Phase I Study of an Immunomodulatory Thalidomide Analog, CC-4047, in Relapsed or Refractory Multiple Myeloma

Abstract

This study demonstrates the safety and efficacy of CC-4047. The MTD of CC-4047 orally was 2 mg/d. This is the first report demonstrating in vivo T-cell costimulation by this class of compound, supporting a potential role for CC-4047 as an immunostimulatory adjuvant treatment.

IMiDs mobilize acute myeloid leukemia blasts to peripheral blood through downregulation of CXCR4 but fail to potentiate AraC/Idarubicin activity in preclinical models of non del5q/5q- AML

“…5 Lenalidomide and pomalidomide possess pleiotropic anti-tumor properties including also tumor-controlling immune-modulating effects in other hematological BM malignances such as MDS and MM. 9-11 We therefore set out to assess the anti-leukemia effects of lenalidomide and pomalidomide in AML. Strikingly, as single agents, lenalidomide and pomalidomide display no cytotoxic effects (assayed at 48h and 72h after drug exposure) on neither AML cell lines (Figure 2A) nor diagnostic primary AMLs (n = 9) covering different cytogenetic/molecular AML subtypes other than del5q/5q- AMLs (Figure 2A, Table 1).…”

“…7-9 They are approved by the FDA and EMA for 5q- MDS and/or MM which are hematological malignances associated with intrinsic dysfunctional BM with remarkable clinical responses. 10,11 However, whether IMiDs may potentiate current standard treatment in AML remains an issue of debate. To bring IMiDs to the forefront of AML therapeutic arsenal, a better understanding of its mechanism of action in AML cells and in the interphase tumor-stroma is required.…”

“…This contrasts the anti-proliferative effects reported for IMiDs in other hematopoietic malignances, evidencing the immature nature of AML cells (progenitor-like cells) and the complex biology of AML. 9-11 However, IMiDs enhanced the immunomodulatory properties of BM-MSCs as demonstrated by the suppression activated T cells proliferation, inhibition of the production of pro-inflammatory cytokines including TNFα, IL1β and IL6 and increased production of the anti-inflammatory cytokine IL10, suggesting that IMiDs may represent safe candidate drugs interfering with the protective BM stroma for combination with current AML chemotherapy.…”

“…Lenalidomide is approved for both 5q- myelodysplastic syndrome (MDS) and multiple myeloma (MM) whereas pomalidomide is approved for MM, which are hematological malignances associated with intrinsic dysfunctional BM. 10,11 Some studies reported that lenalidomide has modest (pre)-clinical activity in lymphoma and AML with manageable toxicity. 9,12,13 Ongoing Phase I clinical trials assaying low- and high-dose lenalidomide for both newly diagnosed and relapsed/refractory AML also support that lenalidomide displays modest activity when given either alone or combined with cytarabine and anthracyclines.…”

A third-generation IMiD for MM

“…6,7 In two subsequent studies enrolling patients with rel/refr MM after 1 to 4 prior lines of treatment, including refractoriness to lenalidomide, salvage therapy with pomalidomide at 2 mg/day was given continuously in 28-day cycles combined with low-dose dexamethasone. 8,9 In one study, the overall rate of at least partial response (PR) was 63%, including 33% complete response or very good partial response (VGPR), and median progressionfree survival (PFS) was 11.6 months.…”