with the last available date.

Secondary Outcome Measures

1. Progression-Free Survival (PFS) [From the date of randomization until the disease progression or participant's death from any cause whichever occured first, as assessed up to 72 weeks after end of treatment visit (ie, 46 days after last dose of study medication)]

   PFS is defined as time from randomization to myeloma progression according to International Myeloma Working Group (IMWG) criteria or death from any cause. IMWG criteria: increase of ≥25 percent from lowest response level in Serum M-component and/or (the absolute increase must be ≥0.5 g/dL) Urine M-component and/or (the absolute increase must be ≥200 mg/24 hour. Only in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain levels. The absolute increase must be >10 mg/dL. Bone marrow plasma cell percentage: the absolute percent must be ≥10 percent. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas. Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.65mmol/L) that can be attributed solely to the plasma cell proliferative disorder. PFS included disease progression as well as death.

2. Overall Survival (OS) [From the date of randomization until Month 49]

   Time interval in months time from randomisation to death from any cause.

3. Overall Response Rate (ORR) - International Myeloma Working Group (IMWG) Response Criteria [Up to 46 days after last bortezomib dose, or as soon as possible after early discontinuation of study treatment or before start of alternative anti-myeloma therapy]

   Percentage of participants who achieved stringent complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR) is reported in the below table. IMWG criteria- CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow; sCR: CR+Normal free light chain ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescencec; PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90%; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level <100mg per 24 hour.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Previously diagnosed with multiple myeloma

• Primary refractory multiple myeloma or relapsed following 1 to 3 previous lines of therapy

• Karnofsky performance status must be equal to 60 percentage (ie, better or equal performance than requiring some help and taking care of most personal requirements)

• Has life expectancy estimated at screening must be of at least 6 months

• Agrees to protocol-defined use of effective contraception

Exclusion Criteria:

• Not received more than three previous lines of therapy for multiple myeloma

• Not received nitrosoureas or any other chemotherapy or immunotherapy or antibody therapy for multiple myeloma within 6 to 8 weeks before enrolment. Plasmapheresis must not be applied within 2 weeks before enrolment

• Patients with peripheral neuropathy or neuropathic pain of Grade 2 or greater intensity

• Patients with poorly controlled cardio vascular, vascular, pulmonary, gastro-intestinal, endocrine, neurological, psychiatric, hepatic, renal or metabolic diseases or hematological disorders

• Not have oligosecretory or non-secretory multiple myeloma

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Augsburg		Germany
2		Berlin		Germany
3		Bielefeld		Germany
4		Bremerhaven		Germany
5		Darmstadt		Germany
6		Donauwörth		Germany
7		Dresden		Germany
8		Frankfurt		Germany
9		Halle		Germany
10		Hamburg		Germany
11		Hamm		Germany
12		Hannover		Germany
13		Hildesheim		Germany
14		Hof		Germany
15		Koblenz		Germany
16		Köln		Germany
17		Lebach		Germany
18		Leer		Germany
19		Lübeck		Germany
20		Magdeburg		Germany
21		Mannheim		Germany
22		Moers		Germany
23		München		Germany
24		Münster		Germany
25		Neunkirchen		Germany
26		Offenburg		Germany
27		Oldenburg		Germany
28		Osnabrück		Germany
29		Passau		Germany
30		Porta Westfalica		Germany
31		Ravensburg		Germany
32		Rostock		Germany
33		Saarbrücken		Germany
34		Singen		Germany
35		Stuttgart		Germany
36		Velbert		Germany
37		Weiden		Germany
38		Wiesbaden		Germany
39		Würselen		Germany
40		Würzburg		Germany

Sponsors and Collaborators

• Janssen-Cilag G.m.b.H

Investigators

• Study Director: Janssen-Cilag G.m.b.H, Germany Clinical Trial, Janssen-Cilag G.m.b.H

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Janssen-Cilag G.m.b.H
• ClinicalTrials.gov Identifier: NCT00813150
• Other Study ID Numbers: CR015247; 26866138MMY3022; 2008-003213-27
• First Posted: Dec 22, 2008
• Last Update Posted: Aug 15, 2014
• Last Verified: Jul 1, 2014

• Keywords provided by Janssen-Cilag G.m.b.H: Multiple myeloma; Bortezomib; Dexamethasone; Cyclophosphamide; Oncology
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Dexamethasone; Cyclophosphamide; Bortezomib

Study Results

Participant Flow

Recruitment Details	The study was conducted between 23 December 2008 and 10 January 2013 and recruited patients from 42 study centers in Germany.
Pre-assignment Detail	A total of 93 participants were randomly allocated and they received at least 1 dose of study drug and were included in the safety analysis. Of these follow-up data on treatment response was not available for 3 participants, so, they were excluded from the Intent-to-treat (ITT) analysis data set and so, ITT included 90 participants.

