This forum thread can be used to discuss the proceedings of the International Myeloma Workshop that take place on Day 2 (Wednesday, May 4) of the conference. Feel free to use this space to highlight interesting abstracts, summarize the presentations as they happen, ask questions, and discuss any relevant topics. Everyone is encouraged to participate.
Feel free to also check out the discussions for Day 1, Day 3, and Day 4.
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Re: IMW 2011 Multiple Myeloma Discussion - Day 2
Good morning, everyone, and welcome to Day 2 of the International Myeloma Workshop. The first session this morning, which is about Newly Diagnosed Myeloma Patients under 65 years of Age - Facts and Questions, is about to start. I'll try to take notes as it goes along, posting updates as things move along.
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Boris Simkovich - Name: Boris Simkovich
Founder
The Myeloma Beacon
Re: IMW 2011 Multiple Myeloma Discussion - Day 2
Dr. Michele Cavo starts off the morning. His presentation is very methodical but also very comprehensive, marshaling results from many different trials to answer the key questions he seeks to address.
His presentation is centered around key questions related to the treatment of younger, newly diagnosed patients. He starts off by noting that there is a broad range of data supporting the notion that the depth and breadth of a patient's initial response to myeloma treatment is a very good predictor of the patient's long-term survival. He believes, therefore, that it is important to achieve as deep a response as possible when first treating myeloma patients. He also believes it is very important to fully understand exactly how deep a patient's response to treatment is using as many different methods as possible.
Dr. Cavo then moves on to several key questions. What is the best induction therapy prior to stem cell transplant? What is the best consolidation therapy? What kind of maintenance therapy -- if any -- is best?
On the issue of induction therapy, Dr. Cavo showed that numerous studies indicate that a combination regimen involving Velcade, dexamethasone, and one or two other agents is likely to achieve the highest response rate. (This point was reiterated during the panel discussion at the end of this set of presentations, when essentially all panel members agreed that Velcade seems like it should be the core of whatever induction therapy a physician follows.)
The highest response rates in the data Dr. Cavo showed appeared to be those associated with the triple regimens Velcade, thalidomide, and dexamethasone (VTD) or the combination often called "PAD", which is Velcade, doxorubicin (Adriamycin), and dexamethasone. [Note, though, that other data -- to be discussed in a later posting -- show very good results for at least two other combination regimens.]
In terms of consolidation therapy, Dr. Cavo believes the data are less conclusive, although he did feel there are good data supporting the VTD regimen for consolidation.
On the issue of maintenance therapy, Dr. Cavo showed data from multiple trials showing a significant benefit to Revlimid maintenance. The benefit is definitely demonstrated in terms of progression free survival. He believes there also are strong signals that overall survival also soon will be demonstrated.
Dr. Cavo concluded his presentation by discussing his personal preferences in regard to most of the issues he covered earlier in his presentation. The main additional bit of information that came out concerns the question many researchers are raising as to whether it really is necessary to do stem cell transplants early in the myeloma treatment cycle given the efficacy of the new myeloma treatments. Dr. Cavo acknowledges that this is a fair issue to raise, but he still believes stem cell transplants early in the treatment cycle is a better approach than waiting to do a transplant later.
His presentation is centered around key questions related to the treatment of younger, newly diagnosed patients. He starts off by noting that there is a broad range of data supporting the notion that the depth and breadth of a patient's initial response to myeloma treatment is a very good predictor of the patient's long-term survival. He believes, therefore, that it is important to achieve as deep a response as possible when first treating myeloma patients. He also believes it is very important to fully understand exactly how deep a patient's response to treatment is using as many different methods as possible.
Dr. Cavo then moves on to several key questions. What is the best induction therapy prior to stem cell transplant? What is the best consolidation therapy? What kind of maintenance therapy -- if any -- is best?
On the issue of induction therapy, Dr. Cavo showed that numerous studies indicate that a combination regimen involving Velcade, dexamethasone, and one or two other agents is likely to achieve the highest response rate. (This point was reiterated during the panel discussion at the end of this set of presentations, when essentially all panel members agreed that Velcade seems like it should be the core of whatever induction therapy a physician follows.)
The highest response rates in the data Dr. Cavo showed appeared to be those associated with the triple regimens Velcade, thalidomide, and dexamethasone (VTD) or the combination often called "PAD", which is Velcade, doxorubicin (Adriamycin), and dexamethasone. [Note, though, that other data -- to be discussed in a later posting -- show very good results for at least two other combination regimens.]
In terms of consolidation therapy, Dr. Cavo believes the data are less conclusive, although he did feel there are good data supporting the VTD regimen for consolidation.
On the issue of maintenance therapy, Dr. Cavo showed data from multiple trials showing a significant benefit to Revlimid maintenance. The benefit is definitely demonstrated in terms of progression free survival. He believes there also are strong signals that overall survival also soon will be demonstrated.
