Combination Chemo, Peripheral Stem Cell Transplant, Biological Therapy, Pamidronate and Thalidomide for Multiple Myeloma

• ClinicalTrials.gov Identifier: NCT00004088
• Recruitment Status: Completed
• First Posted: January 27, 2003
• Results First Posted: July 2, 2019
• Last Update Posted: July 2, 2019
• Sponsor: City of Hope Medical Center
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): City of Hope Medical Center

Study Description

Brief Summary:

RATIONALE: Drugs used in chemotherapy work in different ways to stop cancer cells from dividing so they stop growing or die. Peripheral stem cell transplantation may allow doctors to give higher doses of chemotherapy drugs and kill more cancer cells. Biological therapies, such as interferon alfa, use different ways to stimulate the immune system and stop cancer cells from growing. Thalidomide may stop the growth of cancer cells by stopping blood flow to the tumor. Pamidronate may help to reduce the side effects of treatment for multiple myeloma.

PURPOSE: This phase II trial is studying combination chemotherapy, peripheral stem cell transplantation, biological therapy, pamidronate, and thalidomide to see how well they work in treating patients with stage I, stage II, or stage III multiple myeloma.

Condition or disease	Intervention/treatment	Phase
Multiple Myeloma and Plasma Cell Neoplasm	Biological: filgrastim; Biological: recombinant interferon alfa; Drug: busulfan; Drug: cyclophosphamide; Drug: melphalan; Drug: pamidronate disodium; Drug: thalidomide; Procedure: peripheral blood stem cell transplantation	Phase 2

Detailed Description:

OBJECTIVES:

• Determine the feasibility and toxic effects of high-dose melphalan, busulfan, and cyclophosphamide followed by autologous peripheral blood stem cell rescue, interferon alfa, and pamidronate in patients with responsive or stable, low-bulk multiple myeloma.
• Determine the response rate and progression-free and overall survival of patients treated with this regimen.
• Determine the feasibility of adding thalidomide to interferon alfa and pamidronate in patients who are not in complete remission (CR) 6 months after the second course of high-dose chemotherapy.
• Determine whether administration of thalidomide can increase the CR rate in patients who are not in CR 6 months after the second course of high-dose chemotherapy and determine its effect on progression-free and overall survival of these patients.
• Determine the pharmacokinetics of busulfan and cyclophosphamide and correlate the pharmacokinetics with the toxic effects of these drugs and outcome in these patients.
• Determine the effect of thalidomide on microvascular density of bone marrow and correlate these possible effects with outcome in these patients.
• Determine the cytogenetics, gene rearrangement, and fluorescence in situ hybridization in baseline and post treatment bone marrow and blood specimens and correlate the presence/persistence of these features with treatment outcome in these patients.

OUTLINE: Patients receive cyclophosphamide IV over 2 hours on day 1 and filgrastim (G-CSF) subcutaneously (SC) or IV twice a day beginning on day 2 and continuing until peripheral blood stem cells (PBSCs) are collected. PBSCs are collected beginning on day 10.

Patients receive high-dose melphalan IV on day -1. PBSCs are reinfused on day 0. G-CSF is administered IV or SC daily beginning on day 1 and continuing until blood counts recover. Between 8 and 14 weeks later, patients receive high-dose busulfan IV every 6 hours on days -7 to -4 and cyclophosphamide IV over 2 hours on days -3 and -2. PBSCs are reinfused on day 0 and G-CSF is administered IV or SC daily until blood counts recover.

Patients with responding or stable disease after chemotherapy receive maintenance therapy with interferon alfa beginning 14-20 weeks after day 0 of the second course of chemotherapy. Interferon alfa is administered SC 3 times a week for 3 years. Patients also receive pamidronate IV every 4 weeks until disease progression. Patients who are not in complete remission (CR) 6 months after completing the second course of chemotherapy receive oral thalidomide daily for a maximum of 1 year or for 3 months after achieving CR.

Patients are followed monthly for 1 year, every 3 months for 1 year, and then periodically thereafter.

