Phase II Trial of Bevacizumab Combined with Low Dose Dexamethasone and Lenalidomide (BEV/REV/DEX) for Relapsed or Refractory Myeloma (MM).
Authors: Raschko Martha , Markovina Stephanie , Miyamoto Shigeki , Longo Walter , Williams Eliot , McFarland Thomas , Werndli Jae , Wagner Elisabeth , Juckett Mark , Callander Natalie 
Published: October 2019

The interaction between malignant plasma cells and non malignant bone marrow microenvironment has been recognized as both an important feature of MM propagation and a therapeutic target. One critical interaction appears to involve angiogenesis as evidenced by increased blood vessel density in areas of myeloma cell proliferation. The potent anti MM compound lenalidomide may work partly through down regulation of VEGF expression by bone marrow stromal cells. We hypothesized that the addition of the VEGF-A receptor inhibitor, bevacizumab, in combination with low dose weekly dexamethasone, would provide more complete blockade of VEGF activation and translate to increased activity in MM patients with relapsed or refractory disease.

ELIGIBILTY: relapsed or refractory MM patients (pts), failing >1 therapy, with no previous exposure to lenalidomide, measurable M protein in serum and/or urine, no current history of unstable cardiovascular disease or uncontrolled thrombosis, no therapy for ≥28 days, and no contraindication to aspirin.

METHODS: Each 4 week cycle consisted of lenalidomide 25 mg PO d1–21, bevacizumab 10 mg/kg IV over 2 hours every two weeks, and dexamethasone 40 mg PO q week. All pts received aspirin 325 mg PO daily. Prior to therapy pts underwent bone marrow biopsy and aspirate. MM and stromal cells were isolated for analysis of STAT 3 activation to assess the treatment’s effect on stromal/MM cell interactions. Clinical responses were assessed using IBMTR criteria.

RESULTS: 17 pts have been enrolled, ages 53––89, with median number of previous regimens 3 (range 1–6). Two pts were taken off study during the first cycle, one due to GI perforation occurring d 6 of therapy, and one pt due to rapidly progressive disease during first week of therapy. Ten pts have completed ≥ 4 cycles and can be evaluated for response. Seven of 10 pts achieved a PR after a median of two cycles and have maintained that response. One pt progressed after completing one cycle, one pt progressed after 5 cycles, and one pt had stable disease after 6 cycles. Expected grade 3 toxicities included DVT in 2 patients (both of whom were on aspirin but received erythropoiesis stimulating agents) and 2 pts developed shortness of breath attributed to bevacizumab, with resolved after discontinuation of the drug; one patient developed atrial fibrillation which spontaneously converted. No patient developed hypertension or proteinuria. Most required a dose reduction of lenalidomide due to fatigue. Analysis of STAT3 DNA-binding in MM cells alone or in co-culture with MM-BMSCs revealed variable low levels of constitutive STAT3 activity and enhanced activity in co-culture. No additional effect of bevacizumab + revlimid on constitutive STAT3 activity was observed.

CONCLUSIONS: the combination of lenalidomide, bevacizumab and low dose dexamethasone has activity in relapsed and refractory myeloma. The initial 70% response rate compares favorably with the 58% response rate reported by Stadtmauer et al (Blood 108:3552) in previously treated MM pts receiving lenalidomide and high dose dexamethasone. Toxicities of this regimen are predictable but manageable. The use of ESAs may contribute to the development of DVT and the protocol has been modified to preclude their use.