The Addition of Bevacizumab (B) to Lenalidomide and Low Dose Dexamethasone Does Not Significantly Increase Response in Relapsed or Refractory Multiple Myeloma (NCI#7317).
Authors: Callander Natalie Scott , Markovina Stephanie , Juckett Mark B. , Wagner Elizabeth , Kolesar Jill , Longo Walter , Williams Eliot C. , Kim Kyungmann , Werndli Jae , Miyamoto Shigeki 
Published: October 2019

Abstract
Abstract 3885
Poster Board III-821
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 pathway appears to involve neoangiogenesis 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 boost the response rate in MM patients with relapsed or refractory disease over lenalidomide and dexamethasone alone.

ELIGIBILTY
Relapsed or refractory MM patients (pts), failing >1 prior therapy, and 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
Pts received 4 week cycles consisted of lenalidomide 25 mg PO d1–21, bevacizumab 10 mg/kg IV over 2 hours every 2 weeks, and dexamethasone (D) 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 treatment effect on stromal/MM cell interactions. Plasma VEGF, VEGFR-1 and MIP-1α levels were measured at baseline and after 2 cycles. Clinical responses were assessed using IBMTR criteria every 2 cycles. Pts continued on treatment until progression or toxicity. This study was designed as a Simon minimax two-stage design with 19 pts, followed by 14 additional pts with 10 or more responders out of the initial 19 to detect an objective response rate of 70% with power 0.9 from 45% at a significance level of 0.05.

RESULTS
As of this reporting, 31 pts have been enrolled, ages 41–89, with median number of previous regimens 3 (range 1–7), previous transplant 27%. Three pts are considered unevaluable as they were taken off study before 2 cycles, two due to GI perforation and one pt due to rapidly progressive disease during first week of therapy. One pt is too early for evaluation. Twenty-seven pts have completed >4 cycles and have been evaluated for response. Responses are as follows: Complete response-15% (n=4), Partial response 56% (n=15), stable disease 19% (n=5), and progressive disease 11% (n=3). Overall response rate of 70% (a 95% confidence interval 50%–86%) is not significantly different from that reported by Weber et al (NEJM 357:2133) of 61% (a 95% CI 53%–68%) in patients receiving lenalidomide and high dose D. However, overall grade 3/4 toxicities were significantly less than those reported by Weber. Grade 3/4 toxicities included DVT in 3 patients (all were on aspirin but received erythropoiesis stimulating agents), and 2 pts developed shortness of breath attributed to B, which resolved after discontinuation of the drug; 3 pts developed atrial fibrillation. 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 levels of constitutive STAT3 activity and enhanced activity in co-culture. No additional effect of bevacizumab + lenalidomide on constitutive STAT3 activity was observed. Patients with no constitutive STAT3 activity were those achieving CR. CR was also associated with low plasma MIP-1α and VEGF levels.

CONCLUSIONS
The combination of B added to lenalidomide and low dose D has activity in relapsed and refractory myeloma. The initial 70% response rate is not statistically superior to the 60% response rate reported by Weber et al in previously treated MM pts receiving lenalidomide and high dose D. Toxicities of this regimen are predictable from the expected side effect profile of each drug but manageable. The use of ESAs may contribute to the development of DVT, and the protocol was modified to preclude their use. Low levels of constitutive STAT-3 activation and plasma MIP-1α predict for response in this trial.

Acknowledgments
Supported by the U Wisc Carbone Cancer Center (P30 CA14520), Wisconsin Oncology Network, and NCI Translational Research Initiative 25×5097. Genentech Lab and Celgene Corp provided B and lenalidomide for correlative studies.

Disclosures:
Callander: Millenium: Research Funding. Off Label Use: bevacizumab for multiple myeloma.