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Cyclophosphamide, Bortezomib, and Dexamethasone in Treating Patients With Newly Diagnosed Multiple Myeloma

Primary Purpose

Multiple Myeloma and Plasma Cell Neoplasm

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

bortezomib

cyclophosphamide

dexamethasone

About this trial

This is an interventional treatment trial for Multiple Myeloma and Plasma Cell Neoplasm focused on measuring stage II multiple myeloma, stage III multiple myeloma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

DISEASE CHARACTERISTICS:

Confirmed diagnosis of symptomatic multiple myeloma
- Durie Salmon stage 2 or higher
- Previously untreated multiple myeloma (including immunomodulatory drugs such as thalidomide) with the exception of bisphosphonates
Evaluable or measurable disease, as defined by at least one of the following:
- Serum monoclonal protein ≥ 1 g/dL (measurable disease)
- Urine monoclonal protein ≥ 200 mg/24 hours by protein electrophoresis (measurable disease)
- Serum-free light chains (FLC) ≥ 10 mg/dL, kappa or lambda, accompanied by an abnormal kappa/lambda ratio

Serum FLC's should only be used for patients without measurable serum or urine m-spike

- Monoclonal bone marrow plasmacytosis ≥ 30% (evaluable disease)

* Patients diagnosed with smoldering myeloma or monoclonal gammopathy of undetermined significance are not eligible

PATIENT CHARACTERISTICS:

Inclusion criteria:

Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0, 1, or 2
- ECOG PS of 3 will be allowed if secondary to pain in the opinion of the Investigator
Total bilirubin normal OR direct bilirubin ≤ 2.0 mg/dL
Alkaline phosphatase ≤ 3 times upper limit of normal (ULN)
AST ≤ 3 times ULN
Creatinine ≤ 3.5 mg/dL
Absolute neutrophil count ≥ 1,000/mm³ without transfusion or growth factor
Platelet count ≥ 100,000/mm³ without transfusion or growth factor
Willingness and the physical and mental capability to provide written informed consent
Willingness to return to Mayo Clinic Arizona/Princess Margaret Hospital for follow-up
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception

Exclusion criteria:

Peripheral sensory neuropathy ≥ grade 2 as defined by National Cancer Institute (NCI) Common Terminology for Common Adverse Events (CTCAE) version 3.0
Known hypersensitivity to compounds containing boron or mannitol
Active uncontrolled infection
Severe cardiac comorbidity including but not limited to:
- New York Heart Association class III or IV heart failure
- History of myocardial infarction within the past 6 months
- Uncontrolled angina or electrocardiographic (ECG) evidence of acute ischemia
- Severe uncontrolled ventricular arrhythmias or ECG evidence of active conduction system abnormalities
- Cardiac amyloidosis with hypotension (i.e., systolic blood pressure < 100 mm Hg)
Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent study compliance or completion of study treatment

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
Prior high-dose corticosteroid therapy for 12 days or less is permitted for emergent complications from newly diagnosed multiple myeloma
More than 14 days since prior investigational agents
No concurrent steroids or any other anticancer agents or treatments
- Patients may receive the equivalent of up to 20 mg prednisone per day for concurrent illness or adrenal replacement therapy
Concurrent palliative radiotherapy for bony pain or fracture is allowed

Sites / Locations

Mayo Clinic in Arizona
Princess Margaret Hospital

Outcomes

Primary Outcome Measures

Number of Participants Who Achieved a Confirmed Responses Defined as a Complete Response (CR), Near CR or Very Good Partial Response (VGPR) After the First 4 Months of Treatment

Response that was confirmed on 2 consecutive evaluations during the first 4 months of treatment. Complete Response(CR): Complete disappearance of M-protein from serum and urine on immunofixation, normalization of Free Light Chain (FLC) ratio and <5% plasma cells in bone marrow. near Complete Response (nCR): Patients who meet all criteria for CR except a positive immunofixation will be classified as nCR. Very Good Partial Response(VGPR): >=90% reduction in serum M-component; Urine M-Component <100mg per 24hours; <=5% plasma cells in bone marrow.

