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June 2003 Volume 5, Issue 6:
Myeloma Update
By Brian G. M. Durie, MD
Overview of the IXth International Workshop on Multiple Myeloma, the International Prognostic Index, and Bank On A Curetm
06.05.03

This issue of Myeloma Today is sponsored in part by an unrestricted educational grant from Novartis Pharmaceuticals.



Overview of the IXth International Workshop on Multiple Myeloma, the International Prognostic Index, and Bank On A Curetm


Every two years, the myeloma scientific community gets together to participate in the International Myeloma Workshop. This year, the IXth is being held in Salamanca, Spain. This meeting is co-chaired by IMF Scientific Advisors Prof. Jesus San Miguel and Prof. Joan Blade.

The Salamanca program is packed with invited and submitted presentations starting May 23rd and running through May 27th. The agenda is available for viewing at www.myeloma2003.usal.es.

The core program with invited speakers covers thirteen areas:

  1. Genetics of myeloma cells
  2. New molecular techniques/results
  3. Immune biology
  4. MGUS
  5. Signal transduction pathways
  6. Bone marrow microenvironment
  7. New prognostic systems
  8. Mouse models
  9. Maintenance and supportive care
  10. The role of auto transplantation
  11. Allogeneic transplantation
  12. Novel therapies
  13. Vaccine strategies

The submitted abstracts, numbering over 500, cover a wide range of topics, which will mostly be presented in poster sessions between the oral sessions. This is what makes for such a busy schedule. The two best submitted abstracts in each of the thirteen topic areas have been selected for oral presentation.

Other corporate and foundation meetings make the agenda truly "jam packed." On Friday the 23rd, corporate symposia include arsenic trioxide (Trisenox“: CTI); thalidomide and analogs (Celgene); ArediaTM/ZometaTM (Novartis).

The International Myeloma Foundation has several scheduled programs, including:

  • IMF Working Group dinner – Thursday, May 22nd
  • European Patient Support Group Leaders meeting – Friday, May 23rd
  • Scientific Advisors luncheon – Saturday, May 24th.

CORE PROGRAM

Many of the topics in the core program of the Salamanca workshop are always discussed and updated at the International Workshops. This year, the greatest anticipation surrounds presentations about new molecular information. The other really new aspects are discussed below:

Gene Expression Profiling – has revealed both gene patterns, which can be used for hierarchical classification (to match clinical classifications), as well as genetic expression of specific RNAs and proteins linked to myeloma features such as bone disease and anemia. There is excitement about expression of a protein called DKK1, which is linked to the suppression of osteoblasts and therefore interruption of bone healing in myeloma patients. There has been an exponential increase in understanding of the molecular biology of bone disease in myeloma and details will be presented as part of several sessions. Obviously, the hope is that new therapies can emerge from this higher level of knowledge.

Immune Biology – is also an area of new knowledge. As for molecular biology, the complexity of the processes being uncovered is impressive. Just how to modulate this complexity of immune regulation to the advantage of the myeloma patient will be a challenge.

Myeloma classification, prognosis, and staging [see discussion of the International Prognostic Index]. New systems for classification, prognosis assessment, and staging have been under development in the past 2 years and the results will be presented at the Salamanca meeting. These systems, which are the cornerstone for all programs for myeloma patient management, can provide a reliable framework for international clinical research efforts. For example, the new IPI Staging System is shown in the Table below.

STAGE 1
b2M < 3.5
ALB > 3.5
STAGE 2
b2M < 3.5
ALB < 3.5
or
b2M 3.5 – 5.5
STAGE 3
b2M > 5.5
b2M = serum b2 microglobulin in mg/dl
ALB = serum albumin in g/dl
Good and Poor Risk Groups
  • Age is the only additional factor that significantly impacts outcome.
  • Survival for > 5 years is associated with age < 60 years.
  • Survival for < 2 years is associated with age > 60 years. Other correlations in this category include: platelet count < 130,000/mm3 and LDH serum level above normal.
  • Cytogenetics do influence outcome, however, chromosome 13 deletion and presence of complex chromosome abnormalities do not add to the impact of age, b2M, and ALB.

Signal transduction and bone marrow micro environment – Much new information will be presented. However, just how to use this information and to what extent new therapies target specific pathways and cell-cell interactions remains to be seen. Thus far, the research has been retrospective, in that after it was discovered that thalidomide and its analogs as well as VelcadeTM are very effective treatments, the potential mechanisms of action are being explored. This type of retro research is interesting, but not automatically productive in the development of further therapies. Mouse model systems may help and several will be discussed.