Dr. Cavo concluded his presentation by discussing his personal preferences in regard to most of the issues he covered earlier in his presentation. The main additional bit of information that came out concerns the question many researchers are raising as to whether it really is necessary to do stem cell transplants early in the myeloma treatment cycle given the efficacy of the new myeloma treatments. Dr. Cavo acknowledges that this is a fair issue to raise, but he still believes stem cell transplants early in the treatment cycle is a better approach than waiting to do a transplant later.
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Boris Simkovich - Name: Boris Simkovich
Founder
The Myeloma Beacon
Re: IMW 2011 Multiple Myeloma Discussion - Day 2
Following Dr. Cavo's presentation, a number of other myeloma researchers from different countries in Europe as well as the United States discussed their thoughts on the treatment of younger newly diagnosed myeloma patients, including what they see to be key open questions in regard to this issue. Generally, these presentations also included descriptions of clinical trials the researchers have helped organize to address what they perceive to be key questions.
Instead of going through the presentations one by one, it is useful, instead, to identify some of the common themes and concerns that emerged.
One common concern was the value and timing of autologous stem cell transplants. Several presenters described trials they have designed to test, for example, whether it is better to do a stem cell transplant early in a patient's treatment regimen, or to wait and do a transplant later. A joint trial being carried out by the Dana Farber Cancer Institute at Harvard and the IFM group of French cancer centers will test whether patients who receive a transplant plus Revlimid maintenance therapy for 12 months do any better than patients who receive exactly the same induction therapy, but then only Revlimid maintenance therapy (without the stem cell transplant in between).
Researchers likewise recognize that there is an open question as to whether a single transplant is sufficient for most patients, or whether patients should receive a double stem cell transplant to deepen the response rate they achieve. In this regard, Dr. Pieter Sonneveld from the Netherlands and Dr. Cavo described a trial they are helping carry out that randomizes patients to have either one or two transplants, followed by Revlimid maintenance therapy.
Another common concern that emerged during the discussions is the need to personalize treatment depending on a patient's specific type of myeloma disease. Generally, this concern is described under the rubric "risk-adapted therapy," or tailoring the treatment depending on whether a patient is a low-risk or high-risk myeloma patient.
None of the researchers who spoke during the presentations said that they are planning trials that have different treatment arms for myeloma patients with different risk profiles. But almost all trials that were described will include steps to ensure that patients have their myeloma fully categorized using several different advanced methods such as FISH and gene expression profiling. In addition, Dr. Laura Rosiñol of the Spanish Myeloma Group said that it is planning a trial to investigate different options for treating high risk myeloma patients.
The issue of low-risk versus high-risk myeloma also came up during the presentation by Dr. Gareth Morgan of the United Kingdom. He discussed results showing that induction and maintenance therapy with a combination of cyclophophamide, thalidomide, and dexamethasone (CTD) has very high response rates as well as strong progression free survival and a tendency toward a survival benefit as well. Indeed, the results compare very favorably with the Velcade+thalidomide+dexamethasone regimen that Dr. Cavo spoke highly of during his introductory presentation.
However, Dr. Morgan also mentioned that the CTD regimen does very well in low-risk patients but does not perform as well in high-risk patients.
(Also in regard to induction and consolidation regimens other than VTD, several of the presenters mentioned the Velcade+Revlimid+dexamethasone regimen and discussed data showing that it generates some of the highest pre- and post-transplant response rates of any regimen, including VTD.)
One final interesting point that arose during the panel discussion at the end of the presentations was made by Dr. Bart Barlogie of the University of Arkansas for Medical Sciences. Dr. Barlogie repeatedly urged his colleagues to ensure that they include imaging methods when they determine whether a patient has truly achieved a complete response. He said that many patients he has seen who have achieved a complete response using even very stringent definitions neverless still have myeloma in lesions within their bones. Dr. Barlogie said that "myeloma is a focal disease", with myeloma cells typically concentrating in specific areas within the bones. Not until the disease has been killed in those lesions does he believe the disease is truly suppressed as much as it can be in a patient.
This led someone to ask Dr. Barlogie if he treats lesions with radiotherapy. He said that he doesn't unless a patient needs immediate relief due to pain associated with a lesion (or lesions). Instead, he believes lesions should be treated with chemotherapy to ensure the remaining myeloma cells in all lesions in a patient's body are killed.
Instead of going through the presentations one by one, it is useful, instead, to identify some of the common themes and concerns that emerged.