PROJECTED ACCRUAL: A total of 70 patients will be accrued for this study within approximately 2.5 years.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 77 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Sequential High-Dose Melphalan and Busulfan/Cyclophosphamide Followed by Peripheral Blood Progenitor Cell Rescue, Interferon/Thalidomide and Pamidronate for Patients With Multiple Myeloma
• Study Start Date: April 13, 1999
• Actual Primary Completion Date: January 9, 2018
• Actual Study Completion Date: January 9, 2018

Arms and Interventions

Arm

Intervention/treatment

Experimental: HD chemotherapy followed by PBPC Rescue; Patients receive high-dose (HD) melphalan intra-venously (IV) on day -1. Peripheral blood progenitor cells (PBPCs) are reinfused on day 0. Filgrastim (G-CSF) is administered IV or SC daily beginning on day 1 and continuing until blood counts recover. Between 8 and 14 weeks later, patients receive IV high-dose busulfan every 6 hours on days -7 to -4 and cyclophosphamide IV over 2 hours on days -3 and -2. PBPCs are reinfused on day 0 and G-CSF is administered IV or subcutaneously (SC) daily until blood counts recover.

Biological: filgrastim; Other Names: granulocyte colony-stimulating factor (G-CSF); Neupogen; Biological: recombinant interferon alfa; Other Names: IFN alpha-2B; Intron A; Drug: busulfan; Other Names: Myleran; Busulfex; Drug: cyclophosphamide; Other Names: cytophosphane; Cytoxan; Drug: melphalan; Other Names: Alkeran; Evomela; Drug: pamidronate disodium; Other Name: pamidronic acid; Drug: thalidomide; Other Names: Thalidomid; Immunoprin; Procedure: peripheral blood stem cell transplantation; Other Name: peripheral blood progenitor cell transplantation

Outcome Measures

Primary Outcome Measures :

1. Best Response Prior to Tandem Autologous Stem Cell Transplant [ Time Frame: From enrollment in the study until day -8: before dilantin given pre-first high-dose chemo preceeding first cycle of tandem autologous cell transplant ]
   Response gradations are specified in the "Blade criteria", Br J Haematol 1998; 102: 1115-1123. Serum myeloma protein is measured 2x at least six weeks apart, and urine M-component is measured 2x at least 3 weeks apart. Complete response (CR): less than 3% plasma cells in bone marrow or blood. Very good partial response (VGPR): Greater than 90% decrease in myeloma protein, and urine M-component less than 0.1 gm/day. Partial response (PR) Greater than 50% decrease in myeloma protein; urine M-component less than 0.2 gm/day. Lytic skeletal lesions must not increase, and serum calcium level must remain normal. Stable disease (SD): 25-49% decrease in protein and 25% decrease in urine M-component. Progressive disease (PD): Greater than 25% increase in myeloma protein, or hypercalcemia. Relapse: 1) increase greater than 100% of myeloma protein; 2) More than 25% increase of myeloma protein; 3) reappearance of the myeloma peaks; 4) increase in lytic bone lesions on radiographs.
2. Response After Tandem Autologous Stem Cell Transplant [ Time Frame: After second cycle of tandem autologous stem cell transplant: Day 0 of second transplant to 12 weeks post-cycle 2 cell infusion of the tandem transplant. ]
   Response gradations are specified in the "Blade criteria", Br J Haematol 1998; 102: 1115-1123. Serum myeloma protein is measured 2x at least six weeks apart, and urine M-component is measured 2x at least 3 weeks apart. Complete response (CR): less than 3% plasma cells in bone marrow or blood. Very good partial response (VGPR): Greater than 90% decrease in myeloma protein, and urine M-component less than 0.1 gm/day. Partial response (PR) Greater than 50% decrease in myeloma protein; urine M-component less than 0.2 gm/day. Lytic skeletal lesions must not increase, and serum calcium level must remain normal. Stable disease (SD): 25-49% decrease in protein and 25% decrease in urine M-component. Progressive disease (PD): Greater than 25% increase in myeloma protein, or hypercalcemia. Relapse: 1) increase greater than 100% of myeloma protein; 2) More than 25% increase of myeloma protein; 3) reappearance of the myeloma peaks; 4) increase in lytic bone lesions on radiographs.
3. Three-year Overall Survival [ Time Frame: Estimate reported at three years after day 0 of the first cycle of infusion of cells of the tandem transplant. ]
   Kaplan-Meier estimate at three years post-first transplant of survival. Outcome is death or alive at follow-up (censored). 95 percent confidence interval of the point estimate is calculated using Greenwood's variance.
4. Progression-free Survival [ Time Frame: Estimate reported at three years after day 0 of the first cycle of infusion of cells of the tandem transplant. ]

