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July 2014 Archives : Myeloma Voices

A recent study illustrates just how useful minimal residual disease (MRD) testing by flow cytometry is to predict excellent outcomes with new highly active combination therapies. A phase II study from the Intergroupe Francophone du Myelome (IFM) is reported in the July 14th issue of the Journal of Clinical Oncology. This study served as a pilot protocol for the ongoing IFM/Dana-Farber Cancer Institute 2009 phase II study assessing lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone frontline with or without autologous stem cell transplantation (ASCT). In the phase II study reported in the JCO, 31 patients with newly diagnosed symptomatic myeloma all received RVD followed by ASCT plus RVD consolidation and one year of Revlimid maintenance.

The results with this protocol were extremely good. Very good partial response (VGPR) or better was achieved in 58%, 70%, and 87% of patients after RVD induction, ASCT, and RVD consolidation, respectively. What was especially exciting is that 68% of patients achieved MRD-negative status as measured by flow cytometry. MRD negative by flow is an extremely helpful category as a one-time test measured at the point of maximum response. When MRD negativity is confirmed by subsequent serial testing (i.e. sustained MRD-negativity) and supported by additional testing, such as a negative pet/CT scan and normal HevyLite test, one can use MRD-Zero as a new category indicative of potential cure status.

With a median follow-up of over 3 years (39 months), patients achieving MRD-flow negative status are still in remission. The overall survival is obviously 100% at over 3 years. Thus, as we await the results of the phase III comparison study, the impact of induction, ASCT, consolidation, and maintenance is quite impressive, especially with regard to the MRD-negative status and stable remission status of the patients.

These findings strongly validate the key principle of the IMF's Black Swan Research Initiative. Monitoring with sensitive MRD testing at very low levels of disease both predicts exceptionally good outcomes and can be the basis for additional treatment decisions to achieve the sustained deep responses noted above, which can translate into cure.

It is important to emphasize that these new data support considerable prior data, for example utilizing Velcade plus thalidomide rather than Revlimid with dexamethasone (VTd) for induction, followed by transplant, consolidation, and maintenance. The new RVD results are clearly more promising, but the pattern of benefit throughout the four treatment phases is comparable. For the RVD regimen, it was notable that 13% of patients achieved MRD-negative status during the maintenance period.

The clinical benefit of achieving MRD-negative status documented using the Spanish flow methodology has been recognized for more than 10 years. Two sequential studies by the Spanish team in 2008 and 2012, and one from the UK team have shown that patients achieving MRD-negative status by flow have longer remissions and overall survival. What is remarkable about the new data is the sustained value of the deep responses in the IFM trial: no relapses after more than 3 years.

Thus, with the even more sensitive and standardized new flow method now available and use of increasingly effective novel combinations of therapy, it seems very likely that it will be easily feasible to reliably predict unusually good outcomes and define a patient population potentially curable with comprehensive frontline treatment. This new IFM study thus points the way to incorporation of MRD testing by flow cytometry into tailored approaches to achieve the very best results with therapy throughout the course of disease.

As always, stay tuned for further exciting developments! 


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 InfoLine staff instead. Specific medical questions posted here will be forwarded to the IMF InfoLine. Questions sent to the InfoLine are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate, but will not be posted here. To contact the IMF InfoLine, call 800-452-CURE, toll-free in the US and Canada, or send an email to infoline@myeloma.org. InfoLine hours are 9 am to 4 pm PT. Thank you.

On July 18-19, 2014, the IMF co-hosted the US Myeloma Flow Workshop at the Zuckerman Research Center at the Memorial Sloan Kettering Cancer Center in New York City. There were 24 participating medical centers from across the country plus representatives from the National Cancer Institute (NCI) and US Food and Drug Administration (FDA) in attendance. Attendees included key myeloma experts from the centers as well as technical staff responsible for the running of flow cytometry laboratories. US myeloma experts present included Drs. Vincent Rajkumar, Shaji Kumar, Ola Landgren, Ken Anderson, Saad Usmani, Suzanne Lentzsch, Jonathan Kaufman, Phillip McCarthy, and Andrzej Jakubowiak.

This educational workshop was structured to inform participants about the role of testing for minimal residual disease (MRD) and currently available testing procedures. The main focus was the new automated, highly sensitive flow cytometry method developed by the Spanish team for standardized detection of MRD in myeloma.

The establishment of a reliable MRD test is a key first step for the IMF's Black Swan Research Initiative. The Black Swan Research approach focuses on the use of the best MRD testing to track myeloma at the lowest levels as a basis for treatment decisions to achieve cure. It was therefore very exciting to have the top experts in flow cytometry in the room to assess the value of the new flow test for MRD.

During the workshop's morning session, Dr. Bruno Paiva (University of Navarra, Pamplona, Spain) summarized the importance of MRD testing in assessing treatment outcomes - much as he had done in March at the Salamanca, Spain, Flow Workshop before an audience of 70 global experts waiting to be convinced of the role of MRD testing using flow. After the Spain meeting, the flow cytometrists went home to set up the new method in labs from Germany to Australia. Would it be the same in the US?
Next, Dr. Alberto Orfao (University of Salamanca, Salamanca, Spain) presented to a hushed room. It was clear everyone wanted to hear all the details of the new flow cytometry method he and his team had worked for years to develop, a project that has received IMF support as a key element of the Black Swan Research Initiative.

