Study of Bendamustine, Velcade and Dexamethasone in the Treatment of Elderly Patients With Multiple Myeloma

The present trial is designed as a phase II study that aims at estimating the efficacy of the combination of bendamustine, bortezomib and dexamethasone in relapsed/refractory multiple myeloma (MM). The response rate, i.e. the rate of the patients achieving a Complete Response or Partial Response at cycle 4, divided by the total intent to treat patient number is chosen as primary efficacy endpoint.

The estimation of the efficacy rate is to be based on an explorative pilot study, since immediate embarking on a large-scale comparative efficacy trial would not be acceptable from the point of view of resources. Moreover, this would induce ethical objections, as it does not seem to be justifiable to expose a large number of patients to an experimental approach without sufficient exploratory indications of an improved risk-benefit ratio.

After relapse or after early progression on first-line treatment, the prognosis of multiple myeloma (MM) patients is unfavourable, and the search for new treatment regimens, including drugs with novel mechanisms of action is essential.

Bendamustine and bortezomib have shown high activity boch in first-line regimens and pre-treated patients. The novel mechanism of action of the proteasome inhibitor and the non-cross resistance of bendamustine to other alkylating agents established in the first-line treatment of multiple myeloma seem to recommend a combination of the two drugs for salvage therapy (second-line regimen). Finally, the promising response data in a series of relapsing MM patients treated with bendamustine, bortezomib and prednisone support this assumption, as well as the feasibility and tolerability of the combination.

In summary, there is some evidence for a favorable risk/benefit ratio for the combination of bendamustine, bortezomib and a corticoid drug, warranting the exploration in a larger, prospectively designed multicenter phase II study.

Eligibility Criteria:
Inclusion Criteria:

* Symptomatic multiple myeloma (MM) patient at the time of diagnosis (but not necessarily at the time of relapse), according to International Myeloma Working Group criteria.
* Patient having received conventional chemotherapy in 1st line treatment because of age 65 years or over, or younger than 65 years and ineligible to high-dose therapy plus stem cell transplantation.
* Measurable disease (≥10g/L monoclonal gammapathy and/or ≥ 200 mg/24h proteinuria or involved serum free light chain ≥ 100mg/L with abnormal FLC ratio \< 0.26 or \> 1.65)
* Patient in 1st relapse or refractory to 1st line therapy. Relapse is defined by M-component increase of ≥25% from baseline, in serum and/or urine (the absolute increase in serum must be ≥ 5 g/l - the absolute increase of BJ proteins in urine must be ≥200 mg/24 h). (It is recommended to treat only symptomatic or rapidly evolutive relapses)
* Life expectancy of at least 3 months
* ECOG performance status \<= 2 at study entry
* Laboratory test results within these ranges:
* Absolute neutrophil count \>= 1.5 x 109/L
* Platelet count \>= 100 x 109/L
* Serum creatinine \<= 250 umol/l
* AST (SGOT) and ALT (SGPT) \<= 3 x ULN
* Disease free of prior malignancies for \>= 5 years, with exception of curatively treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast
* Able to adhere to the study visit schedule and other protocol requirements
* Using effective contraceptive methods during and for 6 months after study treatment (for fertile men, women of childbearing potential).
* Provision of informed consent.
* A period of at least 15 days must be respected between the last treatment of myeloma and the beginning of the study.

Exclusion Criteria:

* Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.
* Any comorbidity which places the subject at unacceptable risk if he/she were to participate in the study.
* Patients treated with high-dose therapy plus stem cell transplantation in 1st line therapy
* Any prior use of bortezomib (Velcade) or bendamustine (Ribomustin)
* Concurrent use of other anti-cancer agents or treatments other than those stated in this treatment plan
* Use of any other experimental drug or therapy within 28 days prior to the start of study treatment.
* Known hypersensitivity to the study drugs
* Positive HIV serology, positive hepatitis C serology, active infection hepatitis A, active infection hepatitis B.
* Severe cardiovascular disorders within 12 months prior to the start of study treatment (e.g. myocardial infarct, ischemic episodes, arrhythmias)
* Previous major surgery less than 30 days before start of treatment
* Active infection,
* Pregnant or lactating women.