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Bortezomib, Thalidomide, and Dexamethasone After Melphalan and Stem Cell Transplant in Treating Patients With Stage I-III Multiple Myeloma

Primary Purpose

Multiple Myeloma and Plasma Cell Neoplasm, Neurotoxicity

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

bortezomib

dexamethasone

melphalan

thalidomide

cytogenetic analysis

fluorescence in situ hybridization

laboratory biomarker analysis

questionnaire administration

autologous hematopoietic stem cell transplantation

peripheral blood stem cell transplantation

About this trial

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

Eligibility Criteria

undefined - 70 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Multiple Myeloma patients with symptomatic disease, stage II or III at diagnosis or progressive stage I requiring chemotherapy and/or radiation therapy (by Salmon-Durie classification), who are not eligible for tandem transplant study using TMI; because of previous radiation or eligibility criteria; documentation of disease staging by both Salmon-Durie classification and International Staging System (ISS) is required
Patients with non-secretory myeloma should have measurable serum free-light chain protein by the Free-lite test or measurable disease such as a soft tissue myeloma
A minimum of 4 x 10^6 of CD 34 Positive cell/kg has been harvested
A Karnofsky performance status (KPS) of >= 70% is required unless the KPS is impaired due to bone disease
No contraindication to the collection of a minimum of 4 x 10^6 CD34+ cells/kg by apheresis
All patients must have signed a voluntary, informed consent in accordance with institutional and federal guidelines
Bilirubin =< 1.5 mg/dl
Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvate transaminase (SGPT) < 2.5 x upper limits of normal
Creatinine clearance of >= 40cc/min
Absolute neutrophil count of > 1000/ul
Platelet count of > 100,000/ul
Cardiac ejection fraction >= 45% by multigated acquisition (MUGA) scan and/or by echocardiogram
Diffusing capacity of the lung for carbon monoxide (DLCO) >= 50% of predicted lower limit
Human immunodeficiency virus (HIV) antibody tests negative
No other medical, or psychosocial problems which in the opinion of the primary physician or principal investigator would place the patient at unacceptably high risk from this treatment regimen

Exclusion Criteria:

Presence of peripheral neuropathy >= grade II
Patients with evidence of disease progression (with >= 25% increase in M protein) on bortezomib and or thalidomide therapy prior to transplant
Pregnant or nursing women, as well as women of child bearing age, who are unwilling to use a dual method of contraception and men who are unwilling to use condom
Patients with history of hypersensitivity to bortezomib, boron or mannitol

Sites / Locations

City of Hope Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (stem cell transplant, maintenance treatment)

Arm Description

Patients receive high-dose melphalan IV over 30 minutes on days -2 and -1 and undergo autologous peripheral blood stem cell transplantation on day 0. Patients receive filgrastim IV or SC beginning on day 5 and continuing until blood counts recover. Beginning 4 to 8 weeks after transplantation, patients receive maintenance therapy comprising bortezomib IV on days 1, 8, and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive oral dexamethasone on days 1 to 4. Treatment with dexamethasone repeats every month for 12 months in the absence of disease progression or unacceptable toxicity. Beginning 2 weeks after completion of bortezomib, patients receive oral thalidomide once daily until disease progression.

Outcomes

Primary Outcome Measures

Number of Participants With Adverse Events

All grade 3 and above treatment-related adverse events (AEs) during bortezomib/dexamethasone treatment cycles.

One Year Overall Survival

One year overall survival estimated using the product-limit method of Kaplan and Meier. Defined as the percentage of patients alive at year one after starting treatment.

Secondary Outcome Measures

Count of Response in Patients Started on Maintenance Therapy

Complete Response (CR): Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow. Very Good Partial Response (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-h. Partial Response (PR): > 50% reduction of serum M-protein and reduction in 24-h urinary M-protein by > 90% or to < 200mg per 24-h In addition to the above listed criteria, if present at baseline, a . 50% reduction in the size of soft tissue plasmacytomas is also required. Stable Disease (SD): Not meeting criteria for CR, VGPR, PR or progressive disease. Relapse: Any of the following: Reappearance of serum or urine M-protein by immunofixation or electrophoresis Development of > 5% plasma cells in the bone marrow. Appearance of any other sign of progression (i.e., new plasmacytoma, lytic bone lesion)

One Year Progression-free Survival (PFS)

PFS estimated using the product-limit method of Kaplan and Meier. Defined as the percentage of patients progression-free at year one after starting treatment. International Myeloma Working Group uniform response criteria for disease progression: Increase of > 25% from baseline 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 h; Only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels. The absolute increase must be >l0mg/dl. Bone marrow plasma cell percentage: the absolute % must be > 10%C; 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 2.65 mmol/l) that can be attributed solely to the plasma cell proliferative disorder.