Autologous Stem Cell Transplantation (ASCT) – This may be a watershed meeting with regard to ASCT. For the last decade, the role of ASCT has been under scrutiny. Now, several groups including the French (IFM), U.K. (MRC), Spanish (GEM/ Pethema), and U.S. (UAMS: Barlogie) will present long-term follow-up data for panel discussion. In addition, tandem transplant, and transplant in special circumstances such as renal failure, older patients, and systemic amyloidosis will be addressed. The panel will focus on the question: "Has ASCT become the gold standard treatment in multiple myeloma?" The overall outcome with ASCT is definitely superior in the majority of trials/studies to be presented. Can ASCT now be routinely recommended for all patients? Is ASCT especially recommended for good and/or poor risk subsets of patients? These and other question will be actively debated. The additional role of "mini-allo" (non-myeloablative) transplant will be discussed in a separate roundtable.

Novel Therapies – Most of the results with the "novel" therapies such as thalidomide, RevimidTM, ActimidTM, and VelcadeTM are already widely known. Thalidomide is now one of the most widely used drugs in the myeloma community in the U.S., despite the fact that it is not FDA approved in this setting. The widespread use of thalidomide has been well documented at the IMF Patient & Family Interactive Seminars.

VelcadeTM has now received FDA approval for use in relapsing/refractory myeloma. Undoubtedly, the focus of attention in Salamanca will be the "not-so-novel" follow-up data and discussions with regard to the future integration of these drugs into overall myeloma management, including ASCT.

Salamanca Analysis and Impact – The IMF has recruited a cadre of top researchers, advisors, and clinicians to analyze the impact of the Salmanca presentations. A Salamanca Guide will be published immediately after the meeting and made available to IMF members. In addition, the IMF Myeloma Minute will carry all the breaking news stories and any additional new information. Copies of the Salamanca Abstracts will also be available as hard copy as well as online at www.myeloma2003.usal.es.

INTERNATIONAL PROGNOSTIC INDEX (IPI)

To develop the new IPI staging system, data have been gathered on 11,179 patients from 17 institutions around the world, including the U.S., Europe, and Asia. The prognosis for patients receiving both conventional-dose and high-dose therapy are being assessed. The most promising IPI staging system is a combination of serum b2 microglobulin and serum albumin, very similar to the SWOG system.


Presentation of the International Prognostic Index 2003 IMF Senior Research Grant:
Jesus San Miguel, Phil Greipp, and Brian Durie

The IMF International Study Group is also working to identify patients with particularly poor (median survival 12-24 months) versus very good survival (median survival > 5 years). Risk factors associated with poor survival are elevated serum creatinine, low platelet count, poor performance status, age > 65 years, and elevated LDH values if available. Conversely, survival of >5 years is associated with absence of these factors, as well as absence of chromosome 13 deletion by cytogeneic analysis and/or absence of complex chromosome abnormalities.

More about the International Prognostic Index

BANK ON A CURETM

Bank On A CureTM, a project to establish a comprehensive DNA Bank for patients with multiple myeloma, is Co-Chaired by IMF Scientific Advisors Dr. Gareth Morgan (Leeds General Hospital, Leeds, UK) and Dr. Brian Van Ness (University of Minnesota, USA). Bank On A Cure's initial goal is to collect DNA samples and patient information from 10,000 myeloma patients. The DNA will be collected, stored, and analyzed at the University of Minnesota in the US and the University of Leeds in the UK. The DNA will be tested to determine the presence or absence of gene variants which determine:

  • sensitivity to specific myeloma treatments
  • susceptibility to side effects
  • causal factors and/or predisposition to myeloma

The details of patient myeloma type and staging, response to treatment, side effects of treatment, and overall outcome will be gathered using a web-based computer system. The primary analysis will compare gene variants and outcome. Based upon initial patterns of correlations between gene variants and myeloma treatment outcome, side effects and susceptibility, "gene-directed" clinical trials will be developed. Clinical trials directed by myeloma DNA bank findings will be unique protocols to evaluate targeted therapies.


Presentation of the Bank On A CureTM 2003 IMF Senior Research Grant:
Susie Novis, Brian Van Ness, and Gareth Morgan

Why Establish Bank On A Cure?

  • The IMF is in a special position to interface between its 50,000+ myeloma patient members and the researchers focused on new molecular approaches to myeloma diagnosis and treatment.
  • The DNA bank allows myeloma research to move to the genetic level.
  • Treatment can be selected based upon the unique genetic patterns of individual myeloma patients.
  • Treatment side effects can be predicted. Specific drugs can be selected and drug dosages adjusted accordingly, thus optimizing effectiveness while minimizing toxic side effects.
  • By identifying the genetic pattern of myeloma patients, strategies for early intervention and prevention can be developed.
  • As new genetic information becomes available, Bank On A Cure will be an invaluable resource in interfacing with the pharmaceutical industry in the development of new drugs targeting specific patterns of gene variants.
  • Bank On A Cure will serve as a model for other cancers, as well as a broad spectrum of other diseases.

More about Bank On A CureTM.


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