Administration Of An Oral PDE5 Inhibitor, Tadalafil In Conjunction With a Lenalidomide Containing Regimen In Patients With Multiple Myeloma
Authors: Ghosh Nilanjan , Rudraraju Lakshmi , Ye Xiaobu , Noonan Kimberly , Huff Carol Ann , Borrello Ivan M. 
Published: October 2019

Abstract
Increasing tumor burden has been associated with an immunosuppressive network posing a significant barrier to anti-tumor immunity. Amongst these pathways, myeloid derived suppressor cells (MDSCs) play a critical role in suppressing immune function through upregulation of iNOS and arginase-1 (Arg1). There is evidence of increased MDSCs in patients with multiple myeloma compared to healthy donors [1]. Additionally, it has been shown that MDSCs regulate the growth of myeloma by inhibiting T cells in the bone marrow [2]. We therefore hypothesized that inhibiting MDSCs could augment the anti-tumor activity of the immunomodulatory drug lenalidomide. We have shown previously that phosphodiesterase 5 inhibitors such as tadalafil effectively inhibit MDSC function through downregulation of iNOS and Arg-1 production [3]. To prospectively study the effect of MDSC inhibition in myeloma, we initiated a clinical trial in patients who were refractory to lenalidomide-based regimens, with the oral PDE5 inhibitor, tadalafil, added to their lenalidomide-containing regimen. Refractory to lenalidomide containing regimen was defined as disease progression within 60 days of lenalidomide/dexamethasone (Rd) or Biaxin/lenalidomide/dexamethasone (BiRd). Responses were monitored by International Myeloma Working Group (IMWG) criteria. 13 patients were enrolled between April 2012 and March 2013. Median age was 63, 46.1% female, median number of prior therapies was 4 (range 3-10), 10 patients (80%) had BiRd as their immediate prior therapy, 3 (20%) patients had Rd as the immediate prior therapy, 4 (30.8%) patients had high risk cytogenetics/FISH, 4 (30.8%) patients had ISS III disease and 5 (38.4%) patients had a stem cell transplant in the past. 2 patients were not evaluable, 1 did not meet the eligibility criteria and another patient with a history of gastrointestinal (GI) bleed came off protocol in less than a week because of a recurrent GI bleed. 1 (9%) patient had a minor response (MR) lasting 3 months, 4 (36.4%) patients achieved stable disease (SD), 6 (54.5%) patients developed progressive disease (PD). For patients who achieved SD, the median duration was 66 days (range 48-161 days). Median PFS was 48 days (95% CI 25-71 days). 2 (18.1%) patients needed dose reduction of tadalafil for grade 3 back pain, which was the only toxicity attributable to the drug. There were no deaths on study. At a median follow up of 1 year, the OS is 81.8%. The trial met early stopping rule due to lack of response. Biologic correlates were performed pre and post treatment and included measurement of MDSCs numbers by flow cytometry using CD14+, CD33+, HLADRlow, IL4Rα+ or CD15+, CD33+, HLADRlow, IL4Rα+. Interestingly, MDSCs were not detected in any of the patients at baseline in both blood and marrow and this correlated with the lack of clinical response. In mice, lenalidomide can reduce MDSC numbers [4]. All patients on this trial were heavily pre-treated with lenalidomide for a median duration of 783 days (range 55-1741 days) which could explain the low numbers of MDSCs at enrollment. Strategies aimed at inhibiting MDSC function would be best tested in patients who have elevated levels of MDSCs by flow cytometry.

References
1. Gorgun, G.T., et al., Tumor-promoting immune-suppressive myeloid-derived suppressor cells in the multiple myeloma microenvironment in humans. Blood, 2013. 121(15): p. 2975-87.
2. Ramachandran, I.R., et al., Myeloid-derived suppressor cells regulate growth of multiple myeloma by inhibiting T cells in bone marrow. J Immunol, 2013. 190(7): p. 3815-23.
3. Serafini, P., et al., Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med, 2006. 203(12): p. 2691-702.
4. Sakamaki, I., et al., Lenalidomide enhances the protective effect of a therapeutic vaccine and reverses immune suppression in mice bearing established lymphomas. Leukemia, 2013.

Disclosures:
Off Label Use: Tadalafil for supression of myeloid derived suppressor cells.