   Kaplan-Meier estimate at three years post-first transplant of survival. Event of interest is the first of Death or Progression. Censoring is Alive in Continuous Complete Remission at date of last follow-up.

   95 percent confidence interval of the point estimate is calculated using Greenwood's variance.

5. Best Response at 6 Months Post Tandem Autologous Stem Cell Transplant [ Time Frame: Six months after day 0 of the first cycle of the tandem autologous stem cell transplant. This will be used to determine administration of thalidomide. ]
   Response gradations are specified in the "Blade criteria", Br J Haematol 1998; 102: 1115-1123. Serum myeloma protein is measured 2x at least six weeks apart, and urine M-component is measured 2x at least 3 weeks apart. Complete response (CR): less than 3% plasma cells in bone marrow or blood. Very good partial response (VGPR): Greater than 90% decrease in myeloma protein, and urine M-component less than 0.1 gm/day. Partial response (PR) Greater than 50% decrease in myeloma protein; urine M-component less than 0.2 gm/day. Lytic skeletal lesions must not increase, and serum calcium level must remain normal. Stable disease (SD): 25-49% decrease in protein and 25% decrease in urine M-component. Progressive disease (PD): Greater than 25% increase in myeloma protein, or hypercalcemia. Relapse: 1) increase greater than 100% of myeloma protein; 2) More than 25% increase of myeloma protein; 3) reappearance of the myeloma peaks; 4) increase in lytic bone lesions on radiographs.
6. Best Response After Tandem Autologous Stem Cell Transplant and Maintenance [ Time Frame: Response after six months after day 0 of the first cycle of the tandem transplant, after administration of maintenance thalidomide if necessary, until three years post-day 0 of the first cycle of the tandem transplant. ]
   Response gradations are specified in the "Blade criteria", Br J Haematol 1998; 102: 1115-1123. Serum myeloma protein is measured 2x at least six weeks apart, and urine M-component is measured 2x at least 3 weeks apart. Complete response (CR): less than 3% plasma cells in bone marrow or blood. Very good partial response (VGPR): Greater than 90% decrease in myeloma protein, and urine M-component less than 0.1 gm/day. Partial response (PR) Greater than 50% decrease in myeloma protein; urine M-component less than 0.2 gm/day. Lytic skeletal lesions must not increase, and serum calcium level must remain normal. Stable disease (SD): 25-49% decrease in protein and 25% decrease in urine M-component. Progressive disease (PD): Greater than 25% increase in myeloma protein, or hypercalcemia. Relapse: 1) increase greater than 100% of myeloma protein; 2) More than 25% increase of myeloma protein; 3) reappearance of the myeloma peaks; 4) increase in lytic bone lesions on radiographs.

Eligibility Criteria

• Ages Eligible for Study: up to 65 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

DISEASE CHARACTERISTICS:

• Histologically proven stage I-III multiple myeloma

  • Less than 18 months since diagnosis

  • Smoldering myeloma allowed if there is evidence of progressive disease requiring therapy

    • At least 25% increase in M protein levels or Bence Jones excretion
    • Hemoglobin no greater than 10.5 g/dL
    • Hypercalcemia
    • Frequent infections
    • Rise in serum creatinine above normal on 2 separate occasions
  • Nonquantifiable monoclonal proteins allowed if other criteria for multiple myeloma or smoldering myeloma are met

• Response/status after induction therapy:

