Zevalin for Patients With Incomplete Response to Chemo Prior to Autologous Stem Cell Transplant for Multiple Myeloma

Study Overview
=================
Brief Summary
-----------------
The study involves the use of a targeted form of radiation, in addition to standard high dose chemotherapy and stem cell transplant for multiple myeloma. The use of targeted radiation is designed to kill more multiple myeloma cells while avoiding the side effects of standard radiation. This type of targeted radiation (also known as radioimmunotherapy) has been approved by the Food and Drug Administration (FDA) for the treatment of a related disease, lymphoma under the trade name, Zevalin©. Zevalin© has been added to high dose chemotherapy and stem cell transplants for patients with lymphoma and is now being studied in this clinical trial for patients with multiple myeloma. This trial is only available at Tufts Medical Center. The proposed clinical trial will test whether CD20-targeted radio-immunotherapy can be safe and effective when integrated into a standard regimen of myeloablative chemotherapy and autologous stem cell rescue in patients with measurable disease prior to high dose chemotherapy and autologous stem cell transplant for multiple myeloma.

Detailed Description
-----------------
Patients with multiple myeloma scheduled for standard of care high dose melphalan and autologous stem cell transplant who have an incomplete response to induction treatment (i.e. with measurable disease) following peripheral blood stem cell collection are candidates for participation on this trial. 90Y Zevalin targets CD20 expressed on the surface of mature B-cells and is FDA approved for relapsed/refractory low grade lymphoma. This is a single arm, phase II safety and efficacy study of 90-Y Zevalin in multiple myeloma. Subjects will receive cold antibody (Rituximab 100mg/m2) followed by 5 mCi test dose of 111-In Zevalin on transplant day -21. Gamma camera images are obtained 48 to 72 hours after 111-In Zevalin to document appropriate / expected distribution of radiotracer. On transplant day -14, subjects will receive another cold antibody dose followed by 90Y Zevalin 0.4 mg/kg (max 32 mCi) as single dose. Subjects are admitted for transplant on day -3 and proceed with institution standard high dose melphalan (200mg/m2) on day -2. Subjects are followed for safety for 6 weeks after transplant.

Official Title
-----------------
A Phase II, Safety and Efficacy Study of Fixed Dose Radioimmunotherapy (Zevalin, Yttrium-90 Ibritumomab Tiuxetan) for Patients With Incomplete Response to Chemotherapy Prior to Autologous Stem Cell Transplant for Multiple Myeloma

Conditions
-----------------
Multiple Myeloma

Intervention / Treatment
-----------------
* Drug: indium-111-ibritumomab tiuxetan
* Drug: 90Y Zevalin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Meet established criteria for the diagnosis of multiple myeloma Durie-Salmon stage II or III disease Measurable disease in the serum and/or urine Scheduled to receive high dose chemotherapy and autologous stem cell transplant for multiple myeloma Individuals who have previously undergone autologous stem cell transplant are eligible for this study provided more than 6 months have elapsed from the prior transplant. Minimum stem cell dose of 4x106 CD34+ MNC / kg stored for autologous stem cell rescue. Adequate hematologic reserve as evidenced by ANC ≥ 1500/mm3 and platelets ≥ 100,000/mm3. Serum direct bilirubin ≤ 2.0 mg/dl and transaminases ≤ 3x institution upper limit of normal. Serum creatinine ≤ 2 mg/dl with creatinine clearance ≥ 60 ml/min (either calculated or measured). Exclusion Criteria: Stage I or smoldering myeloma, isolated plasmacytoma, or benign monoclonal gammopathy Non-secretory multiple myeloma Pregnant or lactating women Males and females who do not agree to practice approved methods of birth control for the duration of the study Presence of active infection Receipt of previous radiation therapy to critical organs exceeding any of the following limits: kidney 500 cGy, liver 1000 cGy, lungs 500 cGy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Zevalin<br>1.5mg of 111In Zevalin (containing 5 mCi of 111In) will be used for radioimaging on study day +1. 90Y Zevalin will be administered seven to nine days after 111In Zevalin administration. The dose of 90Y Zevalin will be 0.4 mCi/kg, capped at a maximum dose of 32 mCi. | Drug: indium-111-ibritumomab tiuxetan<br>* 1.5mg of 111In Zevalin (containing 5 mCi of 111In) will be used for radioimaging. 111In Zevalin will be administered by a 10 minute slow IV push injection immediately following completion of the rituximab infusion. 111In Zevalin may be injected by stopping the flow from the IV bag and injecting the radiolabeled antibody directly into the IV line. A 0.22 micron filter must be on line between the drug infusion port and the patient. The line must be flushed with at least 10cc of normal saline after 111In Zevalin has been injected.<br>* Other names: 111 In Zevalin;Drug: 90Y Zevalin<br>* Each patient will receive a single therapeutic dose of 90Y Zevalin at a dose of 0.4 mCi/kg, capped at a maximum dose of 32 mCi. 90Y Zevalin will be administered intravenously as a slow IV push over 10 minutes. 90Y Zevalin may be directly infused by stopping the flow from the IV bag and injecting the radiolabeled antibody directly into the IV line. A 0.22 micron filter must be on line between the syringe and the infusion port. The line must be flushed with at least 10cc normal saline after 90Y Zevalin has been infused.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Efficacy | Efficacy: objective response rate (CR + PR) at 12 and 104 days following radioimmunotherapy. Safety: the rate of occurrence of defined toxic events including non-engraftment and unacceptable biodistribution of 90Y Zevalin occurring by day +42 following transplant. Response determined according to Blade' Criteria (Bladé J, Br J Haematol.1998 Sep;102(5):1115-23) for multiple myeloma; Response based on reduction of monoclonal protein (M-protein) from initial presentation. | Through day +104 following immunotherapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Engraftment in Patients Who Proceed to Myeloablative Chemotherapy After Receiving 90Y Zevalin® (Ibritumomab Tiuxetan). | Number of days from stem cell infusion (day +0) to day of neutrophil engraftment (first of three consecutive days with absolute neutrophil count > 500) | Transplant through day 42 | 
| Degree of CD20 Expression on Plasma Cells and/or Targeting of Post-germinal Center B Cells Correlation With Toxicity, Response and Biodistribution | CD20 immunohistochemical staining of plasma cells on baseline bone marrow biopsy specimen, graded on qualitative scale (0 to +++) | 2 weeks prior - 2 weeks post transplant | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Multiple Myeloma, Zevalin