Bendamustine, Prednisone and Velcade® for First-line Treatment of Patients With Symptomatic Multiple Myeloma

Bendamustine, Prednisone and Velcade® for First-line Treatment of Patients With Symptomatic Multiple Myeloma Not Eligible for High-dose Chemotherapy Followed by Autologous Stem Cell Transplantation (BPV).

The purpose of this study is to improve efficacy of treatment for patients with newly diagnosed multiple myeloma who are not eligible for high-dose chemotherapy followed by autologous stem cell transplantation by Bendamustin, Bortezomib (Velcade), and Prednisone.

1. Objectives Primary

   -Therapeutic efficacy of BPV regimen for multiple myeloma as evidenced by the overall response defined as partial response (PR) or better

   Secondary

   • to assess overall survival (OS) and progression-free survival (PFS)
   • to determine response duration
   • to investigate improvements of renal function
   • to evaluate safety and toxicity (with respect to adverse events of CTCAE grade ≧3 and SAEs)
   • to analyze the efficacy for genetically defined subgroups of myeloma patients based on iFISH and gene-expression profiling

2. Investigational Medicinal Products Bortezomib Bendamustine both in combination with Prednisone

Inclusion Criteria:

1. Newly diagnosed multiple myeloma requiring systemic treatment (according to CRAB criteria as specified in the appendix I) with following characteristics: Subject is not a candidate for high-dose chemotherapy and stem cell transplantation due to age, presence of comorbidities likely to have a negative impact on tolerability of HDT-SCT, or subject preference

2. Measurable disease, defined as any quantifiable monoclonal protein value, defined by at least one of the following three measurements (Durie et al., 2006):

   • Serum M-protein ≥ 10g/l
   • Urine light-chain (M-protein) of ≥ 200 mg/24 hours
   • Serum FLC assay: involved FLC level ≥ 10 mg/dl provided sFLC ratio is abnormal

3. Age>18 years

4. WHO performance status 0-3 (WHO=3 is allowed only when related to MM and not to co-morbid conditions) (see appendix III)

5. For women of childbearing potential: negative pregnancy test at inclusion

6. All patients must be willing and capable to use adequate contraception during the complete therapy.

7. All patients must agree to abstain from donating blood while on study

8. Ability to understand character and individual consequences of the clinical trial

9. Written informed consent (must be available before enrolment in the trial)

Exclusion Criteria:

• Subjects presenting any of the following criteria will not be included in the trial

  1. Patient has known hypersensitivity to bortezomib, bendamustine and prednisone or to any of the constituent compounds (incl. boron and mannitol).
  2. Systemic AL amyloidosis (except for patients with AL amyloidosis of the skin or the bone marrow)
  3. Chemotherapy or radiotherapy during the past 5 years except patients with local radiotherapy in case of local myeloma progression. (Note: patients may have received a cumulative dose of up to 160 mg of dexamethasone or equivalent as emergency therapy within 3 weeks prior to study entry.)
  4. Plasma cell leukemia which requires the presence of 20% of plasma cell in peripheral blood leukocytes and at least 2 plasma cells/nl.
  5. Severe cardiac dysfunction (NYHA classification III-IV, see appendix III)
  6. Significant hepatic dysfunction (serum bilirubin ≥ 2 mg/dl or ASAT and/or ALAT ≥ 2.5 times normal level), unless related to myeloma
  7. Patients known to be HIV-positive
  8. Patients with active, uncontrolled infections
  9. Patients with peripheral neuropathy or neuropathic pain of CTC grade 2 or higher (as defined by the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0, see appendix V)
  10. Second malignancy during the past 5 years except:

• Adequately treated basal cell or squamous cell skin cancer, or

• Carcinoma in situ of the cervix, or

• Prostate cancer < Gleason score 6 with undetectable prostate-specific antigen (PSA) over 12 months, or

• Ductal breast carcinoma in situ with full surgical resection (i.e., negative margins), or

• Similar malignant condition as a.- d. with an expected5-year disease free survival larger than 95% 11. Patients with acute diffuse infiltrative pulmonary and pericardial disease 12. Autoimmune hemolytic anemia with positive Coombs test or immune thrombocytopenia 13. Platelet count < 50 x 109/l (transfusion support within 14 days before the test is not allowed), unless related to myeloma 14. Hemoglobin < 7.5g/dl, unless related to myeloma 15. Absolute neutrophil count (ANC) < 0.75 x 109/l (the use of colony stimulating factors within 14 days before the test is not allowed), unless related to myeloma 16. Pregnancy and lactation 17. Participation in other clinical trials within one month prior to enrolment except for supportive care studies and vaccination studies. (Note: this does not include long-term follow-up periods without active drug treatment of previous studies during the last 6 months).

No subject will be allowed to enrol in this trial more than once.