Arm/Group Title	Vd (Bortezomib + Dexamethasone)	Vcd (Bortezomib + Low-dose Dexamethasone + Cyclophosphamide)
Arm/Group Description	Participants received bortezomib at a dose of 1.3 mg/m² body surface area (BSA) for eight 3-week cycles. Within each cycle it was administered twice weekly (on Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12 through 21). They received single oral doses of 20 mg dexamethasone on Days 1 and 2, 4 and 5, 8 and 9, and 11 and 12 of each cycle.	Participants received bortezomib at a dose of 1.3 mg/m² body surface area (BSA) for eight 3-week cycles. Within each cycle it was administered twice weekly (on Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12 through 21). They received single oral doses of 20 mg dexamethasone on Days 1 and 2, 4 and 5, 8 and 9, and 11 and 12 of each cycle and single oral doses of 50 mg cyclophosphamide on a once daily basis from Day 1, Cycle 1 continuously until Day 21, Cycle 8.
Period Title: Treatment Period
STARTED	46	47
Intent-to-treat Participants	43	47
COMPLETED	14	15
NOT COMPLETED	32	32
Period Title: Treatment Period
STARTED	26	31
COMPLETED	2	0
NOT COMPLETED	24	31

Baseline Characteristics

Arm/Group Title	Vd (Bortezomib + Dexamethasone)	Vcd (Bortezomib + Low-dose Dexamethasone + Cyclophosphamide)	Total
Arm/Group Description	Participants received bortezomib at a dose of 1.3 mg/m² body surface area (BSA) for eight 3-week cycles. Within each cycle it was administered twice weekly (on Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12 through 21). They received single oral doses of 20 mg dexamethasone on Days 1 and 2, 4 and 5, 8 and 9, and 11 and 12 of each cycle.	Participants received bortezomib at a dose of 1.3 mg/m² body surface area (BSA) for eight 3-week cycles. Within each cycle it was administered twice weekly (on Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12 through 21). They received single oral doses of 20 mg dexamethasone on Days 1 and 2, 4 and 5, 8 and 9, and 11 and 12 of each cycle and single oral doses of 50 mg cyclophosphamide on a once daily basis from Day 1, Cycle 1 continuously until Day 21, Cycle 8.	Total of all reporting groups
Overall Participants	43	47	90
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	68 (10)	71 (7)	69 (9)
Sex: Female, Male (Count of Participants)
Female	18 41.9%	21 44.7%	39 43.3%
Male	25 58.1%	26 55.3%	51 56.7%
Race/Ethnicity, Customized (Number) [Number]
Caucasian	42 97.7%	47 100%	89 98.9%
African	1 2.3%	0 0%	1 1.1%

Outcome Measures

1. Primary Outcome

Title	Time to Progression of Disease
Description	'Median time to progression of disease is assessed according to International Myeloma Working Group (IMWG) criteria or death from any cause. IMWG criteria: increase of >=25% from lowest level in Serum M-component or (the absolute increase must be >=0.5 gram per deciliter [g/dL]); Urine M component or (the absolute increase must be >=200 milligram per 24 hour. Only in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain levels. The absolute increase >10 mg/dL. Bone marrow plasma cell percentage >=10%. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing. Development of hypercalcemia. Participants who died or dropped out due to any reason without progression will be censored with the day of death or drop-out, respectively and who are alive at the end of the study without any progression was censored with the last available date.
Time Frame	From the date of randomization until the disease progression or participant's death from any cause whichever occurred first, as assessed up to 72 weeks after end of treatment visit (ie, 46 days after last dose of study medication)

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT): Participants who received at least one dose of study medication and in whom the primary efficacy parameter could be assessed at least once under study medication.