One common concern was the value and timing of autologous stem cell transplants. Several presenters described trials they have designed to test, for example, whether it is better to do a stem cell transplant early in a patient's treatment regimen, or to wait and do a transplant later. A joint trial being carried out by the Dana Farber Cancer Institute at Harvard and the IFM group of French cancer centers will test whether patients who receive a transplant plus Revlimid maintenance therapy for 12 months do any better than patients who receive exactly the same induction therapy, but then only Revlimid maintenance therapy (without the stem cell transplant in between).
Researchers likewise recognize that there is an open question as to whether a single transplant is sufficient for most patients, or whether patients should receive a double stem cell transplant to deepen the response rate they achieve. In this regard, Dr. Pieter Sonneveld from the Netherlands and Dr. Cavo described a trial they are helping carry out that randomizes patients to have either one or two transplants, followed by Revlimid maintenance therapy.
Another common concern that emerged during the discussions is the need to personalize treatment depending on a patient's specific type of myeloma disease. Generally, this concern is described under the rubric "risk-adapted therapy," or tailoring the treatment depending on whether a patient is a low-risk or high-risk myeloma patient.
None of the researchers who spoke during the presentations said that they are planning trials that have different treatment arms for myeloma patients with different risk profiles. But almost all trials that were described will include steps to ensure that patients have their myeloma fully categorized using several different advanced methods such as FISH and gene expression profiling. In addition, Dr. Laura Rosiñol of the Spanish Myeloma Group said that it is planning a trial to investigate different options for treating high risk myeloma patients.
The issue of low-risk versus high-risk myeloma also came up during the presentation by Dr. Gareth Morgan of the United Kingdom. He discussed results showing that induction and maintenance therapy with a combination of cyclophophamide, thalidomide, and dexamethasone (CTD) has very high response rates as well as strong progression free survival and a tendency toward a survival benefit as well. Indeed, the results compare very favorably with the Velcade+thalidomide+dexamethasone regimen that Dr. Cavo spoke highly of during his introductory presentation.
However, Dr. Morgan also mentioned that the CTD regimen does very well in low-risk patients but does not perform as well in high-risk patients.
(Also in regard to induction and consolidation regimens other than VTD, several of the presenters mentioned the Velcade+Revlimid+dexamethasone regimen and discussed data showing that it generates some of the highest pre- and post-transplant response rates of any regimen, including VTD.)
One final interesting point that arose during the panel discussion at the end of the presentations was made by Dr. Bart Barlogie of the University of Arkansas for Medical Sciences. Dr. Barlogie repeatedly urged his colleagues to ensure that they include imaging methods when they determine whether a patient has truly achieved a complete response. He said that many patients he has seen who have achieved a complete response using even very stringent definitions neverless still have myeloma in lesions within their bones. Dr. Barlogie said that "myeloma is a focal disease", with myeloma cells typically concentrating in specific areas within the bones. Not until the disease has been killed in those lesions does he believe the disease is truly suppressed as much as it can be in a patient.
This led someone to ask Dr. Barlogie if he treats lesions with radiotherapy. He said that he doesn't unless a patient needs immediate relief due to pain associated with a lesion (or lesions). Instead, he believes lesions should be treated with chemotherapy to ensure the remaining myeloma cells in all lesions in a patient's body are killed.
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Boris Simkovich - Name: Boris Simkovich
Founder
The Myeloma Beacon
Re: IMW 2011 Multiple Myeloma Discussion - Day 2
The second discussion session today was actually a symposium -- or set of presentations -- sponsored by Celgene Corporation, the company that developed and markets thalidomide and Revlimid (lenalidomide). There were six presentations overall during the symposium, but, in this summary, I will focus on the last two presentations.
One of those two presentations was by Dr. Sergio Giralt of Memorial Sloan-Kettering in New York. He discussed "The Evidence Supporting Continuous Therapy in Multiple Myeloma."
Dr. Giralt began his presentation by asking: Why should one consider treating multiple myeloma patients with additional therapy beyond what we usually call induction therapy?
Dr. Giralt listed a number of potential rationales. First of all, additional therapy definitely increases the time that patients stay in remission after their first round of initial therapy, which minimizes the burden of the disease on the patient. In many patients, this also means avoiding damage to the patient's organs that can result from myeloma when it is not in remission.
Second, additional therapy can help eliminate myeloma cells that may have remained dormant in the patient's body after the first round of treatment -- even in cases where the first round may have achieved what seems to be a complete response.
What are the potential downsides to continued therapy after initial induction therapy? There is, of course, the potential side effects of the therapy. Additional therapy may also create myeloma cell mutations that are more resistant to future myeloma treatments the patient might receive. And, of course, there also may be financial implications of additional therapy.
