The Anti-Proliferative Effect of Lenalidomide On MM Cells in Vitro Is Ameliorated by Prior Exposure to Pomalidomide, An Agent with Activity against Lenalidomide Resistant MM Cells.

Despite recent advances in the treatment of Multiple Myeloma (MM) the disease remains incurable and initial response to therapy is followed inexorably by relapse, chemoresistance and death. Therefore, relapsed and refractory disease remains an area of high unmet need with an urgent need for new therapies that are able to exert significant effects on the tumor. Lenalidomide (Len), an oral anti-proliferative and immunomodulatory drug, has been approved in combination with dexamethasone (Dex) for previously treated MM. Early clinical results also suggest that pomalidomide (Pom) is effective in the treatment of relapsed and refractory MM, including patients who have previously been treated with Len. The achievable plasma levels of each agent and pharmacological activity in vitro suggest very little difference in terms of immune enhancing properties. In contrast, Pom is a more potent anti-proliferative agent. However, it is unknown how MM cell sensitivity to Pom might be affected by resistance to Len or how sensitivity to Len might be affected by prior treatment with Pom. The use of a cellular model mimicking the relapse/resistance issue found in the clinic can provide valuable information directly translatable to the treatment of patients.

In this study we have generated MM cell resistance by long term exposure to either Len or Pom at levels attainable in patient plasma. H929 and KMS-12-BM MM cell lines were exposed to Len or Pom at clinically achievable concentrations (1 μM Len or 0.1 μM Pom) for a continuous period of 5 months. Cell growth was measured by ATP assay. Resistance factors were calculated by dividing the compound growth IC50 in the long term treated cells by the growth IC50 in the parental cells.

The continued culture of H929 and KMS-12-BM cells with Len resulted in Len resistance factors of >2270 and >47600, and Pom resistance factors of 725 and 280, respectively. Therefore, in the Len-resistant cells, cross-resistance to Pom was lower than resistance to Len. Conversely, the continued culture of H929 and KMS-12-BM cells with Pom resulted in Len resistance factors of >2270 and >47600, and Pom resistance factors of only 22 and 130, respectively. There was complete cross-resistance to Len in the Pom-resistant cells. Furthermore, the addition of Dex was able to improve the sensitivity of the resistant cells to Pom to levels that are attainable in the plasma of patients and far more than it improved sensitivity to Len. Thus, while Pom (and Pom/Dex) retained efficacy in Len-resistant MM cells, MM cells previously exposed to Pom became refractory to Len (and Len/Dex).

Recent clinical data suggests that Pom/Dex is active in relapsed/refractory MM patients who have previously been treated with Len/Dex. Our results provide mechanistic support for the importance of the anti-proliferative activity of Pom (and Pom/Dex) in this setting. However, our results also suggest that Len (and Len/Dex) may be less effective in patients who have previously been treated with Pom, especially in the context of relapsed/refractory disease where immune function is likely to get progressively weaker with successive lines of therapy and thereby less amenable to immune enhancing agents.

Adams:Celgene: Employment. Off Label Use: Pomalidomide is an anti-proliferative and immunomodulatory agent that is in clinical development for relapsed/refractory MM. Schafer:Celgene: Employment. Bartlett:Celgene: Employment.