Contributions
Abstract: PB2239
Type: Publication Only
Background
Autophagy inhibitors are being tested in clinical trials for the treatment of malignancy. In multiple myeloma the autophagy inhibitor plaquenil has been tested with bortezomib in vitro with mixed results as well as a clinical trial with disappointing outcomes. Recently the antibiotic clarithromycin has been shown to be an autophagy inhibitor and has also been shown to synergistically increase the response to thalidomide in vitro. There have been previous single cohort studies using thalidomide/ clarithromycin combinations in multiple myeloma. At the time of that study, it was not known that clarithromycin was an autophagy inhibitor. Clarithromycin when trialled with Bortezomib in a clinical trial lead to unacceptable gastrointestinal toxicity without clear benefit. Does the addition of an autophagy inhibitor Hydroxychloroquine when added to an IMID such as thalidomide lead to an improvement over thalidomide alone as suggested by the in vitro studies. A longnitudinal crossover study was undertaken on the effect of adding hydroxychloroquine to patients who had previously been given thalidomide therapy previously. It would be expected that patients would have an inferior response and duration of response the second time they were given thalidomide.
Aims
To determine whether the autophagy inhibitor Hydroxychloroquine when added to thalidomide based therapy improves the response to thalidomide based treatment.
Methods
Three patients received the CTD regimen for a period of 6 months. Thalidomide 100mg a day, Cyclophosphamide 100mg a day orally and Dexamethasone 20mg orally once weekly. One had a partial response 5g/L lasting 16 months from 2014. The second patient had a VGPR 2g/L lasting 17 months 2014. The third patient had no response to either thalidomide or lenalidamide in 2008 at 14g/L. She subsequently underwent bortezomib based therapy and stem cell transplant. All three relapsed with bone pain and increasing paraprotein level > 20% from plateau level. The patients again received CTD at the same dose and duration. Hydroxychloroquine (plaquenil) was added at 200mg twice a day. This dose is a dose used to treat common rheumatological diseases and is safe even in combination with other agents. The absolute response in paraprotein level was documented and the duration of response has been measured every three months.
Results
All patients symptoms of bone pain have resolved. Two patients have achieved a complete remission of 0 g/L paraprotein measured at the end of 6 months therapy with CTD and Hydroxychloroquine. The third patient achieved a Partial remission at 3g/l a 70% reduction. Two patients response duration has already been maintained for a longer period than in their first remission with CTD and the third continues. There has been no grade two or higher toxicity.
Conclusion
Hydroxychlroquine when used with thalidomide based therapy is a cheap non toxic addition to myeloma therapy that appears to deepen the response in all patients tested. It has also increased the response duration in 2 treated patient with the others not progressing. Although the clinical trials have focused on adding autophagy inhibitors to poteasome inhibitors, it appears that they may be more useful when used with IMIDS.
Session topic: 14. Myeloma and other monoclonal gammopathies - Clinical
Keyword(s): Drug sensitivity, Multiple Myeloma, Thalidomide
Abstract: PB2239
Type: Publication Only
Background
Autophagy inhibitors are being tested in clinical trials for the treatment of malignancy. In multiple myeloma the autophagy inhibitor plaquenil has been tested with bortezomib in vitro with mixed results as well as a clinical trial with disappointing outcomes. Recently the antibiotic clarithromycin has been shown to be an autophagy inhibitor and has also been shown to synergistically increase the response to thalidomide in vitro. There have been previous single cohort studies using thalidomide/ clarithromycin combinations in multiple myeloma. At the time of that study, it was not known that clarithromycin was an autophagy inhibitor. Clarithromycin when trialled with Bortezomib in a clinical trial lead to unacceptable gastrointestinal toxicity without clear benefit. Does the addition of an autophagy inhibitor Hydroxychloroquine when added to an IMID such as thalidomide lead to an improvement over thalidomide alone as suggested by the in vitro studies. A longnitudinal crossover study was undertaken on the effect of adding hydroxychloroquine to patients who had previously been given thalidomide therapy previously. It would be expected that patients would have an inferior response and duration of response the second time they were given thalidomide.
Aims
To determine whether the autophagy inhibitor Hydroxychloroquine when added to thalidomide based therapy improves the response to thalidomide based treatment.
Methods
Three patients received the CTD regimen for a period of 6 months. Thalidomide 100mg a day, Cyclophosphamide 100mg a day orally and Dexamethasone 20mg orally once weekly. One had a partial response 5g/L lasting 16 months from 2014. The second patient had a VGPR 2g/L lasting 17 months 2014. The third patient had no response to either thalidomide or lenalidamide in 2008 at 14g/L. She subsequently underwent bortezomib based therapy and stem cell transplant. All three relapsed with bone pain and increasing paraprotein level > 20% from plateau level. The patients again received CTD at the same dose and duration. Hydroxychloroquine (plaquenil) was added at 200mg twice a day. This dose is a dose used to treat common rheumatological diseases and is safe even in combination with other agents. The absolute response in paraprotein level was documented and the duration of response has been measured every three months.
Results
All patients symptoms of bone pain have resolved. Two patients have achieved a complete remission of 0 g/L paraprotein measured at the end of 6 months therapy with CTD and Hydroxychloroquine. The third patient achieved a Partial remission at 3g/l a 70% reduction. Two patients response duration has already been maintained for a longer period than in their first remission with CTD and the third continues. There has been no grade two or higher toxicity.
Conclusion
Hydroxychlroquine when used with thalidomide based therapy is a cheap non toxic addition to myeloma therapy that appears to deepen the response in all patients tested. It has also increased the response duration in 2 treated patient with the others not progressing. Although the clinical trials have focused on adding autophagy inhibitors to poteasome inhibitors, it appears that they may be more useful when used with IMIDS.
Session topic: 14. Myeloma and other monoclonal gammopathies - Clinical
Keyword(s): Drug sensitivity, Multiple Myeloma, Thalidomide