Secondary Outcome Measures

Progression Free Survival (PFS)

PFS was defined as the time from registration to progression or death due to any cause. Progression was defined as any one or more of the following: An increase of 25% from lowest confirmed response in: Serum M-component (absolute increase >= 0.5g/dl) Urine M-component (absolute increase >= 200mg/24hour Difference between involved and uninvolved Free Light Chain levels (absolute increase >= 10mg/dl) Bone marrow plasma cell percentage (absolute increase of >=10%) Definite development of new bone lesion or soft tissue plasmacytomas

Overall Survival (OS)

OS was defined as the time from registration to death of any cause.

Number of Participants Who Responded to Treatment (Complete Response,CR; Near Complete Response, nCR; Very Good Partial Response, VGPR; or Partial Response, PR) After 4 Cycles

Response that was confirmed on 2 consecutive evaluations after 8 months of treatment. CR, nCR and VGPR as defined in the primary outcome. Partial Response(PR): >=50% reduction in serum M-component and/or Urine M-Component >=90% reduction or <200mg per 24hours; or >=50% decrease in difference between involved and uninvolved FLC levels.

Duration of Response

Duration of response was calculated from the documentation (date) of first response (CR, nCR, VGPR, or PR) until the date of progression or last follow-up in the subset of patients who responded.

Number of Participants Who Responded to Treatment (CR, nCR, VGPR or PR) After 8 Cycles

Response that was confirmed on 2 consecutive evaluations after 8 cycles of treatment. Criteria for CR, nCR, VGPR and PR are defined in prior outcomes.

Number of Participants Who Responded to Treatment (CR, nCR, VGPR or PR) After 12 Cycles

Response that was confirmed on 2 consecutive evaluations after 12 cycles of treatment. Criteria for CR, nCR, VGPR and PR are defined in prior outcomes.

Number of Participants With Severe Adverse Events

Severe adverse events were defined as grade 3 or higher, regardless of attribution to study drugs. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.

Participants Who Successfully Completed Collection of Peripheral Blood Stem Cells for Transplant

Evaluation of the ability to successfully collect peripheral blood stem cells following four months (cycles) of combination therapy.

Full Information

NCT ID

NCT00609167

First Posted

January 31, 2008

Last Updated

May 13, 2011

Sponsor

Mayo Clinic

Collaborators

National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT00609167

Brief Title

Cyclophosphamide, Bortezomib, and Dexamethasone in Treating Patients With Newly Diagnosed Multiple Myeloma

Official Title

A Phase II Trial of Cyclophosphamide, Bortezomib and Dexamethasone (CYBOR-D) in Patients With Newly Diagnosed Active Multiple Myeloma

Study Type

Interventional

2. Study Status

Record Verification Date

May 2011

Overall Recruitment Status

Completed

Study Start Date

December 2006 (undefined)

Primary Completion Date

January 2009 (Actual)

Study Completion Date

November 2010 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor

Mayo Clinic

Collaborators

National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy such as cyclophosphamide and dexamethasone work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving cyclophosphamide and dexamethasone together with bortezomib may kill more cancer cells. PURPOSE: This phase II trial is studying giving cyclophosphamide and dexamethasone together with bortezomib to see how well it works in treating patients with newly diagnosed multiple myeloma.

