Blood Journal – Advances in TT3 Treatment for Myeloma
Much of the recent progress in the treatment of multiple myeloma has been attributed to the introduction of several novel agents which, when combined with standard cytotoxic agents and each other, have imparted a high frequency of clinical responses. Read more.
Toward personalized medicine: new discoveries at the Myeloma Institute for Research and Therapy improve prediction of the outcome of individual patients treated with Velcade-containing Total Therapy
70 gene score distinguishes low and high risk myeloma.
We have previously reported that the expression levels of 70 genes in myeloma tumor cells, purified from a bone marrow sample and identified by gene expression profiling, allow for the calculation of a 70 gene risk score which divides myeloma patients into two separate groups. Eighty- five percent of patients have a low risk 70 gene score and have an excellent long term outcome with Velcade-containing Total Therapy. Indeed, we predict that perhaps as many as 55-60% of these patients may prove to be cured from their myeloma. The outcome of the 15% percent of patients with high risk myeloma requires further improvement. Therefore, patients with low and high risk myeloma are treated differently at present: low risk patients receive a treatment regimen called Total Therapy 4, while high risk patients are treated according to Total Therapy 5. The Myeloma Institute for Research and Therapy is the first institution in the world to treat myeloma patients differently according to their gene expression profile defined disease risk.
80 gene score explains why some patients with low or high risk myeloma do not have the predicted out come
. We have found that a minority of patients with a low risk gene expression profile experience an unanticipated relapse, while conversely some patients with a high risk gene expression profile fare unexpectedly well. A new study http://www.ncbi.nlm.nih.gov/pubmed/21628408
, led by Dr. John Shaughnessy and published in Blood, the journal of the American Society of Hematology, explains these observations, further refines the prediction of the prognosis of individual patients, and provides important clues as to why some patients are sensitive or refractory to Velcade.* The observations of Dr. Shaughnessy and his team are an important step forward in personalizing treatment for multiple myeloma.
Patients enrolled in Total Therapy 3 were given a test dose of the proteasome inhibitor Velcade; gene expression profiling analysis of purified myeloma cells was performed both before and 48 hours after the Velcade test dose. Comparison of the gene expression profiles revealed that 80 genes were either highly up-regulated or down- regulated after Velcade test dosing, allowing for the calculation of a new 80 gene risk score. Among the patients with a low risk 70 gene score, 9% had a high risk 80 gene score, indicating a worse outcome than would have been anticipated on the basis of just the 70 gene score. Conversely, patients with a high risk 70 gene score and low risk 80 gene score did significantly better than patients who had both high risk 70 and high risk 80 gene scores.
Mechanisms of Velcade resistance and novel therapeutic options.
| Risk scores
|2- Year Progression Free survival (survival without myeloma relapse)
|| 2- Year Overall survival
| 70 gene low/80 gene low
| 70 gene low/80 gene high
| 70 gene high/80 gene low
| 70 gene high/80 gene low
Many of the 80 up-regulated genes were related to the proteasome, the cellular structure responsible for orderly protein break down in myeloma cells and which is inhibited by Velcade. Also, many of the proteasome genes were located on chromosome 1. Further studies revealed that the up-regulation of the proteasome was likely due to the presence of myeloma cells that have more than 2 copies of chromosome 1 and that the number of copies of chromosome 1 (normal cells have 2 copies) was directly related to outcome. Patients with 3 copies of chromosome 1 fared worse than patients with 2 copies of chromosome 1, while patients with 4 or more copies of chromosome 1 had the worst outcome. Given the fact that Velcade can completely suppress proteasome activity, it is possible that patients with high proteasome gene levels may quickly restore proteasome function after receiving Velcade. Another explanation is that patients with more advanced or high risk myeloma often produce less myeloma protein. In other words, the myeloma cells of these patients have both a lower protein load and therefore less need for protein break down; in these patients high proteasome levels could lead to increased protein degradation. These factors combined may explain why Velcade may not be effective in all high risk patients. The solution could be to give a higher dose of Velcade, use more effective proteasome inhibitors or alternatively suppress other pathways involved in protein break down using novel drugs such as heat shock protein inhibitors.
In summary, the new 80 gene score helps to further refine the prognosis of individual patients and sheds new clues about Velcade resistance. New therapeutic options for high risk patients are being actively explored at the Myeloma Institute for Research and Therapy.
*Pharmacogenomics of bortezomib test-dosing identifies hyperexpression of proteasome genes, especially PSMD4
, as novel high-risk feature in myeloma treated with Total Therapy 3. Blood. 2011 Sep 29;118(13):3512-24.PMID:21628408