This month we will be focusing on data from the recent 12th International Myeloma Workshop (IMW) 2009. This meeting was held on February 26 - March 1, 2009 in Washington, DC. A large amount of information from that meeting was covered for you during our Best of the Day program from the IMW. I would encourage you to view those interviews to gain the perspective of a number of the national thought leaders in multiple myeloma.

“Best of the Day^SM from the 12th International Myeloma Workshop”

Guidelines for Risk Stratification

Drs Nikhil Munshi and Herve Avet Loiseau chaired the IMW Consensus Panel on Guidelines for Risk Stratification. I thought it would be worthwhile to review some of the findings and recommendations from that panel. Patients can be stratified by a number of means including their metaphase cytogenetics, the results of cytogenetic analysis by fluorescent in situ hybridization (FISH) or by the international staging system (ISS) stage.

The first item Drs Munshi and Avet Loiseau tackled was a discussion of the purpose of risk stratification. Will it help us choose the most effective therapy for our patients? Will it predict response to specific treatments? Or does it help stratify patients by prognosis?

The Chairs stated emphatically that “The general purpose of risk stratification is not to decide whether to treat or not, but to prognosticate”. Risk factors currently available help to stratify patients who are receiving conventional therapies as well as high-dose therapy and stem cell transplant. However, there is increasing evidence that the recently developed novel therapies may abrogate and overcome some of the factors traditionally felt to indicate poor-risk. Ongoing efforts to assess the impact of risk factors and novel therapies remain very important.

What about the therapeutic decision making process – does risk stratification help us here? The Chairs respond by stating that “Currently, to mandate definitive treatment according to cytogenetic abnormalities is premature, although there is emerging data suggesting that some of the novel agents could overcome the negative prognosis of the cytogenetic abnormalities”.

When should risk stratification be performed – certainly at diagnosis, but what about at the time of relapse? Risk factors can change after initial treatment and at relapse. It is felt that if a patient acquires high-risk features at relapse or at progression, that patient should be reclassified as having high-risk disease. The same cytogenetic abnormalities considered poor-risk at diagnosis should also be considered poor-risk if they are first noted at relapse. However, redetermination of β2M and recalculation of ISS stage at relapse are not considered to be of value in predicting a change in risk status.

Clinical factors at relapse that are considered predictive of future risk include the quality of response to initial therapy as well as the duration of that response prior to the need for additional treatment. Because of the importance of changes in cytogenetics at the time of relapse, the Consensus Panel recommended that metaphase cytogenetics and FISH should be performed at relapse.

Can risk status predict for response or non-response to certain therapies? The Consensus Panel felt that the answer to this question is still unclear but there is increasing evidence that novel therapies including bortezomib and lenalidomide may be able to overcome the negative risk associated with deletion 13 and the t(4;14) translocation.

So this raises the question of what type of risk assessment should we be doing. Since metaphase cytogenetics detects significant abnormalities in only about 30% of patients with myeloma, cytogenetics by FISH looking for specific high-risk features, should also be performed. While metaphase cytogenetics may be able to detect hypodiploidy, del13, del 17p and t(4;14), FISH may also detect t(4;14), t(14;16) and del 17p in a higher proportion of patients. Del 13 detected only by FISH and not by metaphase cytogenetics does not appear to have negative prognostic significance unless it is associated with the t(4;14) translocation. Recent evidence suggests that del 1p and 1qGain may also have significant negative prognostic impact in risk stratification.

Serum β2M and serum albumin remain significant factors as part of the ISS staging system and have validated prognostic significance for conventional treatments. However, the validity of the ISS system with combination novel agent therapies is unknown. High β2M and low serum albumin are felt to be predictive of high-risk disease, but integration of these factors with cytogenetic changes would make for a much more robust staging system.

Other clinical features that may be significant prognostic factors, but for whom clinical applicability remains uncertain, include serum LDH, IgA isotype, extramedullary disease, high serum free light chains and abnormal serum FLC rations, plasmablastic disease and plasma cell leukemia.

An area of increasing interest is that of genomics and gene expression profiling. Two systems have been reported by the University of Arkansas group and by the French Intergroupe Francophone du Myélome (IFM) group. While these two 17 and 15 gene models are both extremely interesting, they have no genes in common and still require extensive analysis and validation before being generally adopted for clinical practice.

In summary, risk stratification is important for prognostication, but it does not tell us whether or not to treat nor does it as yet tell us which treatment to select for which patient. However, that may be changing as increasing information is collected regarding differential responses to currently available agents in standard-risk versus high-risk patients.

In addition, these factors for determination of risk are in evolution and as new treatments are developed and evaluated the negative or positive significance of certain factors will almost certainly change.

OncoFacts™ Editor:

James Epstein, MD

Contact

4325 Alexander Drive
Alpharetta, GA 30022
Fax: +1(770) 751-7334
www.imedex.com
Email: elearning@imedex.com

For ongoing improvement, we would appreciate your comments and suggestions. Email your suggestions to: elearning@imedex.com

OncoFacts is produced by Imedex^®, LLC (Imedex). Imedex is solely responsible for this program’s content. Although Imedex attempts to ensure that the information in our programs is accurate and timely, matters and opinions discussed and/or presented with respect to clinical matters are those of the discussion participants only, and not necessarily those of Imedex. Moreover, although Imedex attempts to identify and integrate the most qualified medical professionals and key thought leaders in our programs, TO THE FULLEST EXTENT PERMITTED BY LAW, IMEDEX EXPRESSLY DISCLAIM ALL WARRANTIES, EITHER EXPRESS OR IMPLIED, STATUTORY OR OTHERWISE, INCLUDING BUT NOT LIMITED TO THE IMPLIED WARRANTIES OF MERCHANTABILITY, NON-INFRINGEMENT OF THIRD PARTIES’ RIGHTS, AND FITNESS FOR A PARTICULAR PURPOSE, WITH RESPECT TO THE CONTENT PRESENTED. IMEDEX FURTHER MAKES NO REPRESENTATIONS OR WARRANTIES ABOUT THE ACCURACY, RELIABILITY, COMPLETENESS OR TIMELINESS OF THE CONTENT OR ANY MATERIAL PRESENTED. In addition, the material presented and related discussions are not intended to be medical advice, and the presentation or discussion of such material is not intended to create and does not establish a physician-patient relationship. Medical advice of any nature should be sought from an individual’s own physician.

Neither Imedex nor any of its subsidiaries or affiliates is affiliated with or formally endorsed by a medical society.

© 2009 Imedex, LLC. All rights reserved.