1. Clinical and pharmacodynamic analysis of pomalidomide dosing strategies in myeloma: impact of immune activation and cereblon targets
by Kartik Sehgal, Rituparna Das, Lin Zhang, Rakesh Verma, Yanhong Deng, Mehmet Kocoglu, Juan Vasquez, Srinivas Koduru, Yan Ren, Maria Wang, Suzana Couto, Mike Breider, Donna Hansel, Stuart Seropian, Dennis Cooper, Anjan Thakurta, Xiaopan Yao, Kavita M. Dhodapkar, and Madhav V. Dhodapkar
Blood
Volume 125(26):
June 25, 2015
©2015 by American Society of Hematology

2. Clinical response and survival following pomalidomide/dexamethasone in Len-refractory myeloma.
Clinical response and survival following pomalidomide/dexamethasone in Len-refractory myeloma. Patients were randomized to therapy with pomalidomide at 2 mg/day on a 28/28-day continuous schedule (n = 19; cohort 1), or 4 mg/day on a 21/28-day intermittent schedule (n = 20; cohort 2). All patients received Pom alone for cycle 1 and with weekly dexamethasone with cycle 2 and beyond. (A) Waterfall plot of maximal reduction in measurable disease. (B) Kaplan-Meier plot comparing event-free survival in the 2 cohorts. (C) Kaplan-Meier plot comparing overall survival in the 2 cohorts.
Kartik Sehgal et al. Blood 2015;125:
©2015 by American Society of Hematology

3. Mid-cycle changes in treatment-induced immune profile following Pom therapy.
Mid-cycle changes in treatment-induced immune profile following Pom therapy. (A-C) Phenotypic and numeric changes in immune cells. (A) Changes in T, NK, B, and monocytes at baseline and 1 week after therapy. (B) Changes in the expression of NKG2D, CD16, and CD56 on NK cells at baseline and after 1 week of therapy. (C) Fold change (compared with baseline) in T cells (i) and NK cells (ii) at 1 week after initiation of therapy in patients with a 28/28-day schedule (cohort 1) or a 21/28-day schedule (cohort 2) at 7 days following initiation of therapy in cycle 1 (Pom alone) or with dexamethasone (cycle 2). (D-G) Changes in functional properties of T and NK cells. (D) Changes in cytokine profile of CD4+ or CD8+ T cells. Intracellular cytokine production by CD4/CD8+ T cells was analyzed by flow cytometry at baseline vs 7 days after initiation of therapy. (E) Changes in cytokine profile of NK cells. Intracellular cytokine production by NK cells was analyzed by flow cytometry at baseline vs 7 days after initiation of therapy. (F) Changes in cytolysis proteins in T and NK cells. Expression of granzymeB and perforin by NK and CD8+ T cells was analyzed by flow cytometry at baseline vs 7 days after initiation of therapy. (G) Changes in polyfunctional T cells. Intracellular cytokine production by CD4/CD8+ T cells was analyzed by flow cytometry at baseline vs 7 days after initiation of therapy. (H) Changes in CD25hi FOXP3hi Tregs. Changes in circulating CD25hiFOXP3hi Tregs following Pom therapy were analyzed by flow cytometry. (Left) Representative FACS plot. (Center) Summary of changes before and after therapy. (Right) Comparison of changes following cycles 1 and 2. (I) Changes in coinhibitory receptors. Changes in the expression of BTLA, PD1, and Tim3 on CD4/CD8+ T or NK cells at baseline and after 1 week of therapy.
Kartik Sehgal et al. Blood 2015;125:
©2015 by American Society of Hematology

4. Correlation of immunologic effects following Pom and clinical response to therapy.
Correlation of immunologic effects following Pom and clinical response to therapy. (A) Changes in T and NK cells vs objective clinical response (≥PR). (B) Changes in cytokine production by T cells vs objective clinical response (≥PR). (C) Changes in cytokine production by polyfunctional CD8+ T cells vs objective clinical response (≥PR).
Kartik Sehgal et al. Blood 2015;125:
©2015 by American Society of Hematology

5. Expression of cereblon, ikaros, and aiolos protein in tumor cells and its correlation with clinical response.
Expression of cereblon, ikaros, and aiolos protein in tumor cells and its correlation with clinical response. Expression of these proteins in bone marrow biopsies at baseline at study entry was quantified by immunohistochemistry as an H-score. (A) Correlation between immunohistochemical H-scores for ikaros, cereblon, and aiolos protein expression in tumor cells. (B) Expression of ikaros, cereblon, and aiolos protein vs objective clinical response (≥PR).
Kartik Sehgal et al. Blood 2015;125:
©2015 by American Society of Hematology

6. Changes in ikaros levels in immune cells following Pom therapy.
Changes in ikaros levels in immune cells following Pom therapy. Pre- and posttherapy samples were thawed and analyzed together for the expression of intranuclear ikaros levels in T and NK cells by flow cytometry. Data are representative of 2 patients each in cohorts 1 and 2.
Kartik Sehgal et al. Blood 2015;125:
©2015 by American Society of Hematology