Fase II Study With BRB for Non-Hodgkin Lymphoplasmacytic Lymphoma/Waldenstrom Macroglobulinemia's

This is a prospective, multicenter phase II trial designed to determine efficacy and safety of Bortezomib plus Rituximab plus Bendamustine in patients with relapsed/refractory Waldenstrom's Macroglobulinemia.

The progression free survival (PFS) expected for lymphoplasmacytic/lymphoplasmocytoid lymphoma/Waldenstrom macroglobulinemia with the same characteristics indicated into the study and treated with standard Rituximab plus chemotherapy may be estimated to be 50% at 18 months.

The Investigators would consider a positive result to increase 18 months-PFS rate from 50 to 65%.

Eligibility Criteria:
Inclusion Criteria:

* Histological proven diagnosis of Lymphoplasmacytic/cytoid lymphoma/Waldenstrom macroglobulinemia according to REAL/WHO Classification
* Relapsed/refractory disease after receiving one line chemotherapy (rituximab). If patients received bortezomib or bendamustine and have obtained a partial response lasting at least two years.
* Age \>= 18
* Presence of at least one of the following criteria for the definition of active disease: Systemic symptoms or Hemoglobin less than 10 g/dL (due to lymphoma) or Platelets less than 100 x 109/L (due to lymphoma) or symptomatic splenomegaly or Bulky disease (\>7 cm) or Hyperviscosity syndrome, peripheral neuropathy up to grade 1 (Waldenstrom's disease-related), hemolytic anemia, and immune complex vasculitis
* Life expectancy \>6 months
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* left ventricular ejection fraction (LVEF) ≥45% or FS ≥37%
* Creatinine up to 1.5 x upper limit of normal
* Conjugated bilirubin up to 2 x upper limit of normal
* Alkaline phosphatase and transaminases up to 2 x upper limit of normal
* Written informed content

Exclusion Criteria:

* Patients who received bortezomib or bendamustine first-line therapy, that or haven't obtained at least partial response nor partial response lasting at least two years.
* Patients not agreeing to take adequate contraceptive precautions during and for at least 6 months after cessation of therapy
* History of other malignancies within 3 years prior to study entry except for: adequately treated carcinoma in situ of the cervix; basal or squamous cell skin cancer; low grade, early stage, localized prostate cancer treated surgically with curative intent; good prognosis ductal carcinoma in situ (DCIS) of the breast treated with lumpectomy alone with curative intent
* Medical condition requiring long term use (\>1 months) of systemic corticosteroids
* Active bacterial, viral, or fungal infection requiring systemic therapy
* Peripheral neuropathy of any grade ≥ 2 \[see Appendix Section A\]
* Concurrent medical condition which might exclude administration of therapy
* Cardiac insufficiency (NYHA grade III/IV)
* Myocardial infarction within 6 months of entry on study
* Severe chronic obstructive pulmonary disease with hypoxemia
* Severe diabetes mellitus difficult to control with adequate insulin therapy
* Hypertension that is difficult to control
* Impaired renal function with creatinine clearance \<30 ml/min
* HIV positivity HBV positivity with the exception of patients HbsAg and HBV-DNA negative and Ab anti-HB core positive (these patients need to receive prophylaxis with Lamivudine)
* HCV positivity with the exception of patients with HCV RNA negative
* Participation at the same time in another study in with investigational drugs are used
* Known hypersensitivity or anaphylactic reactions to murine antibodies or proteins
* Any other co-existing medical or psychological condition that would preclude participation in the study or compromise ability to give informed consent.
* Women in pregnancy or breastfeeding