Arm/Group Title	Vd (Bortezomib + Dexamethasone)	Vcd (Bortezomib + Low-dose Dexamethasone + Cyclophosphamide)
Arm/Group Description	Participants received bortezomib at a dose of 1.3 mg/m² body surface area (BSA) for eight 3-week cycles. Within each cycle it was administered twice weekly (on Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12 through 21). They received single oral doses of 20 mg dexamethasone on Days 1 and 2, 4 and 5, 8 and 9, and 11 and 12 of each cycle.	Participants received bortezomib at a dose of 1.3 mg/m² body surface area (BSA) for eight 3-week cycles. Within each cycle it was administered twice weekly (on Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12 through 21). They received single oral doses of 20 mg dexamethasone on Days 1 and 2, 4 and 5, 8 and 9, and 11 and 12 of each cycle and single oral doses of 50 mg cyclophosphamide on a once daily basis from Day 1, Cycle 1 continuously until Day 21, Cycle 8.
Measure Participants	43	47
Median (95% Confidence Interval) [Months]	12.6	9.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vd (Bortezomib + Dexamethasone), Vcd (Bortezomib + Low-dose Dexamethasone + Cyclophosphamide)
	Comments	Null Hypothesis: The (median) time to progression is equal in both treatment groups
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.196
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.71
	Confidence Interval	(2-Sided) 95%; 0.43 to 1.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Progression-Free Survival (PFS)
Description	PFS is defined as time from randomization to myeloma progression according to International Myeloma Working Group (IMWG) criteria or death from any cause. IMWG criteria: increase of ≥25 percent from lowest response level in Serum M-component and/or (the absolute increase must be ≥0.5 g/dL) Urine M-component and/or (the absolute increase must be ≥200 mg/24 hour. Only in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain levels. The absolute increase must be >10 mg/dL. Bone marrow plasma cell percentage: the absolute percent must be ≥10 percent. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas. Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.65mmol/L) that can be attributed solely to the plasma cell proliferative disorder. PFS included disease progression as well as death.
Time Frame	From the date of randomization until the disease progression or participant's death from any cause whichever occured first, as assessed up to 72 weeks after end of treatment visit (ie, 46 days after last dose of study medication)

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT): all participants who received at least one dose of study medication and in whom the primary efficacy parameter could be assessed at least once under study medication. Participants without progression and who are still alive at the end of the study or dropped out will be censored with the last available date.

Arm/Group Title	Vd (Bortezomib + Dexamethasone)	Vcd (Bortezomib + Low-dose Dexamethasone + Cyclophosphamide)
Arm/Group Description	Participants received bortezomib at a dose of 1.3 mg/m² body surface area (BSA) for eight 3-week cycles. Within each cycle it was administered twice weekly (on Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12 through 21). They received single oral doses of 20 mg dexamethasone on Days 1 and 2, 4 and 5, 8 and 9, and 11 and 12 of each cycle.	Participants received bortezomib at a dose of 1.3 mg/m² body surface area (BSA) for eight 3-week cycles. Within each cycle it was administered twice weekly (on Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12 through 21). They received single oral doses of 20 mg dexamethasone on Days 1 and 2, 4 and 5, 8 and 9, and 11 and 12 of each cycle and single oral doses of 50 mg cyclophosphamide on a once daily basis from Day 1, Cycle 1 continuously until Day 21, Cycle 8.
Measure Participants	43	47
Median (95% Confidence Interval) [Months]	12.6	9.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vd (Bortezomib + Dexamethasone), Vcd (Bortezomib + Low-dose Dexamethasone + Cyclophosphamide)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.196
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.71
	Confidence Interval	(2-Sided) 95%; 0.43 to 1.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Overall Survival (OS)
Description	Time interval in months time from randomisation to death from any cause.
Time Frame	From the date of randomization until Month 49

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT): Participants received at least 1 dose of study medication were included in the ITT analysis set. Participants still alive at the end of the study or dropped out will be censored with the last available date.

Arm/Group Title	Vd (Bortezomib + Dexamethasone)	Vcd (Bortezomib + Low-dose Dexamethasone + Cyclophosphamide)
Arm/Group Description	Participants received bortezomib at a dose of 1.3 mg/m² body surface area (BSA) for eight 3-week cycles. Within each cycle it was administered twice weekly (on Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12 through 21). They received single oral doses of 20 mg dexamethasone on Days 1 and 2, 4 and 5, 8 and 9, and 11 and 12 of each cycle.	Participants received bortezomib at a dose of 1.3 mg/m² body surface area (BSA) for eight 3-week cycles. Within each cycle it was administered twice weekly (on Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12 through 21). They received single oral doses of 20 mg dexamethasone on Days 1 and 2, 4 and 5, 8 and 9, and 11 and 12 of each cycle and single oral doses of 50 mg cyclophosphamide on a once daily basis from Day 1, Cycle 1 continuously until Day 21, Cycle 8.
Measure Participants	43	47
Median (95% Confidence Interval) [Months]	NA	41.50

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vd (Bortezomib + Dexamethasone), Vcd (Bortezomib + Low-dose Dexamethasone + Cyclophosphamide)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.645
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95%; 0.41 to 1.73
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Overall Response Rate (ORR) - International Myeloma Working Group (IMWG) Response Criteria
Description	Percentage of participants who achieved stringent complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR) is reported in the below table. IMWG criteria- CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow; sCR: CR+Normal free light chain ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescencec; PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90%; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level <100mg per 24 hour.
Time Frame	Up to 46 days after last bortezomib dose, or as soon as possible after early discontinuation of study treatment or before start of alternative anti-myeloma therapy

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT): Participants who received at least one dose of study medication and in whom the primary efficacy parameter could be assessed at least once under study medication.

