Neoplasms

Heart and Blood Diseases

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Rare Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Plasmacytoma

Neoplasms by Histologic Type

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hematologic Diseases

Hemorrhagic Disorders

Lymphoproliferative Disorders

Immunoproliferative Disorders

Micronutrients

All Drugs and Chemicals

Anti-Inflammatory Agents

Antineoplastic Agents

Antiemetics

Gastrointestinal Agents

Anti-Infective Agents

Vitamins

Ascorbic Acid

Dexamethasone

Immunomodulating Agents

Dexamethasone acetate

Mitogens

Thalidomide

Arsenic Trioxide

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Immunosuppressive Agents

Immunologic Factors

Anti-Bacterial Agents

Angiogenesis Inhibitors

Growth Inhibitors

Antioxidants

Protective Agents

Trace Elements

Vitamin C

arsenic trioxide

ascorbic acid

dexamethasone

thalidomide

anti-cytokine therapy

antiangiogenesis therapy

biological therapy

chemotherapy

drug resistance inhibition

growth factor antagonist therapy

non-specific immune-modulator therapy

Mohamad A. Hussein, MD

RATIONALE: Drugs used in chemotherapy, such as arsenic trioxide and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Thalidomide may stop the growth of multiple myeloma by blocking blood flow to the cancer. Giving arsenic trioxide together with ascorbic acid, dexamethasone, and thalidomide may kill more cancer cells.

PURPOSE: This phase II trial is studying how well giving arsenic trioxide together with ascorbic acid, dexamethasone, and thalidomide work in treating patients with multiple myeloma.

OBJECTIVES:

Primary

* Determine the response rate in patients with previously untreated high-risk or relapsed or refractory multiple myeloma (MM) treated with arsenic trioxide, ascorbic acid, dexamethasone, and thalidomide.
* Determine the safety of this regimen in these patients.

Secondary

* Determine the duration of response, progression-free survival, and overall survival of patients with previously untreated high-risk MM treated with this regimen.

OUTLINE: This is an open-label study.

* Induction therapy: Patients receive arsenic trioxide IV over 1-4 hours and ascorbic acid IV over 15-30 minutes on days 1-5 in week 1 and then twice weekly in weeks 2-12; oral dexamethasone on days 1-4, 11-14, 29-32, 39-42, 57-60, and 67-70 (weeks 1, 2, 5, 6, 9, and 10); and oral thalidomide once daily in weeks 1-12.
* Consolidation therapy: Beginning 4 weeks after completion of induction therapy, patients receive arsenic trioxide and ascorbic acid as in induction therapy; oral dexamethasone on days 1-4, 29-32, and 57-60 (weeks 1, 5, and 9); and oral thalidomide once daily in weeks 1-12.
* Maintenance therapy: Beginning 4 weeks after completion of consolidation therapy, patients receive arsenic trioxide IV over 1-4 hours and ascorbic acid IV over 15-30 minutes on days 1, 8, 15, and 22. Treatment with arsenic trioxide and ascorbic acid repeats every 90 days (every 12 weeks). Patients also receive oral dexamethasone on days 1-4. Treatment with dexamethasone repeats every 28 days. Patients receive oral thalidomide once daily. Maintenance therapy continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed at 4 weeks and then every 6 months thereafter.

PROJECTED ACCRUAL: A total of 33-68 patients (15-34 with previously untreated high-risk multiple myeloma \[MM\] and 18-34 with relapsed or refractory MM) will be accrued for this study.

Arsenic Trioxide, Ascorbic Acid, Dexamethasone, and Thalidomide in Treating Patients With Multiple Myeloma

Phase II Study of Arsenic Trioxide, Ascorbic Acid, Dexamethasone, and Thalidomide in Patients With Previously Untreated High-Risk or Relapsed or Refractory Multiple Myeloma

The Cleveland Clinic

Antirheumatic Agents

Dermatologic Agents

Melphalan

Cyclosporine

Cyclosporins

Lenograstim

Mycophenolic Acid

BB 1101

One autologous transplant along with a second autologous transplant will be preformed followed by one year of Dexamethasone and Thalidomide maintenance therapy.

One autologous transplant along with a second autologous transplant will be preformed followed by one year of observation.

One autologous transplant and one non-myeloablative allogeneic transplant will be preformed and followed by one year of observation.

Melphalan will be administered at a dose of 200 mg/m2. Melphalan will be given in one dose infused on Day -2. Melphalan dose is based on ideal body weight (IBW) for patients who weigh 100-120% of their IBW. All patients will receive an autologous graft with a minimum cell dose of 2.0 x 106 CD34+ cells/kg patient weight. Patients will receive \~5 ug/kg/day of Granulocyte-Colony Stimulating Factor (G-CSF) subcutaneously from Day 5 post-transplant until absolute neutrophil count (ANC) \> 500/mm3 for two days.