Full Information

NCT ID

NCT00792142

First Posted

November 14, 2008

Last Updated

August 17, 2021

Sponsor

City of Hope Medical Center

Collaborators

National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT00792142

Brief Title

Bortezomib, Thalidomide, and Dexamethasone After Melphalan and Stem Cell Transplant in Treating Patients With Stage I-III Multiple Myeloma

Official Title

A Phase II Study of Maintenance Treatment With Sequential Bortezomib, Thalidomide and Dexamethasone Following Autologous Peripheral Blood Stem Cell Transplant in Patients With Multiple Myeloma

Study Type

Interventional

2. Study Status

Record Verification Date

January 2020

Overall Recruitment Status

Completed

Study Start Date

January 16, 2008 (undefined)

Primary Completion Date

April 21, 2014 (Actual)

Study Completion Date

April 21, 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

City of Hope Medical Center

Collaborators

National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

RATIONALE: Bortezomib and thalidomide may stop the growth of multiple myeloma by blocking blood flow to the cancer. Bortezomib may also stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving bortezomib together with thalidomide and dexamethasone may kill any cancer cells that remain after high-dose melphalan and stem cell transplant in patients with multiple myeloma. PURPOSE: This phase II trial is studying the side effects of giving bortezomib together with thalidomide and dexamethasone after melphalan and stem cell transplant and to see how well it works in treating patients with stage I-III multiple myeloma.

Detailed Description

OBJECTIVES: Primary To assess the feasibility and toxicities of maintenance therapy with sequential bortezomib, thalidomide, and dexamethasone after high-dose melphalan and autologous peripheral blood stem cell transplantation in patients with multiple myeloma. To assess whether administration of sequential bortezomib, thalidomide, and dexamethasone can improve progression-free survival of these patients. Secondary To assess whether administration of sequential bortezomib, thalidomide, and dexamethasone can increase complete remission rate and duration of response in these patients. To assess the impact of maintenance therapy with sequential bortezomib, thalidomide, and dexamethasone after transplantation on overall survival of these patients. To evaluate the influence of cytogenetic abnormalities (e.g., chromosome 13 deletion, 14 q32 abnormality, t [4;14], chromosome 1 q21 amplification, and chromosome 17 deletion) on outcome by performing conventional cytogenetic study and fluorescence in situ hybridization (FISH) studies on baseline and post-transplant bone marrow specimens. OUTLINE: High-dose melphalan and autologous peripheral blood stem cell transplantation (PBSCT): Patients receive high-dose melphalan IV over 30 minutes on days -2 and -1 and undergo autologous PBSCT on day 0. Patients receive filgrastim (G-CSF) IV or subcutaneously beginning on day 5 and continuing until blood counts recover. Maintenance therapy: Beginning 4-8 weeks after transplantation, patients receive bortezomib IV on days 1, 8, and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive oral dexamethasone on days 1-4; treatment with dexamethasone repeats every month for 12 months in the absence of disease progression or unacceptable toxicity. Beginning 2 weeks after completion of bortezomib, patients receive oral thalidomide once daily until disease progression. Patients complete the FACT-GOG neurotoxicity questionnaire periodically. Bone marrow samples are collected at baseline and post-transplant for cytogenetic analysis by FISH.

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, Neurotoxicity

Keywords

neurotoxicity, stage I multiple myeloma, 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

45 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Treatment (stem cell transplant, maintenance treatment)

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

bortezomib

Intervention Description

Given IV

Intervention Type

Drug

Intervention Name(s)

dexamethasone

Intervention Description

Given orally

Intervention Type

Drug

Intervention Name(s)

melphalan

Intervention Description

Given IV

Intervention Type

Drug

Intervention Name(s)

thalidomide

Intervention Description

Given orally

Intervention Type

Genetic

Intervention Name(s)

cytogenetic analysis

Intervention Description

Performed on baseline and post transplant bone marrow specimens

Intervention Type

Genetic

Intervention Name(s)

fluorescence in situ hybridization

Intervention Description

Performed on baseline and post transplant bone marrow specimens

Intervention Type

Other

Intervention Name(s)

laboratory biomarker analysis

Intervention Description

Baseline, post transplant and prior to start of bortezomib, every 3 months post transplant for the first year, after 6 cycles of bortezomib, every year after transplant for 2-4 years.

