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December 2013 Archives : Myeloma Voices

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In the current issue of the journal Science there is a special section called "Single-Cell Biology" (cells go solo). It is now technically feasible to study individual cells in great detail at the molecular, metabolic and functional levels. What is being discovered is that a reading of the "average" from 100, 1,000 or a million cells as has previously been done disguises the great diversity at the individual cell level. 

This raises the question: Are there high-risk genetic features in myeloma cells? 

The answer turns out to be yes and no! Some do and some don't have really abnormal genetic profiles. Discovering the ones that do can guide us to the next phase of therapy for myeloma patients. 

This is significant for the International Myeloma Foundation's signature project, the Black Swan Research Initiative, which is directed towards finding a cure for myeloma. If a myeloma patient's treatment produces an excellent result, with achievement of Minimal Residual Disease (MRD) Zero (no detectable myeloma), follow-up monitoring is required. Although it is hoped and assumed that many patients will have sustained MRD-Zero and may be cured, some will not be cured with the first attempt. These patients will start to have single cells of myeloma detectable by flow cytometry on MRD testing. 

Studies of these single residual myeloma cells will provide the clues needed to eradicate the cells with new alternate and/or higher dose therapy. Checking cells one by one, as BSRI team members Dr. Alberto Orfao and Dr. Ola Landgren are now able to do, will illustrate the diversity and need most likely for a combination approach  to eradicate all these residual myeloma cells. This new technology for single-cell analyses can be key in coming up with the answers to achieving cure! And it is just another piece of the puzzle that is the BSRI, a multifaceted approach to cure myeloma. 

To learn more, stay tuned as we update with blogs, teleconferences, and reports in 2014. 

Dr. Durie sincerely appreciates and reads all comments left here. However, he cannot answer specific medical questions and encourages readers to contact the trained IMF Hotline staff instead. Questions are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate. To contact the IMF Hotline, call  800-452-CURE, toll-free in the US and Canada, or send an email to hotline@myeloma.org. Hotline hours are 9 am to 4 pm PST. Thank you.
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This year's annual meeting of the American Hematological Society (ASH) was truly exhausting, but especially exciting. So many abstracts, so little time!  One had to be a magician to cover major sessions running in parallel. Add to that the cold weather in New Orleans, travel delays, a vast, maze-like, conference center, and you end up with multiple 18-hour days.

But there was much to learn and the IMF's goal is to see the research results through the language and lens of science and point the way forward for patients towards better outcomes and a cure.

On the final evening, the IMF's Conference Series debate, "Making Sense of Treatment" went a long way to capturing the key outcomes from this year's ASH. Four topics were covered: Best Frontline Options; the Role of Maintenance; Minimal Residual Disease: Is This Important?; and New Drugs: Which Will Make an Impact?  The panel from our Stockholm Conference Series --- Doctors Antonio Palumbo, Ola Landgren, Joseph Mikhael and myself--returned to do battle again!

Best Frontline Options

The impact of novel therapies is clearly evident in the improved outcomes in the frontline setting. The panelists grappled with two main questions: How many drugs should be used in an ideal combination? And is carfilzomib (Kyprolis) now preferred over bortezomib (Velcade)? An important ancillary question  was whether or not treatment should change based upon the age or "fitness" of the patient, which is an important research interest for Antonio Palumbo.

Two drugs (Revlimid/low dose dexamethasone (Rd)) prevailed in the MM-020 trial presented at the plenary session. Rd as continuous therapy was superior for patients over age 65 years versus Rd for 18 months and MPT (Melphalan, prednisone, thalidomide) for 12 cycles- which is the standard, approved MPT protocol. So there was a clear vote for 2 drugs (Rd) in this elderly setting. But what about transplant eligible patients? 

Results with both Velcade and Kyprolis combinations as 3 drug combinations are really good. It was generally agreed that 3 drugs are enough (versus 4 or even 5 drug combinations) unless possibly one of the new monoclonal antibodies adds an important new mechanism of action.

Results incorporating either Revlimid (VRd or CRd) or Cytoxan (VCd [Cybord] or CRd) into the combinations are really excellent. But even higher percentage and deeper responses are clearly occurring with the Kyprolis combinations. 

So what did our experts have to say about all this? 

Joseph Mikhael felt that the longer term results with Cybord (Velcade/Cytoxan/dex), with, for example, 81% survival at 5 years in standard risk patients, justifies use of this regimen as a first step, especially since it is cost effective and well tolerated. Conversely, Ola Landgren indicated that CRd (carfilzomib/Revlimid/dex) gives higher and deeper responses, is well-tolerated even in the elderly and works well for both standard and higher risk patients. His perspective is that CRd can be an option across the board for all frontline patients. 