  • Responding or stable disease AND no greater than 40% myelomatous involvement of bone marrow
• No Waldenstrom's macroglobulinemia

PATIENT CHARACTERISTICS:

Age:

• 65 and under

Performance status:

• Karnofsky 80-100%

Life expectancy:

• Not specified

Hematopoietic:

• See Disease Characteristics
• Absolute neutrophil count greater than 1,500/mm^3
• Platelet count greater than 100,000/mm^3

Hepatic:

• Bilirubin no greater than 1.5 mg/dL
• Serum glutamic axaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) less than 2.5 times upper limit of normal
• Hepatitis B antigen or hepatitis C ribonucleaic acid (RNA) negative

Renal:

• See Disease Characteristics
• Creatinine no greater than 1.4 mg/dL
• Creatinine clearance greater than 65 mL/min

Cardiovascular:

• Cardiac ejection fraction at least 50% by multigated acquisition scan (MUGA) or echocardiogram

Pulmonary:

• Forced-expiratory volume in one second (FEV_1) greater than 60% of normal
• Diffusing capacity for carbon monoxide (DLCO) greater than 50% of predicted lower limit

Other:

• Not pregnant
• Negative pregnancy test
• Fertile patients must use effective contraception
• Human immunodeficiency virus (HIV) negative
• No other medical or psychosocial problems that would increase patient risk
• No other malignancy within past 5 years except nonmelanomatous skin cancer or carcinoma in situ of the cervix
• No known hypersensitivity to filgrastim (G-CSF) or Escherechi coli-derived proteins

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• See Disease Characteristics
• No more than 3 prior chemotherapy regimens
• At least 4 weeks since prior chemotherapy

Endocrine therapy:

• Not specified

Radiotherapy:

• At least 4 weeks since prior radiotherapy

Surgery:

• Not specified

Contacts and Locations

Locations

United States, Arizona

Banner Good Samaritan Medical Center

Phoenix, Arizona, United States, 85006

United States, California

City of Hope Comprehensive Cancer Center

Duarte, California, United States, 91010-3000

Sponsors and Collaborators

City of Hope Medical Center

National Cancer Institute (NCI)

Investigators

• Principal Investigator: George Somlo, MD; City of Hope Medical Center

  Study Documents (Full-Text)

Documents provided by City of Hope Medical Center:

Study Protocol and Statistical Analysis Plan  [PDF] February 3, 2004

More Information

Publications:

Long-term Progression-free (PFS) and Overall Survival (OS) with Tandem Autologous Transplant (TASCT) After High-dose Induction With Melphalan (MEL) and Busulfan/cyclophosphamide (BU/CY), or a Novel Regimen of MEL and Total Marrow Irradiation (TMI), Followed by Maintenance With Interferon A-2 (IF) and/or Thalidomide (THAL). Haematologica 96(s1), 2011, s103. G. Somlo, J. Palmer, A. Dagis, M. O'Donnell, D. Snyder, F. Sahebi, N. Kogut, A. Brown, R. Spielberger, P.Parker, C. Karanes, L. Popplewell, A. Stein, A. Krishnan, J. Alvarnas, J. Wong, S. Forman.

• Responsible Party: City of Hope Medical Center
• ClinicalTrials.gov Identifier: NCT00004088
• Other Study ID Numbers: 99021; P30CA033572 ( U.S. NIH Grant/Contract ); CHNMC-IRB-99021 ( Other Identifier: City of Hope Institutional Review Board ); NCI-G99-1583 ( Other Identifier: National Cancer Institute ); CDR0000067301 ( Registry Identifier: NCI PDQ )
• First Posted: January 27, 2003
• Results First Posted: July 2, 2019
• Last Update Posted: July 2, 2019
• Last Verified: January 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by City of Hope Medical Center:

stage I multiple myeloma; stage II multiple myeloma; stage III multiple myeloma

Additional relevant MeSH terms:

Multiple Myeloma; Neoplasms, Plasma Cell; Plasmacytoma; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Pamidronate; Interferons; Interferon-alpha; Thalidomide; Cyclophosphamide; Melphalan; Busulfan; Lenograstim; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action