Detailed Description

OBJECTIVES: Primary * To evaluate the response rate (complete response [CR], near CR [nCR], and very good partial response) in patients with newly diagnosed multiple myeloma treated with bortezomib in combination with cyclophosphamide and dexamethasone . Secondary Determine the overall response rate (partial response, PR, or better) in these patients after 4, 8, and 12 courses of this regimen. Determine the duration of progression-free and overall survival of patients treated with this regimen. To evaluate the toxicity of this regimen in these patients. To evaluate the ability to successfully collect peripheral blood stem cells from these patients after 4 months of this regimen. To evaluate the CR or nCR rate in these patients after 8 and 12 courses of this regimen. OUTLINE: This is a multicenter study. Patients receive oral cyclophosphamide on days 1, 8, 15, and 22; bortezomib IV on days 1, 4, 8 , and 11 OR days 1, 8, 15 and 22; and dexamethasone on days 1-4, 9-12, and 17-20 in courses 1 and 2 and days 1, 18, 15, and 22 in all subsequent courses. Courses repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Multiple Myeloma and Plasma Cell Neoplasm

Keywords

stage II multiple myeloma, stage III multiple myeloma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

63 (Actual)

8. Arms, Groups, and Interventions

Intervention Type

Drug

Intervention Name(s)

bortezomib

Intervention Description

First 33 patients: 1.3 mg/m^2 IV Days 1, 4, 8 & 11 Remaining 30 patients: 1.5 mg/m^2 IV Days 1, 8, 15 & 22

Intervention Type

Drug

Intervention Name(s)

cyclophosphamide

Intervention Description

300mg/m^2 PO days 1, 8, 15 & 22

Intervention Type

Drug

Intervention Name(s)

dexamethasone

Intervention Description

First 33 patients: 40 mg PO Days 1-4, 9-12, 17-20 Remaining 30 patients: 40 mg PO Days 1-4, 9-12, 17-20 for cycles 1-2; Days 1, 8, 15, 22 for cycle 3+2 for cycle 3 and beyond

Primary Outcome Measure Information:

Title

Number of Participants Who Achieved a Confirmed Responses Defined as a Complete Response (CR), Near CR or Very Good Partial Response (VGPR) After the First 4 Months of Treatment

Description

Time Frame

After 4 months of treatment

Secondary Outcome Measure Information:

Title

Progression Free Survival (PFS)

Description

Time Frame

up to 5 years

Title

Overall Survival (OS)

Description

OS was defined as the time from registration to death of any cause.

Time Frame

From date of registration until death (up to 5 years)

Title

Number of Participants Who Responded to Treatment (Complete Response,CR; Near Complete Response, nCR; Very Good Partial Response, VGPR; or Partial Response, PR) After 4 Cycles

Description

Time Frame

4 cycles

Title

Duration of Response

Description

Duration of response was calculated from the documentation (date) of first response (CR, nCR, VGPR, or PR) until the date of progression or last follow-up in the subset of patients who responded.

Time Frame

Duration of study (up to 12 cycles)

Title

Number of Participants Who Responded to Treatment (CR, nCR, VGPR or PR) After 8 Cycles

Description

Response that was confirmed on 2 consecutive evaluations after 8 cycles of treatment. Criteria for CR, nCR, VGPR and PR are defined in prior outcomes.

Time Frame

After 8 cycles of treatment

Title

Number of Participants Who Responded to Treatment (CR, nCR, VGPR or PR) After 12 Cycles

Description

Response that was confirmed on 2 consecutive evaluations after 12 cycles of treatment. Criteria for CR, nCR, VGPR and PR are defined in prior outcomes.

Time Frame

After 12 cycles of treatment

Title

Number of Participants With Severe Adverse Events

Description

Time Frame

Every cycle during treatment (up to 12 cycles)

Title

Participants Who Successfully Completed Collection of Peripheral Blood Stem Cells for Transplant

Description

Evaluation of the ability to successfully collect peripheral blood stem cells following four months (cycles) of combination therapy.