Arm/Group Title	Vd (Bortezomib + Dexamethasone)	Vcd (Bortezomib + Low-dose Dexamethasone + Cyclophosphamide)
Arm/Group Description	Participants received bortezomib at a dose of 1.3 mg/m² body surface area (BSA) for eight 3-week cycles. Within each cycle it was administered twice weekly (on Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12 through 21). They received single oral doses of 20 mg dexamethasone on Days 1 and 2, 4 and 5, 8 and 9, and 11 and 12 of each cycle.	Participants received bortezomib at a dose of 1.3 mg/m² body surface area (BSA) for eight 3-week cycles. Within each cycle it was administered twice weekly (on Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12 through 21). They received single oral doses of 20 mg dexamethasone on Days 1 and 2, 4 and 5, 8 and 9, and 11 and 12 of each cycle and single oral doses of 50 mg cyclophosphamide on a once daily basis from Day 1, Cycle 1 continuously until Day 21, Cycle 8.
Measure Participants	43	47
Number [Percentage of participants]	74.4 173%	70.2 149.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vd (Bortezomib + Dexamethasone), Vcd (Bortezomib + Low-dose Dexamethasone + Cyclophosphamide)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.814
	Comments
	Method	Fisher Exact
	Comments

Adverse Events

Time Frame	Approximately 5 years
Adverse Event Reporting Description	A total of 96 patients were randomly allocated to the 2 treatment arms in the study. 93 patients received at least 1 dose of study drug and were included in the safety analysis. Of these follow-up data on treatment response was not available for 3 patients, so, they were excluded from the Intent-to-treat analysis data set.
Arm/Group Title	Vd (Bortezomib + Dexamethasone)		Vcd (Bortezomib + Low-dose Dexamethasone + Cyclophosphamide)
Arm/Group Description	Participants received bortezomib at a dose of 1.3 mg/m² body surface area (BSA) for eight 3-week cycles. Within each cycle it was administered twice weekly (on Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12 through 21). They received single oral doses of 20 mg dexamethasone on Days 1 and 2, 4 and 5, 8 and 9, and 11 and 12 of each cycle.		Participants received bortezomib at a dose of 1.3 mg/m² body surface area (BSA) for eight 3-week cycles. Within each cycle it was administered twice weekly (on Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12 through 21). They received single oral doses of 20 mg dexamethasone on Days 1 and 2, 4 and 5, 8 and 9, and 11 and 12 of each cycle and single oral doses of 50 mg cyclophosphamide on a once daily basis from Day 1, Cycle 1 continuously until Day 21, Cycle 8.
All Cause Mortality
