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%.

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