Even with these potential downsides, Dr. Giralt believes it make sense to do additional therapy beyond just initial induction therapy. The fact is that, even in the age of novel myeloma therapies like Revlimid and Velcade (bortezomib), initial induction therapy still achieves a complete response in less than 50 percent of all patients. Additional therapy -- whether it's a stem cell transplant, consolidation therapy, or maintenance therapy -- increases the share of patients achieving complete response, and these additional rounds of therapy have definitely been shown to increase progression free survival, and there is increasing evidence that overall survival also may be increased.
The new myeloma therapies also are much safer than older therapies, making it harder to argue that extended treatment is not worth the extra potential survival benefit.
Near the end of his presentation, Dr. Giralt turned to an important question related to extended (continuous) therapy for myeloma patients, namely: Is it better to do stem cell transplants earlier or later in a patient's treatment plan? Dr. Giralt says the only real data on this question so far is the study done recently by Dr. David Siegel of the John Theurer Cancer Center in New Jersey, and, although the study is not perfect, it shows a benefit to doing transplants earlier rather than later. This is also Dr. Giralt's preference in the matter. (The Beacon's article about the Siegel study is available here: https://myelomabeacon.org/news/2010/12/17/early-stem-cell-transplantation-may-improve-survival-in-newly-diagnosed-multiple-myeloma-patients-ash-2010/ .)
The last presentation during the Celgene symposium was by Dr. Kenneth Anderson of the Dana Farber Cancer Institute in Boston. Dr. Anderson spoke mainly about new myeloma treatments that are still under development. Many of his comments mirrored those that he made in a recent interview with The Myeloma Beacon (see link below). He discussed elotuzumab, saying it is likely to be used in combination wiih Revlimid and dexamethasone. He also mentioned perifosine, which probably will be used in combination with Velcade. Similarly, panobinostat and Zolinza (vorinostat) are likely to be used in combination with either Velcade or carfilzomib (assuming it eventually is approved by the FDA).
Carfilzomib and pomalidomide are likely to be sufficiently active against myeloma, Dr. Anderson believes, that they could be used on their own (typically with dexamethasone), or together with dexamethasone and one of the newer agents such as thalidomide, Revlimid, or Velcade.
(The Beacon interview with Dr. Anderson, in which he discusses potential new myeloma drugs, can be viewed here: https://myelomabeacon.org/news/2011/02/28/thought-leader-perspective-dr-kenneth-anderson-on-the-future-of-multiple-myeloma-treatment/ .)
One of those two presentations was by Dr. Sergio Giralt of Memorial Sloan-Kettering in New York. He discussed "The Evidence Supporting Continuous Therapy in Multiple Myeloma."
Dr. Giralt began his presentation by asking: Why should one consider treating multiple myeloma patients with additional therapy beyond what we usually call induction therapy?
Dr. Giralt listed a number of potential rationales. First of all, additional therapy definitely increases the time that patients stay in remission after their first round of initial therapy, which minimizes the burden of the disease on the patient. In many patients, this also means avoiding damage to the patient's organs that can result from myeloma when it is not in remission.
Second, additional therapy can help eliminate myeloma cells that may have remained dormant in the patient's body after the first round of treatment -- even in cases where the first round may have achieved what seems to be a complete response.
What are the potential downsides to continued therapy after initial induction therapy? There is, of course, the potential side effects of the therapy. Additional therapy may also create myeloma cell mutations that are more resistant to future myeloma treatments the patient might receive. And, of course, there also may be financial implications of additional therapy.
Even with these potential downsides, Dr. Giralt believes it make sense to do additional therapy beyond just initial induction therapy. The fact is that, even in the age of novel myeloma therapies like Revlimid and Velcade (bortezomib), initial induction therapy still achieves a complete response in less than 50 percent of all patients. Additional therapy -- whether it's a stem cell transplant, consolidation therapy, or maintenance therapy -- increases the share of patients achieving complete response, and these additional rounds of therapy have definitely been shown to increase progression free survival, and there is increasing evidence that overall survival also may be increased.
The new myeloma therapies also are much safer than older therapies, making it harder to argue that extended treatment is not worth the extra potential survival benefit.
Near the end of his presentation, Dr. Giralt turned to an important question related to extended (continuous) therapy for myeloma patients, namely: Is it better to do stem cell transplants earlier or later in a patient's treatment plan? Dr. Giralt says the only real data on this question so far is the study done recently by Dr. David Siegel of the John Theurer Cancer Center in New Jersey, and, although the study is not perfect, it shows a benefit to doing transplants earlier rather than later. This is also Dr. Giralt's preference in the matter. (The Beacon's article about the Siegel study is available here: https://myelomabeacon.org/news/2010/12/17/early-stem-cell-transplantation-may-improve-survival-in-newly-diagnosed-multiple-myeloma-patients-ash-2010/ .)