	Vd (Bortezomib + Dexamethasone)		Vcd (Bortezomib + Low-dose Dexamethasone + Cyclophosphamide)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Vd (Bortezomib + Dexamethasone)		Vcd (Bortezomib + Low-dose Dexamethasone + Cyclophosphamide)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/46 (32.6%)		14/47 (29.8%)
Blood and lymphatic system disorders
Anaemia	0/46 (0%)	0	1/47 (2.1%)	1
Disseminated intravascular coagulation	1/46 (2.2%)	1	0/47 (0%)	0
Cardiac disorders
Bradycardia	0/46 (0%)	0	1/47 (2.1%)	1
Myocardial infarction	1/46 (2.2%)	1	0/47 (0%)	0
Endocrine disorders
Adrenocortical insufficiency acute	0/46 (0%)	0	1/47 (2.1%)	1
Pituitary haemorrhage	0/46 (0%)	0	1/47 (2.1%)	1
Eye disorders
Diplopia	0/46 (0%)	0	1/47 (2.1%)	1
Gastrointestinal disorders
Constipation	1/46 (2.2%)	1	1/47 (2.1%)	1
Abdominal pain	0/46 (0%)	0	1/47 (2.1%)	1
Diarrhoea	0/46 (0%)	0	1/47 (2.1%)	1
Diverticulum	0/46 (0%)	0	1/47 (2.1%)	1
Ileus paralytic	1/46 (2.2%)	1	0/47 (0%)	0
Inguinal hernia, obstructive	1/46 (2.2%)	1	0/47 (0%)	0
Vomiting	0/46 (0%)	0	1/47 (2.1%)	1
General disorders
Fatigue	0/46 (0%)	0	1/47 (2.1%)	1
Multi-organ failure	1/46 (2.2%)	1	0/47 (0%)	0
Pyrexia	0/46 (0%)	0	1/47 (2.1%)	1
Infections and infestations
Pneumonia	4/46 (8.7%)	4	4/47 (8.5%)	4
Diverticulitis	2/46 (4.3%)	2	0/47 (0%)	0
Sepsis	2/46 (4.3%)	2	0/47 (0%)	0
Bronchitis	0/46 (0%)	0	1/47 (2.1%)	1
Cellulitis	0/46 (0%)	0	1/47 (2.1%)	1
Infection	1/46 (2.2%)	1	0/47 (0%)	0
Varicella	0/46 (0%)	0	1/47 (2.1%)	1
Viral upper respiratory tract infection	0/46 (0%)	0	1/47 (2.1%)	1
Injury, poisoning and procedural complications
Femoral neck fracture	1/46 (2.2%)	1	0/47 (0%)	0
Rib fracture	1/46 (2.2%)	1	0/47 (0%)	0
Tendon rupture	0/46 (0%)	0	1/47 (2.1%)	1
Metabolism and nutrition disorders
Hypercalcaemia	1/46 (2.2%)	1	0/47 (0%)	0
Musculoskeletal and connective tissue disorders
Osteonecrosis	1/46 (2.2%)	1	0/47 (0%)	0
Pain in extremity	1/46 (2.2%)	1	0/47 (0%)	0
Soft tissue necrosis	0/46 (0%)	0	1/47 (2.1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Multiple myeloma	3/46 (6.5%)	3	0/47 (0%)	0
Pituitary tumour	0/46 (0%)	0	1/47 (2.1%)	1
Nervous system disorders
Syncope	0/46 (0%)	0	2/47 (4.3%)	2
Headache	0/46 (0%)	0	1/47 (2.1%)	1
IIIrd nerve paresis	0/46 (0%)	0	1/47 (2.1%)	1
Neuropathy peripheral	1/46 (2.2%)	1	0/47 (0%)	0
Polyneuropathy	0/46 (0%)	0	1/47 (2.1%)	1
Transient ischaemic attack	0/46 (0%)	0	1/47 (2.1%)	1
Psychiatric disorders
Depression	0/46 (0%)	0	1/47 (2.1%)	1
Disorientation	0/46 (0%)	0	1/47 (2.1%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	2/46 (4.3%)	2	1/47 (2.1%)	1
Epistaxis	0/46 (0%)	0	1/47 (2.1%)	1
Vascular disorders
Circulatory collapse	0/46 (0%)	0	1/47 (2.1%)	1
Haemorrhage	0/46 (0%)	0	1/47 (2.1%)	1
Hypertension	1/46 (2.2%)	1	0/47 (0%)	0
Intermittent claudication	1/46 (2.2%)	1	0/47 (0%)	0
Other (Not Including Serious) Adverse Events