Intervention Type

Other

Intervention Name(s)

questionnaire administration

Intervention Description

Completed at baseline (within 6 weeks prior to enrollment) and at 2 months post transplant and once a month after that for the first year. For the second year the questionnaire will be completed every 3 months as long as on thalidomide for the duration of the study.

Intervention Type

Procedure

Intervention Name(s)

autologous hematopoietic stem cell transplantation

Intervention Description

Minimum dose of 2 X 10(6) CD34 + cells/kg day 0 after two days of treatment with Melphalan

Intervention Type

Procedure

Intervention Name(s)

peripheral blood stem cell transplantation

Intervention Description

Minimum dose of 2 X 10(6) CD34 + cells/kg day 0 after two days of treatment with Melphalan

Primary Outcome Measure Information:

Title

Number of Participants With Adverse Events

Description

All grade 3 and above treatment-related adverse events (AEs) during bortezomib/dexamethasone treatment cycles.

Time Frame

After 4 months of maintenance therapy

Title

One Year Overall Survival

Description

One year overall survival estimated using the product-limit method of Kaplan and Meier. Defined as the percentage of patients alive at year one after starting treatment.

Time Frame

From date of treatment initiation until death from any cause, assessed up to one year.

Secondary Outcome Measure Information:

Title

Count of Response in Patients Started on Maintenance Therapy

Description

Time Frame

Post-Thalidomide at 1 year.

Title

One Year Progression-free Survival (PFS)

Description

Time Frame

From start of treatment initiation until disease progression, relapse or death from any cause, assessed up to 1 year.

10. Eligibility

Sex

All

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Multiple Myeloma patients with symptomatic disease, stage II or III at diagnosis or progressive stage I requiring chemotherapy and/or radiation therapy (by Salmon-Durie classification), who are not eligible for tandem transplant study using TMI; because of previous radiation or eligibility criteria; documentation of disease staging by both Salmon-Durie classification and International Staging System (ISS) is required Patients with non-secretory myeloma should have measurable serum free-light chain protein by the Free-lite test or measurable disease such as a soft tissue myeloma A minimum of 4 x 10^6 of CD 34 Positive cell/kg has been harvested A Karnofsky performance status (KPS) of >= 70% is required unless the KPS is impaired due to bone disease No contraindication to the collection of a minimum of 4 x 10^6 CD34+ cells/kg by apheresis All patients must have signed a voluntary, informed consent in accordance with institutional and federal guidelines Bilirubin =< 1.5 mg/dl Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvate transaminase (SGPT) < 2.5 x upper limits of normal Creatinine clearance of >= 40cc/min Absolute neutrophil count of > 1000/ul Platelet count of > 100,000/ul Cardiac ejection fraction >= 45% by multigated acquisition (MUGA) scan and/or by echocardiogram Diffusing capacity of the lung for carbon monoxide (DLCO) >= 50% of predicted lower limit Human immunodeficiency virus (HIV) antibody tests negative No other medical, or psychosocial problems which in the opinion of the primary physician or principal investigator would place the patient at unacceptably high risk from this treatment regimen Exclusion Criteria: Presence of peripheral neuropathy >= grade II Patients with evidence of disease progression (with >= 25% increase in M protein) on bortezomib and or thalidomide therapy prior to transplant Pregnant or nursing women, as well as women of child bearing age, who are unwilling to use a dual method of contraception and men who are unwilling to use condom Patients with history of hypersensitivity to bortezomib, boron or mannitol

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Firoozeh Sahebi, MD

Organizational Affiliation

City of Hope Medical Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

City of Hope Medical Center

City

Duarte

State/Province

California

ZIP/Postal Code

91010-3000

Country

United States

12. IPD Sharing Statement

Learn more about this trial

Bortezomib, Thalidomide, and Dexamethasone After Melphalan and Stem Cell Transplant in Treating Patients With Stage I-III Multiple Myeloma

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