The last presentation during the Celgene symposium was by Dr. Kenneth Anderson of the Dana Farber Cancer Institute in Boston. Dr. Anderson spoke mainly about new myeloma treatments that are still under development. Many of his comments mirrored those that he made in a recent interview with The Myeloma Beacon (see link below). He discussed elotuzumab, saying it is likely to be used in combination wiih Revlimid and dexamethasone. He also mentioned perifosine, which probably will be used in combination with Velcade. Similarly, panobinostat and Zolinza (vorinostat) are likely to be used in combination with either Velcade or carfilzomib (assuming it eventually is approved by the FDA).
Carfilzomib and pomalidomide are likely to be sufficiently active against myeloma, Dr. Anderson believes, that they could be used on their own (typically with dexamethasone), or together with dexamethasone and one of the newer agents such as thalidomide, Revlimid, or Velcade.
(The Beacon interview with Dr. Anderson, in which he discusses potential new myeloma drugs, can be viewed here: https://myelomabeacon.org/news/2011/02/28/thought-leader-perspective-dr-kenneth-anderson-on-the-future-of-multiple-myeloma-treatment/ .)
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Boris Simkovich - Name: Boris Simkovich
Founder
The Myeloma Beacon
Re: IMW 2011 Multiple Myeloma Discussion - Day 2
The third session of presentations today focused on the biology and treatment of high-risk multiple myeloma. Many of these presentations were quite technical, focusing on advanced aspects of the biology of high-risk multiple myeloma. As I've mentioned in at least one earlier session summary, these kinds of discussions often are more relevant to the longer-term development of future myeloma treatments. Nevertheless, despite the technical nature of these discussions, there were many findings and themes that directly bear on the treatment of multiple myeloma patients today.
For example, in the first presentation, "t(4;14) and Genomic Instability in High-Risk Myeloma," Dr. Leif Bergsagel of the Mayo Clinic in Arizona reported results of lab research he's done that show that using lower-than-optimal drug doses when treating myeloma can lead to more rapid recurrence of the disease and shorter survival times. He also said his research leads him to believe that combining a so-called HDAC-inhibitor, such as Zolinza (vorinostat) or panobinostat, with Velcade may be a viable approach for patients who have developed resistance to Velcade therapy on its own.
Dr. Keith Stewart also shared a number of practical ideas in his presentation on "Whole Genome Analysis in High Risk Multiple Myeloma." The presentation was unusual in that it focused on data from just a single multiple myeloma patient. The patient, however, had entire genome sequences done a total of four times during the course of her treatment, providing researchers with significant insight into the way myeloma -- in this case, high-risk myeloma -- reacts to a number of different treatments.
Based on the experience with this high-risk patient and other work he has done, Dr. Stewart believes that it is probably best to treat high-risk myeloma with a combination of several drugs. He also thinks there is evidence that just because a high-risk patient does not respond at one point during their treatment to a particular drug regimen this does not mean they will not respond to the same drug regimen at a later time. The characteristics of their disease can vary quite a bit over time.
In addition, Dr. Stewart believes high-risk patients have relatively unstable DNA -- this is partly what makes the characteristics of their disease vary a lot over time. However, the instability of the DNA means that it may be risky to treat them with drugs that can damage DNA, thereby causing further mutations and potentially shortening time to progression. Common myeloma drugs that can damage DNA include melphalan (Alkeran) and cyclophosphamide (Cytoxan).
Dr. Bart Barlogie of the University of Arkansas for Medical Sciences (UAMS) described in his presentation how UAMS researchers define high-risk myeloma. He said that research done at UAMS leads him to believe that about 15 percent of all myeloma patients with active myeloma are properly categorized as high risk.
At the same time, Dr. Barlogie believes that even low-risk patients eventually develop characteristics that are very similar to the characteristics high-risk patients have when they're first diagnosed. Low-risk patients develop the same characterstics, Dr. Barlogie believes, later as their disease progresses.
This is just one of the reasons Dr. Barlogie feels it is so important that researchers start working harder on understanding how best to treat high-risk myeloma. If they can develop better treatments for high-risk myeloma patients, they also may then have better options for low-risk patients when they have progressed to a disease state which, today, is difficult to treat.
Dr. Barlogie's presentation was followed by one given by Dr. Gareth Morgan of the Royal Marsden Hospital in the United Kingdom. His presentation summarized research by Dr. Morgan and his colleagues into the genetic mutations correlated with poor prognosis in myeloma patients. A key finding Dr. Morgan presented is that, apparently, having the t(4;14) genetic mutation by itself is not nearly as negative for a patient's prognosis as previously thought. Instead, it appears that the reason patients with the t(4;14) mutation often have a poor prognosis is because they have additional mutations that, together with the t(4;14) mutation, cause a poor prognosis.
Dr. Morgan's finding suggests that a patient who has only a t(4;14) mutation -- with no other mutations -- may not have a prognosis that is much different than that of a traditional low-risk myeloma patient.