	Vd (Bortezomib + Dexamethasone)		Vcd (Bortezomib + Low-dose Dexamethasone + Cyclophosphamide)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	43/46 (93.5%)		46/47 (97.9%)
Blood and lymphatic system disorders
Thrombocytopenia	17/46 (37%)	87	18/47 (38.3%)	83
Anaemia	12/46 (26.1%)	22	6/47 (12.8%)	10
Leukopenia	4/46 (8.7%)	10	7/47 (14.9%)	12
Neutropenia	1/46 (2.2%)	7	1/47 (2.1%)	4
Pancytopenia	0/46 (0%)	0	1/47 (2.1%)	1
Cardiac disorders
Tachycardia	1/46 (2.2%)	1	1/47 (2.1%)	1
Arrhythmia	0/46 (0%)	0	1/47 (2.1%)	1
Bradycardia	0/46 (0%)	0	1/47 (2.1%)	1
Cardiac disorder	0/46 (0%)	0	1/47 (2.1%)	1
Cardiac failure	1/46 (2.2%)	1	0/47 (0%)	0
Right ventricular hypertrophy	1/46 (2.2%)	1	0/47 (0%)	0
Supraventricular extrasystoles	0/46 (0%)	0	1/47 (2.1%)	1
Ventricular extrasystoles	0/46 (0%)	0	1/47 (2.1%)	1
Ear and labyrinth disorders
Vertigo	1/46 (2.2%)	1	9/47 (19.1%)	9
Hypoacusis	0/46 (0%)	0	1/47 (2.1%)	1
Eye disorders
Conjunctivitis	2/46 (4.3%)	2	3/47 (6.4%)	3
Visual impairment	1/46 (2.2%)	1	4/47 (8.5%)	4
Lacrimation increased	1/46 (2.2%)	2	2/47 (4.3%)	2
Colour blindness acquired	0/46 (0%)	0	1/47 (2.1%)	1
Keratitis	0/46 (0%)	0	1/47 (2.1%)	1
Gastrointestinal disorders
Diarrhoea	11/46 (23.9%)	14	17/47 (36.2%)	28
Constipation	10/46 (21.7%)	16	13/47 (27.7%)	16
Nausea	7/46 (15.2%)	7	11/47 (23.4%)	15
Vomiting	3/46 (6.5%)	5	5/47 (10.6%)	6
Abdominal pain	4/46 (8.7%)	5	3/47 (6.4%)	3
Abdominal pain upper	1/46 (2.2%)	1	3/47 (6.4%)	4
Stomatitis	0/46 (0%)	0	5/47 (10.6%)	5
Abdominal discomfort	1/46 (2.2%)	2	1/47 (2.1%)	1
Dyspepsia	2/46 (4.3%)	2	0/47 (0%)	0
Enteritis	1/46 (2.2%)	1	0/47 (0%)	0
Faecal incontinence	0/46 (0%)	0	1/47 (2.1%)	1
Flatulence	0/46 (0%)	0	1/47 (2.1%)	1
Mouth ulceration	0/46 (0%)	0	1/47 (2.1%)	1
Dry mouth	0/46 (0%)	0	1/47 (2.1%)	1
dysphagia	1/46 (2.2%)	1	0/47 (0%)	0
General disorders
Fatigue	13/46 (28.3%)	15	18/47 (38.3%)	32
Oedema peripheral	7/46 (15.2%)	7	10/47 (21.3%)	13
Pyrexia	3/46 (6.5%)	4	7/47 (14.9%)	10
Pain	4/46 (8.7%)	5	5/47 (10.6%)	5
Asthenia	2/46 (4.3%)	2	1/47 (2.1%)	1
Oedema	2/46 (4.3%)	2	1/47 (2.1%)	1
Chills	1/46 (2.2%)	1	1/47 (2.1%)	1
Feeling cold	1/46 (2.2%)	1	1/47 (2.1%)	1
Local swelling	2/46 (4.3%)	2	0/47 (0%)	0
Chest pain	1/46 (2.2%)	1	0/47 (0%)	0
Discomfort	0/46 (0%)	0	1/47 (2.1%)	1
Gait Disturbance	0/46 (0%)	0	1/47 (2.1%)	1
Mucosal inflammation	0/46 (0%)	0	1/47 (2.1%)	1
Infections and infestations
Nasopharyngitis	3/46 (6.5%)	3	11/47 (23.4%)	11
Herpes zoster	2/46 (4.3%)	2	4/47 (8.5%)	7
Bronchitis	2/46 (4.3%)	2	6/47 (12.8%)	6
Respiratory tract infection	3/46 (6.5%)	3	2/47 (4.3%)	2
Cystitis	2/46 (4.3%)	2	1/47 (2.1%)	1
Urinary tract infection	1/46 (2.2%)	1	2/47 (4.3%)	2
Eye infection	1/46 (2.2%)	1	1/47 (2.1%)	1
Oesophageal candidiasis	1/46 (2.2%)	1	1/47 (2.1%)	1
Oral candidiasis	1/46 (2.2%)	1	1/47 (2.1%)	1
Oral herpes	1/46 (2.2%)	1	1/47 (2.1%)	1
Rhinitis	1/46 (2.2%)	1	1/47 (2.1%)	1