Afterwards, the usual technical questions emerged and were answered in Alberto's typical calm, complete fashion. An interactive session followed to determine what barriers may exist to the adoption of the new flow method in the US.

As workshop presenter Dr. Brent Wood (University of Washington, Seattle, Washington) would later ask, "What is more important for us? To do our own thing? Or to come together and standardize in a way that is good for our patients?"

The consensus among workshop participants was "Yes, we want to standardize. But how?" Among the practical questions and concerns voiced were the following:

  • Do samples need to be processed in 24 hours?
  • When is the best time to get samples for response assessment?
  • How can we find the time to set up a new method in a very busy laboratory?
  • What about the costs? 
  • We have contracts for the old antibodies--how about the new antibodies?
  • What about the new software which standardizes the analysis and results?

The software for this cutting-edge test is a very important aspect because the cytometer uses eight colors and the results consist of clusters displayed in eight dimensions! If this sounds mind-bending, it really is.  Sophisticated software is required to accurately sort or "gate" the cells and determine which are myeloma cells and which are not! This is the fundamental question the new flow method can answer: are there any myeloma cells left or not--and ARE WE REALLY SURE?

Clearly everyone who attended the flow workshop was eager to have the means to answer to this question, and to be really sure. That left the matter of whether or not the practical laboratory implementation issues can be resolved in order to begin using the new flow method. The workshop participants asked the IMF team to help. There was immediate agreement that every effort will be made to assist labs that are anxious to start the new method, but which face challenges doing so.

After much excellent discussion, a dinner, and a morning session with further questions answered, participants left well informed and highly motivated to implement a new highly sensitive flow MRD method.

In the coming weeks and months, Dr. Bruno Paiva, Dr. Alberto Orfao, their teams, and the IMF team will be at the ready to assist. There is a strong sense of optimism that a reliable MRD test will be available very soon for US patients.

Stay tuned and updates will be posted along the way!

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In the early 1980s, I was testing anti-malarial drugs such as quinine against cultured myeloma cells in the laboratory. We had developed drug-resistant myeloma cells specifically for this purpose. Several lines of research had revealed that resistance to drugs such as Adriamycin (an anthracycline), a key component of the "VAD" (Velcade, Adriamycin, dexamethasone) chemotherapy regimen popular at the time, was mediated by a cell membrane protein called P-glycoprotein, which conferred an MDR (multi-drug-resistant) phenotype. What P-glycoprotein does is pump drugs such as Adriamycin out of the cell - a protection mechanism against cell toxicity. However, in the case of Adriamycin, we want the Adriamycin to stay in the cell and kill the myeloma.

This can be achieved by giving drugs which block P-glycoprotein! I became interested in this because of another drug called verapamil (a cardiac drug which can slow the heart and reduce blood pressure), which blocks P-glycoprotein. I showed that giving verapamil to patients resistant to VAD chemotherapy produced new responses and remissions at the safe doses of verapamil.

Another drug studied was the anti-malarial drug quinine, which had similar effects, but more challenging side effects. SWOG (Southwestern Oncology Group) study #9210 was conducted to evaluate the efficacy of quinine along with the VAD regimen. I was co-chair of the SWOG myeloma committee at that time. Unfortunately, we had to discontinue the quinine/VAD study because of the unacceptable toxicities.

Meanwhile, a much more promising and safe drug called cyclosporine (an immune suppressive agent) proved to be effective in laboratory studies, and a clinical trial was initiated in collaboration with the HOVON group in the Netherlands. Results were published in the journal The Lancet in 1992, with my friend and colleague Dr. Pieter Sonneveld as the first author. Patients completely resistant to VAD chemotherapy had remarkable sustained benefit with remissions lasting nine months or longer in this relapsed/refractory setting. Although a number of other agents were subsequently tested, these results remain the best utilizing this anti-P-glycoprotein strategy. However, with the advent of novel therapies in the later 1990s, we moved away from this MDR-targeted approach.

But be assured the anti-malarials were rigorously evaluated as part of this strategy. Like many other agents, such as alpha interferon (anti-viral agent), there is always the potential for important anti-myeloma therapy in the appropriate setting in the future. These agents are not neglected, only superseded by much better novel agents. Nonetheless, it may be that one of these agents will provide the solution to the complex puzzle which is myeloma and lead to a cure. I still have my P-glycoprotein files and publications - now stored in the cloud somewhere! Stay tuned for any updates, whenever they occur.

 

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 InfoLine staff instead. Specific medical questions posted here will be forwarded to the IMF InfoLine. Questions sent to the InfoLine are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate, but will not be posted here. To contact the IMF InfoLine, call 800-452-CURE, toll-free in the US and Canada, or send an email to infoline@myeloma.org. InfoLine hours are 9 am to 4 pm PT. Thank you.