The last presentation during this session was by Dr. Herman Einsele of the University Hospital of Würzburg, Germany, who discussed "Allogeneic Transplantation for High-Risk Multiple Myeloma." Allogeneic ("allo") transplants are stem cell transplants where patients receive stem cells from a donor. This is different than the most common type of stem cell transplant for myeloma patients -- autologous ("auto") stem cell transplants -- where a patient's own stem cells are re-transplanted into the patient.
Dr. Einsele started off with some basic observations. He said that, in his opinion, sound evidence exists that allogeneic transplants do have an anti-myeloma effect, and that they can, in fact, be curative. The question that is harder to answer right now, however, is whether allogeneic transplants should be a standard consideration for high-risk myeloma patients.
To explain why the question is difficult to answer, Dr. Einsele reviewed the results of five trials with evidence that bears on the issue. The evidence is conflicting not only because some trials have results supportive of the use of allo transplants, while others do not. It is conflicting as well because the trials have been small; most of them did not separate patients into high-risk and low-risk subgroups; and few (if any) of the trials made use of newer myeloma treatments such as Revlimid (lenalidomide) or Velcade (bortezomib).
Most of the trials reviewed by Dr. Einsele examine whether an allo transplant is better or worse for myeloma patients than an auto transplant, In fact, the comparison in most trials is not just between auto and allo transplants. In most cases, the comparison is between a sequence of two auto transplants versus a regimen involving one auto transplant followed by an allo transplant.
Overall, Dr. Einsele reported that 3 of the 5 trials he reviewed support the use of allogeneic transplants as a treatment option for high-risk patients. In addition, it appears that the serious risks that were once commonly thought to be associated with allogeneic transplants have declined significantly as myeloma researchers have learned how to deal with those risks.
For these reasons, Dr. Einsele believes that allo transplantation should be viewed as a legitimate treatment option for high-risk myeloma patients.
For example, in the first presentation, "t(4;14) and Genomic Instability in High-Risk Myeloma," Dr. Leif Bergsagel of the Mayo Clinic in Arizona reported results of lab research he's done that show that using lower-than-optimal drug doses when treating myeloma can lead to more rapid recurrence of the disease and shorter survival times. He also said his research leads him to believe that combining a so-called HDAC-inhibitor, such as Zolinza (vorinostat) or panobinostat, with Velcade may be a viable approach for patients who have developed resistance to Velcade therapy on its own.
Dr. Keith Stewart also shared a number of practical ideas in his presentation on "Whole Genome Analysis in High Risk Multiple Myeloma." The presentation was unusual in that it focused on data from just a single multiple myeloma patient. The patient, however, had entire genome sequences done a total of four times during the course of her treatment, providing researchers with significant insight into the way myeloma -- in this case, high-risk myeloma -- reacts to a number of different treatments.
Based on the experience with this high-risk patient and other work he has done, Dr. Stewart believes that it is probably best to treat high-risk myeloma with a combination of several drugs. He also thinks there is evidence that just because a high-risk patient does not respond at one point during their treatment to a particular drug regimen this does not mean they will not respond to the same drug regimen at a later time. The characteristics of their disease can vary quite a bit over time.
In addition, Dr. Stewart believes high-risk patients have relatively unstable DNA -- this is partly what makes the characteristics of their disease vary a lot over time. However, the instability of the DNA means that it may be risky to treat them with drugs that can damage DNA, thereby causing further mutations and potentially shortening time to progression. Common myeloma drugs that can damage DNA include melphalan (Alkeran) and cyclophosphamide (Cytoxan).
Dr. Bart Barlogie of the University of Arkansas for Medical Sciences (UAMS) described in his presentation how UAMS researchers define high-risk myeloma. He said that research done at UAMS leads him to believe that about 15 percent of all myeloma patients with active myeloma are properly categorized as high risk.
At the same time, Dr. Barlogie believes that even low-risk patients eventually develop characteristics that are very similar to the characteristics high-risk patients have when they're first diagnosed. Low-risk patients develop the same characterstics, Dr. Barlogie believes, later as their disease progresses.
This is just one of the reasons Dr. Barlogie feels it is so important that researchers start working harder on understanding how best to treat high-risk myeloma. If they can develop better treatments for high-risk myeloma patients, they also may then have better options for low-risk patients when they have progressed to a disease state which, today, is difficult to treat.
Dr. Barlogie's presentation was followed by one given by Dr. Gareth Morgan of the Royal Marsden Hospital in the United Kingdom. His presentation summarized research by Dr. Morgan and his colleagues into the genetic mutations correlated with poor prognosis in myeloma patients. A key finding Dr. Morgan presented is that, apparently, having the t(4;14) genetic mutation by itself is not nearly as negative for a patient's prognosis as previously thought. Instead, it appears that the reason patients with the t(4;14) mutation often have a poor prognosis is because they have additional mutations that, together with the t(4;14) mutation, cause a poor prognosis.