Sinusitis	2/46 (4.3%)	2	0/47 (0%)	0
Upper respiratory tract infection	2/46 (4.3%)	2	0/47 (0%)	0
Acute tonsillitis	0/46 (0%)	0	1/47 (2.1%)	1
Diverticulitis	1/46 (2.2%)	1	0/47 (0%)	0
Fungal infection	0/46 (0%)	0	1/47 (2.1%)	1
Gastroenteritis	1/46 (2.2%)	1	0/47 (0%)	0
Hordeolum	1/46 (2.2%)	1	0/47 (0%)	0
Infection	0/46 (0%)	0	1/47 (2.1%)	1
Infective aneurysm	1/46 (2.2%)	1	0/47 (0%)	0
Influenza	1/46 (2.2%)	1	0/47 (0%)	0
Orchitis	1/46 (2.2%)	1	0/47 (0%)	0
Paronychia	0/46 (0%)	0	1/47 (2.1%)	1
Pneumonia	0/46 (0%)	0	1/47 (2.1%)	1
Pulmonary mycosis	0/46 (0%)	0	1/47 (2.1%)	1
Pyelonephritis acute	1/46 (2.2%)	1	0/47 (0%)	0
Injury, poisoning and procedural complications
Post procedural haemorrhage	1/46 (2.2%)	2	0/47 (0%)	0
Traumatic haematoma	1/46 (2.2%)	1	1/47 (2.1%)	1
Arthropod bite	1/46 (2.2%)	1	0/47 (0%)	0
Drug dispensing error	0/46 (0%)	0	1/47 (2.1%)	1
Excoriation	1/46 (2.2%)	1	0/47 (0%)	0
Eyelid injury	1/46 (2.2%)	1	0/47 (0%)	0
Fall	0/46 (0%)	0	1/47 (2.1%)	1
Laceration	1/46 (2.2%)	1	0/47 (0%)	0
Lumbar vertebral fracture	0/46 (0%)	0	1/47 (2.1%)	1
Investigations
Haemoglobin decreased	2/46 (4.3%)	2	2/47 (4.3%)	5
Weight decreased	4/46 (8.7%)	6	0/47 (0%)	0
C-reactive protein increased	3/46 (6.5%)	4	1/47 (2.1%)	1
Blood alkaline phosphatase increased	2/46 (4.3%)	2	1/47 (2.1%)	1
Blood lactate dehydrogenase increased	2/46 (4.3%)	2	1/47 (2.1%)	1
Weight increased	2/46 (4.3%)	3	0/47 (0%)	0
Blood creatinine increased	0/46 (0%)	0	2/47 (4.3%)	2
Platelet count decreased	0/46 (0%)	0	2/47 (4.3%)	2
Alanine aminotransferase increased	1/46 (2.2%)	1	0/47 (0%)	0
Blood creatine phosphokinase increased	0/46 (0%)	0	1/47 (2.1%)	1
Eastern cooperative oncology group performance status worse	0/46 (0%)	0	1/47 (2.1%)	1
Heart rate increased	0/46 (0%)	0	1/47 (2.1%)	1
Protein urine present	1/46 (2.2%)	1	0/47 (0%)	0
Transaminases increased	1/46 (2.2%)	1	0/47 (0%)	0
Metabolism and nutrition disorders
Hyperglycaemia	2/46 (4.3%)	11	3/47 (6.4%)	4
Anorexia	5/46 (10.9%)	5	1/47 (2.1%)	1
Hypercalcaemia	1/46 (2.2%)	2	0/47 (0%)	0
Hypocalcaemia	1/46 (2.2%)	1	1/47 (2.1%)	1
Hypokalaemia	1/46 (2.2%)	1	1/47 (2.1%)	1
Gout	1/46 (2.2%)	1	0/47 (0%)	0
Hypoalbuminaemia	0/46 (0%)	0	1/47 (2.1%)	1
Vitamin D deficiency	0/46 (0%)	0	1/47 (2.1%)	1
Musculoskeletal and connective tissue disorders
Back pain	3/46 (6.5%)	3	7/47 (14.9%)	7
Bone pain	4/46 (8.7%)	5	3/47 (6.4%)	3
Pain in extremity	4/46 (8.7%)	4	4/47 (8.5%)	4
Arthralgia	2/46 (4.3%)	3	1/47 (2.1%)	1
Muscle spasms	1/46 (2.2%)	1	3/47 (6.4%)	3
Myalgia	1/46 (2.2%)	1	2/47 (4.3%)	2
Musculoskeletal pain	0/46 (0%)	0	2/47 (4.3%)	2
Exostosis	1/46 (2.2%)	1	0/47 (0%)	0
Groin pain	0/46 (0%)	0	1/47 (2.1%)	1
Muscle twitching	1/46 (2.2%)	1	0/47 (0%)	0
Muscular weakness	0/46 (0%)	0	1/47 (2.1%)	1
Neck pain	0/46 (0%)	0	1/47 (2.1%)	1