One Autologous Transplant

Upon recovery and at least Day 60 post-autograft, patients with an available 6/6 HLA matched sibling will receive an allograft after non-myeloablative conditioning. Day 0 patients will receive Total Body Irradiation (TBI) 2.0 Gy from a linear accelerator ≤ 20 cGy/min, followed by allogeneic peripheral blood stem cell (PBSC) infusion. Commence cyclosporine (CSA) on Day -3 at 5 mg/kg bid PO for a daily dose of 10 mg/kg/day through Day +84 based on actual body weight. Starting on Day 84, patients in partial or complete response with the absence of graph versus host disease (GVHD) will have CSA tapered so the patient will be off CSA by Day 180. Oral administration of Mycophenolate Mofetil will be at a daily dose of 30 mg/kg/day from the evening of Day 0 until Day 27 post-transplant.

Non-Myeloablative Allogeneic Transplant

Upon recovery from the first autograft, but at least 60 days (preferably between 60-120 days) after the first autograft, patients without an HLA-matched sibling donor will receive a second autograft, also conditioned with melphalan 200 mg/m2.

Second Autologous Transplant

Patients will be initiated on a starting dose of 50 mg/day. The dose will be increased weekly by 50 mg as tolerated to achieve a target dose of 200 mg/day. Patients will be treated for 12 months with thalidomide.

Patients will receive dexamethasone at a dose of 40 mg per day during Days 1-4 of each month for 12 months. The first dose of dexamethasone to be given the same day the patient starts thalidomide.

One year of observation post-transplants.

Observation

Mary Horowitz, MD

The study is designed as a Phase III, multi-center trial of tandem autologous transplants versus the strategy of autologous followed by Human Leukocyte Antigen (HLA)-matched sibling non-myeloablative allogeneic transplant. Study subjects will be biologically assigned to the appropriate arm depending on the availability of an HLA-matched sibling. There is a nested randomized phase III trial of observation versus maintenance therapy following the second autologous transplant for patients on the tandem autologous transplant arm.

Multiple myeloma (MM), characterized by malignant plasma cell proliferation, bone destruction, and immunodeficiency, is a disease with a median age at diagnosis of approximately 65 years. It is responsible for about 1 percent of all cancer-related deaths in Western Countries. Conventional treatments with chemotherapy and radiation therapy are non-curative but improve quality of life and duration of survival. Attempts to cure myeloma through high-dose therapy followed by autografting or allografting have largely failed due to a combination of relapsed disease or transplant related mortality (TRM). High-dose therapy with autologous transplantation is safe and has low TRM (less than 5%), but is associated with a continuing and nearly universal risk of disease progression and relapse. Even so, autologous transplantation is superior to continued conventional chemotherapy. Recent data indicate that tandem autologous transplants are superior to a single procedure. Even with this approach, patients remain at risk of relapse and additional approaches are needed.

DESIGN NARRATIVE:

The overall study design is that of biologic assignment, based on the availability of an HLA-matched sibling, to one of two treatment strategies for MM patients. Patients without an HLA-matched sibling will undergo tandem autologous transplants. Patients with an HLA-matched sibling will undergo an autologous transplant followed by a non-myeloablative allogeneic transplant. In addition, the tandem autologous transplant recipients will be randomized to either observation or one year of maintenance therapy to begin following the second autologous transplant. The large number of MM patients without an HLA-matched sibling enables us to evaluate the role of maintenance therapy following tandem autologous transplants.

Stem Cell Transplantation in Individuals With Multiple Myeloma (BMT CTN 0102)

A Trial of Tandem Autologous Stem Cell Transplants +/- Post Second Autologous Transplant Maintenance Therapy vs Single Autologous Stem Cell Transplant Followed by Matched Sibling Non-myeloablative Allogeneic Stem Cell Transplant for Patients With Multiple Myeloma (BMT CTN #0102)

Results will be published in a manuscript and supporting information submitted to NIH BioLINCC (including data dictionaries, case report forms, data submission documentation, documentation for outcomes dataset, etc where indicated).

Patients are considered a failure for this endpoint if they die or if they progress or relapse.

The event is death from any cause, patients alive at the time of last observation are considered censored.

Patients are considered experiencing an event when they progress. Deaths without progression are considered as a competing risk. Patients initiating non-protocol anti-myeloma therapy are considered to have progressed on this protocol.

TRM is defined as death occurring in a patient from causes other than relapse or progression.

Upon recovery from the first autograft, but at least 60 days (preferably between 60-120 days) after the first autograft, patients will receive a second transplant according to treatment assignments.

Incidence and severity of GVHD will be scored according to the BMT clinical trials network Manual of Procedures.

Incidence and severity of chronic GVHD will be scored according to the BMT clinical trials network Manual of Procedures.

