Bone Effect of Bortezomib in Patients With Relapsed/Refractory Multiple Myeloma
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Bortezomib (Velcade)
Intervention description: Bortezomib will be administered as a 3-5 second bolus IV injection at the dose of 0.7 mg/m2 on days 1, 4, 8, and 11 q. 21 days times three cycles.
Patients will undergo three 21-day cycles.
Intervention MeSH terms: Bortezomib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 6.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Cancer; Hematologic malignancy

Summary:

      The primary aim of this trial is to determine the effect of a short course (i.e., 3 cycles)
      of low-dose Bortezomib (Velcade) on bone remodeling and on disease progression. The dose of
      bortezomib used in this trial of 0.7 mg/m2 is the lowest dose which has shown efficacy in the
      3 largest monotherapy trials with bortezomib. 17% of patients in the APEX, 9% patients in
      CREST and 24% in SUMMIT trials were treated with 0.7 mg/m2 dosages. Bortezomib will be given
      on days 1, 8, 15, 22 over 42 days to reduce the incidence of possible drug related side
      effects.

      OBJECTIVES:

      Primary Objective

      The primary objective of this study is to:

        -  To evaluate the effect of Velcade at 0.7 mg/m2 dose on inducing osteoblast activation as
           measured by ALP and other bone markers in patients with relapsed/refractory myeloma.

      Secondary Objectives

      The secondary objectives of this study are to:

        -  To evaluate the association between osteoblastic activation and myeloma response to
           Velcade.

        -  To identify predictive factors for Velcade-associated osteoblastic activation.
    

Eligibility criteria:

        Inclusion Criteria:

          1. History of histologically documented MM with relapsed or progressive disease after at
             least one line of prior therapy.

          2. Patient has measurable disease in which to capture response, defined as one or more of
             the following:

               1. Serum M-protein level > 1.0 gm/dl (10.0 g/L) measured by serum protein
                  electrophoresis or immunoglobulin electrophoresis; or

               2. Urinary M-protein excretion > 200 mg/24 hrs; or

               3. Bone marrow plasmacytosis of > 30% by bone marrow aspirate and/or biopsy; or

               4. Serum Free Light Chains (By the Freelite test) > 2X ULN, in the absence of renal
                  failure

               5. Radiographic evidence of disease

          3. Performance status of < 2 as per ECOG scale, unless PS of 3-4 based solely on bone
             pain.

          4. Patients must have a platelet count > 100,000/L and an ANC of at least 1,000/μl.

          5. Patients must have adequate renal function defined as serum creatinine ≤2.5 mg/dL.

          6. Patients must have adequate hepatic function defined as serum transaminases and direct
             bilirubin < 3 x the upper limit of normal.

          7. Male or female adults of at least 18 years of age.

          8. Voluntary written informed consent before performance of any study-related procedure
             not part of normal medical care, with the understanding that consent may be withdrawn
             by the subject at any time without prejudice to future medical care.

          9. Female subject is either post-menopausal or surgically sterilized or willing to use an
             acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine
             device, diaphragm with spermicide, condom with spermicide, or abstinence) for the
             duration of the study.

         10. Growth factors are allowed during the study

         11. Male subject agrees to use an acceptable method for contraception for the duration of
             the study.

        Exclusion Criteria:

          1. Platelet count of <100x 10(9)/L within 14 days before enrollment.

          2. Absolute neutrophil count (ANC) <1.0 x 10(9)/L

          3. Serum creatinine ≥ 2.5 mg/dL within 14 days before enrollment.

          4. Patient has >Grade 2 peripheral neuropathy within 14 days before enrollment.

          5. Myocardial infarction within 6 months prior to enrollment or has New York Heart
             Association (NYHA) Class III or IV heart failure (see section 1.4), uncontrolled
             angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence
             of acute ischemia or active conduction system abnormalities. Prior to study entry, any
             ECG abnormality at Screening has to be documented by the investigator as not medically
             relevant.

          6. Patients with a history of treatment for clinically significant ventricular cardiac
             arrhythmias.

          7. Patient has hypersensitivity to bortezomib, boron or mannitol.

          8. Chemotherapy or radiotherapy received within the previous 4 weeks of study enrollment.

          9. Female subject is pregnant or breast-feeding. Confirmation that the subject is not
             pregnant must be established by a negative serum beta-human chorionic gonadotropin
             (beta-hCG) pregnancy test result obtained during screening. Pregnancy testing is not
             required for post-menopausal or surgically sterilized women.

         10. Patient has received other investigational drugs with 14 days before enrollment

         11. Serious medical or psychiatric illness likely to interfere with participation in this
             clinical study.

         12. Diagnosed or treated for another malignancy within 3 years of enrollment, with the
             exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
             the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.

         13. POEMS Syndrome

         14. Clinically significant hepatic dysfunction as noted by bilirubin or AST > 3 times the
             upper normal limit or clinically significant concurrent hepatitis.

         15. Uncontrolled, active infection

         16. Patients that have taken bisphosphonates within 30 days of screening will not be
             eligible for this trial.

         17. Must not have received VELCADE 90 days prior to enrolling in this trial.