Sensation of heaviness	1/46 (2.2%)	1	0/47 (0%)	0
Spinal disorder	1/46 (2.2%)	1	0/47 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Multiple myeloma	2/46 (4.3%)	2	3/47 (6.4%)	3
Nervous system disorders
Polyneuropathy	7/46 (15.2%)	14	9/47 (19.1%)	16
Peripheral sensory neuropathy	3/46 (6.5%)	4	9/47 (19.1%)	13
Dizziness	7/46 (15.2%)	8	3/47 (6.4%)	4
Headache	1/46 (2.2%)	1	5/47 (10.6%)	11
Paraesthesia	4/46 (8.7%)	4	5/47 (10.6%)	5
Dysgeusia	3/46 (6.5%)	3	5/47 (10.6%)	5
Neuropathy peripheral	3/46 (6.5%)	3	4/47 (8.5%)	4
Neuralgia	3/46 (6.5%)	3	1/47 (2.1%)	1
Sciatica	2/46 (4.3%)	2	2/47 (4.3%)	2
Ageusia	1/46 (2.2%)	1	1/47 (2.1%)	1
Hypoaesthesia	0/46 (0%)	0	2/47 (4.3%)	2
Burning sensation	1/46 (2.2%)	1	0/47 (0%)	0
Hemicephalgia	0/46 (0%)	0	1/47 (2.1%)	1
Hypogeusia	0/46 (0%)	0	1/47 (2.1%)	1
Hyposmia	1/46 (2.2%)	1	0/47 (0%)	0
Neurotoxicity	1/46 (2.2%)	1	0/47 (0%)	0
Post herpetic neuralgia	1/46 (2.2%)	1	0/47 (0%)	0
Tremor	1/46 (2.2%)	1	0/47 (0%)	0
Psychiatric disorders
Sleep disorder	4/46 (8.7%)	4	3/47 (6.4%)	3
Insomnia	1/46 (2.2%)	1	5/47 (10.6%)	5
Depression	0/46 (0%)	0	2/47 (4.3%)	2
Restlessness	0/46 (0%)	0	2/47 (4.3%)	2
Agitation	0/46 (0%)	0	1/47 (2.1%)	1
Dyssomnia	1/46 (2.2%)	1	0/47 (0%)	0
Mood altered	0/46 (0%)	0	1/47 (2.1%)	1
Renal and urinary disorders
Nocturia	1/46 (2.2%)	1	1/47 (2.1%)	1
Strangury	0/46 (0%)	0	1/47 (2.1%)	2
Haematuria	0/46 (0%)	0	1/47 (2.1%)	1
Leukocyturia	1/46 (2.2%)	1	0/47 (0%)	0
Nephrolithiasis	1/46 (2.2%)	1	0/47 (0%)	0
Urinary incontinence	0/46 (0%)	0	1/47 (2.1%)	1
Respiratory, thoracic and mediastinal disorders
Cough	5/46 (10.9%)	6	4/47 (8.5%)	4
Dyspnoea exertional	0/46 (0%)	0	3/47 (6.4%)	5
Dyspnoea	0/46 (0%)	0	3/47 (6.4%)	3
Epistaxis	1/46 (2.2%)	1	1/47 (2.1%)	2
Lung infiltration	1/46 (2.2%)	1	0/47 (0%)	0
Oropharyngeal pain	0/46 (0%)	0	1/47 (2.1%)	1
Pulmonary oedema	1/46 (2.2%)	1	0/47 (0%)	0
Skin and subcutaneous tissue disorders
Rash	2/46 (4.3%)	2	3/47 (6.4%)	3
Hyperhidrosis	1/46 (2.2%)	1	3/47 (6.4%)	3
Alopecia	1/46 (2.2%)	1	1/47 (2.1%)	1
Dry skin	1/46 (2.2%)	1	1/47 (2.1%)	1
Pruritus	2/46 (4.3%)	2	0/47 (0%)	0
Rash pruritic	1/46 (2.2%)	2	0/47 (0%)	0
Petechiae	0/46 (0%)	0	1/47 (2.1%)	1
Rash vesicular	1/46 (2.2%)	1	0/47 (0%)	0
Swelling face	0/46 (0%)	0	1/47 (2.1%)	1
Vascular disorders
Hypertension	5/46 (10.9%)	5	2/47 (4.3%)	2
Hypotension	2/46 (4.3%)	2	3/47 (6.4%)	4
Haematoma	1/46 (2.2%)	1	2/47 (4.3%)	2
Orthostatic hypotension	2/46 (4.3%)	2	1/47 (2.1%)	1
Deep vein thrombosis	1/46 (2.2%)	1	1/47 (2.1%)	1
Circulatory collapse	1/46 (2.2%)	1	0/47 (0%)	0
Flushing	0/46 (0%)	0	1/47 (2.1%)	1
Peripheral arterial occlusive disease	1/46 (2.2%)	1	0/47 (0%)	0
Thrombophlebitis supeficial	0/46 (0%)	0	1/47 (2.1%)	1
Thrombosis	1/46 (2.2%)	1	0/47 (0%)	0
Venous thrombosis limb	0/46 (0%)	0	1/47 (2.1%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.