Blood and Marrow Transplant Clinical Trials Network

National Cancer Institute (NCI)

National Marrow Donor Program

National Heart, Lung, and Blood Institute (NHLBI)

Serious adverse events are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected adverse events were required to be reported through the adverse event system per protocol.

Tandem autologous transplant plus thalidomide/dexamethasone or observation for standard risk patients

Auto-Auto Standard Risk

Autologous transplant plus non-myeloablative allogeneic transplant for standard risk patients

Auto-Allo Standard Risk

Tandem autologous transplant plus thalidomide/dexamethasone or observation for high risk patients

Auto-Auto High Risk

Autologous transplant plus non-myeloablative allogeneic transplant for high risk patients

Auto-Allo High Risk

Tandem autologous transplant plus thalidomide/dexamethasone (Thal-Dex) or observation (Obs) for standard risk patients

PFS and OS did not differ between the Thal-Dex and the Obs arms and were thus pooled for analysis.

Tandem autologous transplant plus thalidomide/dexamethasone (Thal-Dex) or observation (Obs) for high risk patients

PFS and OS did not differ between the Thal-Dex and the Obs arms and were thus pooled for analysis.

Total

Age, Continuous

Sex: Female, Male

African American

Caucasian

Other

Race/Ethnicity, Customized

100 - 90

< 90

Assesses patient self-perceived global quality of life and functioning (excellent, very good, good, fair, poor), where 100 equals perfect quality of life.

Karnofsky Performance score

β-2 Microglobulin

Stages I-II

Stage III

The Durie and Salmon classification uses three multiple myeloma stages. Stage I has all of the following: Hemoglobin greater than 10 g/dL, Serum calcium less than 12 mg/dL, Normal bone structure or solitary plasmacytoma on radiographs, and Low M component. Stage II does not fit either Stage I or Stage III. Stage III has one or more of the following: Hemoglobin less than 8.5 g/dL, Serum calcium greater than 12 mg/dL, Advanced lytic bone lesions, and/or Hyper M component.

Durie-Salmon

Interval from diagnosis to transplantation

Near CR

Very Good PR

Not Evaluable

Unknown

Disease status at time of first autologous transplantation represents the results from initial multiple myeloma therapy received prior to trial enrollment: Complete Response (CR), Partial Response (PR), Minimal Response (MR), Stable Disease (SD)

Disease status

Analysis is based on intention-to-treat data. Primary analysis of the clinical trial focused on patients meeting protocol criteria of standard risk multiple myeloma.

Adam Mendizabal

Patients that completed second transplant

Progression-Free Survival (PFS)

1 year

2 years

3 years

Overall Survival (OS) for Standard Risk

Overall Survival (OS) for High Risk

Cumulative Incidence of Progression/Relapse

Cumulative Incidence of Treatment Related Mortality (TRM)

Interval From First to Second Transplantation

Grades II-IV

Grades III-IV

GVHD was only assessed on the Auto-Allo arm for standard risk patients that completed second transplant

Incidences of Graft Versus Host Disease (GVHD)

Incidences of Chronic GVHD

Tandem autologous transplant plus thalidomide/dexamethasone (Thal-Dex) or observation (Obs) for standard risk patients PFS and OS did not differ between the Thal-Dex and the Obs arms and were thus pooled for analysis.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Arsenic Trioxide, Ascorbic Acid, Dexamethasone, and Thalidomide in Treating Patients With Multiple Myeloma	NCT00112879	Stage I Multipl... Stage II Multip... Stage III Multi... Refractory Plas...	arsenic trioxid... ascorbic acid dexamethasone thalidomide anti-cytokine t... antiangiogenesi... biological ther... chemotherapy drug resistance... growth factor a... non-specific im...	18 Years -	National Cancer Institute (NCI)
Stem Cell Transplantation in Individuals With Multiple Myeloma (BMT CTN 0102)	NCT00075829	Multiple Myelom...	One Autologous ... Non-Myeloablati... Second Autologo... Thalidomide Dexamethasone Observation	- 70 Years	National Heart, Lung, and Blood Institute (NHLBI)
Stem Cell Transplantation in Individuals With Multiple Myeloma (BMT CTN 0102)	NCT00075829	Multiple Myelom...	One Autologous ... Non-Myeloablati... Second Autologo... Thalidomide Dexamethasone Observation	- 70 Years	National Heart, Lung, and Blood Institute (NHLBI)
Stem Cell Transplantation in Individuals With Multiple Myeloma (BMT CTN 0102)	NCT00075829	Multiple Myelom...	One Autologous ... Non-Myeloablati... Second Autologo... Thalidomide Dexamethasone Observation	- 70 Years	National Heart, Lung, and Blood Institute (NHLBI)

Spots Global Cancer Trial Database for refractory plasma cell neoplasm