Time Frame

After 4 cycles of treatment

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

DISEASE CHARACTERISTICS: Confirmed diagnosis of symptomatic multiple myeloma Durie Salmon stage 2 or higher Previously untreated multiple myeloma (including immunomodulatory drugs such as thalidomide) with the exception of bisphosphonates Evaluable or measurable disease, as defined by at least one of the following: Serum monoclonal protein ≥ 1 g/dL (measurable disease) Urine monoclonal protein ≥ 200 mg/24 hours by protein electrophoresis (measurable disease) Serum-free light chains (FLC) ≥ 10 mg/dL, kappa or lambda, accompanied by an abnormal kappa/lambda ratio Serum FLC's should only be used for patients without measurable serum or urine m-spike - Monoclonal bone marrow plasmacytosis ≥ 30% (evaluable disease) * Patients diagnosed with smoldering myeloma or monoclonal gammopathy of undetermined significance are not eligible PATIENT CHARACTERISTICS: Inclusion criteria: Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0, 1, or 2 - ECOG PS of 3 will be allowed if secondary to pain in the opinion of the Investigator Total bilirubin normal OR direct bilirubin ≤ 2.0 mg/dL Alkaline phosphatase ≤ 3 times upper limit of normal (ULN) AST ≤ 3 times ULN Creatinine ≤ 3.5 mg/dL Absolute neutrophil count ≥ 1,000/mm³ without transfusion or growth factor Platelet count ≥ 100,000/mm³ without transfusion or growth factor Willingness and the physical and mental capability to provide written informed consent Willingness to return to Mayo Clinic Arizona/Princess Margaret Hospital for follow-up Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Exclusion criteria: Peripheral sensory neuropathy ≥ grade 2 as defined by National Cancer Institute (NCI) Common Terminology for Common Adverse Events (CTCAE) version 3.0 Known hypersensitivity to compounds containing boron or mannitol Active uncontrolled infection Severe cardiac comorbidity including but not limited to: New York Heart Association class III or IV heart failure History of myocardial infarction within the past 6 months Uncontrolled angina or electrocardiographic (ECG) evidence of acute ischemia Severe uncontrolled ventricular arrhythmias or ECG evidence of active conduction system abnormalities Cardiac amyloidosis with hypotension (i.e., systolic blood pressure < 100 mm Hg) Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent study compliance or completion of study treatment PRIOR CONCURRENT THERAPY: See Disease Characteristics Prior high-dose corticosteroid therapy for 12 days or less is permitted for emergent complications from newly diagnosed multiple myeloma More than 14 days since prior investigational agents No concurrent steroids or any other anticancer agents or treatments - Patients may receive the equivalent of up to 20 mg prednisone per day for concurrent illness or adrenal replacement therapy Concurrent palliative radiotherapy for bony pain or fracture is allowed

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

A. Keith Stewart, M.B., Ch.B.

Organizational Affiliation

Mayo Clinic

Official's Role

Principal Investigator

Facility Information:

Facility Name

Mayo Clinic in Arizona

City

Scottsdale

State/Province

Arizona

ZIP/Postal Code

85259-5499

Country

United States

Facility Name

Princess Margaret Hospital

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M5G 2N9

Country

Canada

12. IPD Sharing Statement

Citations:

PubMed Identifier

19225538

Citation

Reeder CB, Reece DE, Kukreti V, Chen C, Trudel S, Hentz J, Noble B, Pirooz NA, Spong JE, Piza JG, Zepeda VH, Mikhael JR, Leis JF, Bergsagel PL, Fonseca R, Stewart AK. Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia. 2009 Jul;23(7):1337-41. doi: 10.1038/leu.2009.26. Epub 2009 Feb 19.

Results Reference

result

PubMed Identifier

20413666

Citation

Reeder CB, Reece DE, Kukreti V, Chen C, Trudel S, Laumann K, Hentz J, Pirooz NA, Piza JG, Tiedemann R, Mikhael JR, Bergsagel PL, Leis JF, Fonseca R, Stewart AK. Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood. 2010 Apr 22;115(16):3416-7. doi: 10.1182/blood-2010-02-271676. No abstract available.

Results Reference

result

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Cyclophosphamide, Bortezomib, and Dexamethasone in Treating Patients With Newly Diagnosed Multiple Myeloma

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