Antonio Palumbo is very much focused upon the need to assess the "fitness" of patients at diagnosis including the presence or absence of so called "co-morbidities"--other medical problems and other needed medications. Antonio's protocol results also support the value of multi-drug combinations and even high dose therapy for "fit" elderly patients. So there was a sense that the Rd two drug combos is a simple excellent option, but in fit patients it is certainly reasonable to explore the value of more aggressive combination therapies.

The Role of Maintenance

The greatest controversy emerged over the role of maintenance. The controversy at ASH this year was triggered by the presentation by Michel Attal from the IFM team, who presented the longer-term results of Revlimid maintenance following autologous stem cell transplant. As had been expected, the presentation showed improved length of remission with Revlimid maintenance, but no overall survival benefit. There have been many speculations about reasons for the lack of survival benefit, including use of 2 months of Revlimid consolidation after transplant given to all patients (including those with no maintenance). 

But what brought a flood of myeloma experts to the microphone for questions at ASH was an analysis which showed dramatically better outcomes for patients on placebo (no Revlimid maintenance) at the point of first relapse. As pointed out by Dr. Shaji Kumar from the Mayo Clinic, this was a flawed analysis in an already flawed study. But many issues were left unresolved at the time of the presentation. Other abstracts strongly affirmed the value of Revlimid maintenance (in addition to continuous or extended use in the frontline setting) using meta analyses of available trial results. 

Joseph Mikhael said he does not routinely recommend maintenance because of the confusion surrounding the data. Conversely, Antonio Palumbo, Ola Landgren, and I said we feel that the preponderance of data supports the use of maintenance, which we feel comfortable recommending, certainly from the standpoint of efficacy. 

Minimal Residual Disease -- Is It Important?

There was unanimity on the subject of the importance of Minimal Residual Disease.  MRD is important. We need to now measure MRD in a standardized fashion and use the information to compare results in randomized trials and to direct treatment to achieve MRD-Zero in trials designed to seek a cure.

Thus the central concepts of the Black Swan Research Initiative® are being enthusiastically endorsed by the myeloma expert community. 2014 is indeed going to be exciting as we see the research results and the rapid process to achieving a cure.

New Drugs -- Which Will Make an Impact?

I listed 8 drugs which are most promising from the 2013 ASH presentations: anti-CD38 monoclonal antibodies (daratumumab and SAR650984); MLN 9708; ARRY 520; ACY 1215; Selinexor; anti-CD138; panobinostat; and bendamustine. There were interesting discussion points about all 8 compounds. However, everyone agreed that the anti-CD38 compounds are both the most exciting and most likely to add a new mechanism of action to our current combination approaches.

Joe, for the first time, presented the more detailed results with SAR antibody as a single agent. About half of the patients responded, some with very deep responses (greater than VGPR).

Follow-up results with the daratumumab antibody were also presented showing substantial benefit. There is great anticipation that even more promising results are to come with anti-CD38 trials moving forward rapidly in 2014.

The IMWG Conference Series at ASH closed with a follow-up from Joseph Mikhael about the new acronym, "Lobster" that he proposed at our last debate. He now suggests that the new acronym will be "CRAB-LEGS" to identify patients with early active myeloma who do not yet have "CRAB" features. So stay tuned to hear more details about this. 

And finally, it was realized that if progress in treatment continues at the current pace, myeloma experts are in danger of putting themselves out of a job. It was agreed that if both doctors and patients end up on permanent vacation in Hawaii, it will be fine!

So here is to further improved outcomes in 2014 and an improving future for all myeloma patients everywhere!

A more comprehensive overview will be provided on the "Post-ASH" teleconference scheduled for January 16, 2014. Register here: http://bestofash2013.myeloma.org/ 

To view the archived video of the IMWG Conference Series: Making Sense of Treatment click here: http://bit.ly/1bHvql7

Dr. Durie sincerely appreciates and reads all comments left here. However, he cannot answer specific medical questions and encourages readers to contact the trained IMF Hotline staff instead. Specific medical questions posted here will be forwarded to the IMF Hotline. Questions sent to the Hotline are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate. To contact the IMF Hotline, call  800-452-CURE, toll-free in the US and Canada, or send an email to hotline@myeloma.org. Hotline hours are 9 am to 4 pm PST. Thank you.