Dr. Morgan's finding suggests that a patient who has only a t(4;14) mutation -- with no other mutations -- may not have a prognosis that is much different than that of a traditional low-risk myeloma patient.
The last presentation during this session was by Dr. Herman Einsele of the University Hospital of Würzburg, Germany, who discussed "Allogeneic Transplantation for High-Risk Multiple Myeloma." Allogeneic ("allo") transplants are stem cell transplants where patients receive stem cells from a donor. This is different than the most common type of stem cell transplant for myeloma patients -- autologous ("auto") stem cell transplants -- where a patient's own stem cells are re-transplanted into the patient.
Dr. Einsele started off with some basic observations. He said that, in his opinion, sound evidence exists that allogeneic transplants do have an anti-myeloma effect, and that they can, in fact, be curative. The question that is harder to answer right now, however, is whether allogeneic transplants should be a standard consideration for high-risk myeloma patients.
To explain why the question is difficult to answer, Dr. Einsele reviewed the results of five trials with evidence that bears on the issue. The evidence is conflicting not only because some trials have results supportive of the use of allo transplants, while others do not. It is conflicting as well because the trials have been small; most of them did not separate patients into high-risk and low-risk subgroups; and few (if any) of the trials made use of newer myeloma treatments such as Revlimid (lenalidomide) or Velcade (bortezomib).
Most of the trials reviewed by Dr. Einsele examine whether an allo transplant is better or worse for myeloma patients than an auto transplant, In fact, the comparison in most trials is not just between auto and allo transplants. In most cases, the comparison is between a sequence of two auto transplants versus a regimen involving one auto transplant followed by an allo transplant.
Overall, Dr. Einsele reported that 3 of the 5 trials he reviewed support the use of allogeneic transplants as a treatment option for high-risk patients. In addition, it appears that the serious risks that were once commonly thought to be associated with allogeneic transplants have declined significantly as myeloma researchers have learned how to deal with those risks.
For these reasons, Dr. Einsele believes that allo transplantation should be viewed as a legitimate treatment option for high-risk myeloma patients.
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Boris Simkovich - Name: Boris Simkovich
Founder
The Myeloma Beacon
Re: IMW 2011 Multiple Myeloma Discussion - Day 2
The session on high-risk myeloma was followed today by a session that was quite different from the previous sessions at the Workshop. The session was a debate between two well-known multiple myeloma researchers: Dr. Maria-Victoria Mateos of the University Hospital of Salamanca, Spain, and Dr. Sagar Lonial of Emory University.
The question addressed during the debate was: Should we treat some patients with Stage I (smoldering) multiple myeloma?
Dr. Mateos presented her position on the question first, arguing that some smoldering myeloma patients should be treated.
Dr. Mateos first reviewed some key information about smoldering myeloma. She said that data are clear that it is not a uniform disease. Ten percent of smoldering myeloma patients each year progress to active myeloma in the first five years after initial diagnosis. After five years, another three percent per year progress during the next five years. After that, only about one percent per year progress.
Thus, it is clearly the case that there are some smoldering myeloma patients at initial diagnosis who have a much higher chance of progressing to active myeloma than other smoldering myeloma patients.
And, in fact, characteristics have been identified that predict whether a smoldering myeloma patient is likely to progress sooner rather than later to active myeloma.
Dr. Mateos believes that it is high-risk smoldering myeloma patients that should be treated, and she went on to explain why she believes this.
The key evidence she relied on was from a Spanish trial that is still ongoing. The trial involves high-risk smoldering myeloma patients who have been randomly assigned to one of two "treatment" options. One group of patients is given an initial round of treatment with Revlimid (lenalidomide) and dexamethasone, followed by maintenance therapy with Revlimid by itself. The other group of patients gets no treatment whatsoever.
Treatment with Revlimid is definitely affecting whether or not patients progress to active disease. Among the patients receiving Revlimid, only 10 percent so far have progressed to active disease. In contrast, 46 percent of the patients receiving no treatment have progressed to active myeloma.
Even more importantly, Dr. Mateos announced at the Workshop that the data from the trial now show a statistically significant survival benefit in favor of treatment with Revlimid.
Dr. Mateos went on to say that the side effects of the Revlimid treatment have not been very significant. There was at one point concern because two patients (3.5 percent) in the Revlimid arm developed secondary cancers, while no secondary cancers developed among the no-treatment patients. However, closer analysis of the two cases of secondary cancer indicate that the patients probably already had the cancers -- or initial stages of the cancer -- when they started treatment with Revlimid, indicating that the Revlimid treatment most likely was not responsible for the secondary cancers.
