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Summary of the Second Annual International Myeloma Working Group Summit
London June 7-9 2011
By Brian G.M. Durie, MD
This Summit had a unique format with a focus on six work/discussion groups that debated important current issues and made recommendations for both publications and research projects or clinical trials.

The annual Summit was again a very lively and productive meeting. The unique format with a focus on 6 work/discussion groups was greatly appreciated by the attendees. Many important current issues were debated and recommendations were made for both consensus or guideline publications and research projects or clinical trials.

In, GROUP 1, led by S. Vincent Rajkumar and GiamPaolo Merlini, the crucial question was how to maximize benefits of early treatment for patients with high-risk smoldering myeloma, yet avoid unnecessary treatment and toxicities.

Tests are needed to predict >90% chance of early disease progression without therapy. The group considered the potential role of imaging. For example, >3 lesions on MRI or PET/CT can indicate significant risk of disease activation. However, at this point, definitive data are lacking.

The group proposed to gather and analyze imaging data as soon as possible to allow evidence-based recommendations to be developed. It was also proposed that more precise measurement of renal function (eGFR) could indicate an earlier need for intervention, but data are needed and will be collected by the group.

Clearly, the group feels that early intervention has great potential for improved overall survival and quality of life. However, better diagnostic criteria are required and a range of trials will be needed to assess the best options for interventions. The options are for both disease control and attempted curative approaches.

In GROUP 2, led by Antonio Palumbo and Shaji Kumar, several aspects of treatment selection and disease monitoring were reviewed and discussed.

The role of Freelite™ testing was addressed: use in response assessment in patients with less than measurable disease by SPEP (<1 gm/dl) and UPEP (<200 mg/24 hrs) was affirmed as the primary recommendation.

There was a strong endorsement for the new dose (and schedule/route) modifications for Velcade® (bortezomib) to limit potential neurotoxicity. There are new guidelines that have just been submitted for publication by the IMWG. Antonio Palumbo presented updated recommendations for the identification and management of "frail" patients. The categories, "go-go", "moderate-go", and "slow-go", are helpful and clear. The group spent considerable time reviewing the numbers and types of cycles of therapy required for ideal initial or frontline treatment. Considering response, length of remission, and overall survival, as well as ongoing quality of life, different combinations and sequences can be considered. In general, they favored starting with a more limited combo, such as with 2 drugs, and adding drugs if needed. They also favored stratification within trials to assess the impact within different risk groups (e.g. good vs. poor risk). Several different trial structures were recommended.

In GROUP 3, led by Philippe Moreau, Gareth Morgan, and Michele Cavo, the current role of high-dose chemotherapy with stem cell transplant (SCT) was reviewed and discussed.

The recommendations were rather clear-cut and included:

  • SCT still recommended as "standard of care" for eligible patients under age 65 years.
  • For patients aged 65-70 years, SCT can be considered and recommended on a patient-by-patient basis.
  • SCT is still recommended if complete response has been achieved with induction.
  • 4-6 cycles of induction therapy are recommended.
  • If >VGPR is not achieved, SCT can still be considered. There is no need to persist with longer induction pre-transplant in this setting.
  • Double or second transplant can be considered for patients with <VGPR after a first transplant, but is not recommended as a routine procedure.
  • Several ideas for new preparative regimens were discussed.

In GROUP 4, led by Heinz Ludwig and Michel Attal, the current role of maintenance was discussed at length. A new guideline manuscript is in the final stages of preparation.

The main recommendations included:

  • Thalidomide
    • This is an option for maintenance for patients who have not achieved CR, are not "high-risk," and do not have significant underlying neuropathy.
    • A starting dose of 100 mg/daily is recommended for a duration of >6-12 months. The ideal duration is currently unknown.
  • Revlimid® (lenalidomide)
    • The recent phase III trial results from IFM and CALGB were noted.
    • Although maintenance is considered a valid approach, the group felt that it was not possible to make a definite recommendation at this time. Overall survival is considered the appropriate endpoint to assess benefit.
    • Enhanced monitoring and assessment with respect to the potential risk of second primary malignancies (SPMs) was recommended.
  • Velcade® (bortezomib)
    • It was felt that it is too early to make any recommendation with regard to Velcade® maintenance. More data are required.
    • The potential for every 2 week IV or SQ regimens with Velcade® was noted.
  • Needed trials
    • Clearly, additional trials are required involving one or more of Thalomid®, Revlimid®, and/or Velcade® as well as potential new agents, such as elotuzumab, HDAC inhibitors, or new oral derivatives.

In GROUP 5, led by Sundar Jagannath, Pieter Sonneveld, Jatin Shah, and Paul Richardson, new drugs were discussed.

Assessments were very similar to discussions in Barcelona last year. Carfilzomib and Pomalidomide are the drugs most likely to obtain FDA approval in 2012. There are many ongoing trials to assess these agents, both individually and as a part of new combinations. Although response is crucial as part of initial assessment, ultimately prolonged remission and improved overall survival are essential endpoints.

In GROUP 6, led by Brian Durie, Hervé Avet-Loiseau, and Wee Joo Chng, the key question was how to tailor therapy to accommodate the risk features of all patients.

It was noted that we already routinely "risk adapt" therapy based upon age, performance status, kidney function, and other medical issues encountered by individual patients. The question was how best to fine-tune therapy based upon molecular or genetic features of the myeloma. Consensus was reached upon the best definitions for "poor-" and "good-" risk myeloma . This is based upon a recent IMWG analysis submitted for publication by Hervé Avet-Loiseau.  For now, it is felt that ISS and FISH results can be used and are available for most patients. Results with GEP can be assessed within ongoing clinical trials.  It is very important to note that the Group unanimously recommended that risk groups continue to be assessed within large clinical trials that incorporate both "poor-" and "good-" risk groups. These trials require sufficient patients to adequately assess the impact of risk AND to provide as much molecular testing as possible (including GEP when feasible) to gather the best correlative data. A manuscript, with recommendations, is in development, and further analyses within the IMWG are planned.

An exciting new feature on the Summit’s agenda this year was the "Cure vs. Control" debate (with Jonathan Kaufman [cure] and Rafat Abonour [control]). Although "cure" is clearly an ideal goal, for now, "control" is a more achievable and broadly applicable option. The good news is that with the advent of the novel agents, long-term disease control is a tangible reality. Although complete remissions lasting >4 years (sometimes called "functional cures") are achievable, true "cures" (disease-free with no evidence of residual disease for >1-2 decades) are still elusive and largely undocumented. The debate was heated. Those supporting potential curative approaches feel that "functional cures" are an acceptable endpoint for now. Ultimately the question becomes: "In which patients is it reasonable to propose the added toxicities of more aggressive therapy for the chance of achieving cure?" The dilemma is that patients who are "good" risk are the most readily "controlled" long term with simpler approaches to therapy, but nonetheless could potentially achieve cure with more aggressive treatment. The debate will clearly continue. New trials are planned.

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