After Dr. Mateos finished her presentation, Dr. Lonial argued in his presentation that, although he is sympathetic to Dr. Mateos's argument, he believes physicians still should be hesitant to treat smoldering myeloma patients for their disease -- even high-risk smoldering patients.
The key point, Dr. Lonial argued, is that smoldering myeloma patients have no symptoms of myeloma whatsoever. By treating these patients, physicians automatically will make many of the patients feel worse than they did before treatment, due to the side effects of the treatment regimen they will receive.
On that front, Dr. Lonial noted that the side effects of the treatment received by patients in Dr. Mateos's clinical trial were hardly negligible. Some rather uncomfortable, even serious, side effects were experienced by relatively large numbers of patients. Are those side effects worth the (marginally) statistically significant improvement in overall survival that has appeared in the trial results Dr. Mateos presented? Would there still be a benefit to treatment with Revlimid if patient quality of life also was tracked in the trial, not just progression and overall survival?
To bolster his argument, Dr. Lonial noted that consensus guidelines for the treatment of smoldering myeloma clearly state that no smoldering myeloma patients should be treated before their disease progresses. These guidelines were developed even though physicians have long been aware that not all smoldering myeloma patients are alike; that is, that some smoldering patients have a considerably higher risk of progressing to active disease than others.
Finally, Dr. Lonial noted the trial Dr. Mateos described is probably flawed because of the inclusion of dexamethasone in the treatment given to the treated patients. The dexamethasone, in particular, causes many undesirable side effects.
Thus, Dr. Lonial feels a better trial would be one that has only Revlimid as the tested treatment, and he also believes the trial should include both high-risk as well as medium-risk patients.
And, in fact, Dr. Lonial is currently leading a trial that has exactly this kind of design. Moreover, the trial is tracking measures of patient quality of life.
It was not entirely clear in the discussion that followed the debate if the audience was swayed by the data presented by Dr. Mateos. The data certainly seemed to make many in the audience receptive to her position. It may take more data from the Spanish trial, however, to actually change standard treatment practices.
The question addressed during the debate was: Should we treat some patients with Stage I (smoldering) multiple myeloma?
Dr. Mateos presented her position on the question first, arguing that some smoldering myeloma patients should be treated.
Dr. Mateos first reviewed some key information about smoldering myeloma. She said that data are clear that it is not a uniform disease. Ten percent of smoldering myeloma patients each year progress to active myeloma in the first five years after initial diagnosis. After five years, another three percent per year progress during the next five years. After that, only about one percent per year progress.
Thus, it is clearly the case that there are some smoldering myeloma patients at initial diagnosis who have a much higher chance of progressing to active myeloma than other smoldering myeloma patients.
And, in fact, characteristics have been identified that predict whether a smoldering myeloma patient is likely to progress sooner rather than later to active myeloma.
Dr. Mateos believes that it is high-risk smoldering myeloma patients that should be treated, and she went on to explain why she believes this.
The key evidence she relied on was from a Spanish trial that is still ongoing. The trial involves high-risk smoldering myeloma patients who have been randomly assigned to one of two "treatment" options. One group of patients is given an initial round of treatment with Revlimid (lenalidomide) and dexamethasone, followed by maintenance therapy with Revlimid by itself. The other group of patients gets no treatment whatsoever.
Treatment with Revlimid is definitely affecting whether or not patients progress to active disease. Among the patients receiving Revlimid, only 10 percent so far have progressed to active disease. In contrast, 46 percent of the patients receiving no treatment have progressed to active myeloma.
Even more importantly, Dr. Mateos announced at the Workshop that the data from the trial now show a statistically significant survival benefit in favor of treatment with Revlimid.
Dr. Mateos went on to say that the side effects of the Revlimid treatment have not been very significant. There was at one point concern because two patients (3.5 percent) in the Revlimid arm developed secondary cancers, while no secondary cancers developed among the no-treatment patients. However, closer analysis of the two cases of secondary cancer indicate that the patients probably already had the cancers -- or initial stages of the cancer -- when they started treatment with Revlimid, indicating that the Revlimid treatment most likely was not responsible for the secondary cancers.
After Dr. Mateos finished her presentation, Dr. Lonial argued in his presentation that, although he is sympathetic to Dr. Mateos's argument, he believes physicians still should be hesitant to treat smoldering myeloma patients for their disease -- even high-risk smoldering patients.
The key point, Dr. Lonial argued, is that smoldering myeloma patients have no symptoms of myeloma whatsoever. By treating these patients, physicians automatically will make many of the patients feel worse than they did before treatment, due to the side effects of the treatment regimen they will receive.
On that front, Dr. Lonial noted that the side effects of the treatment received by patients in Dr. Mateos's clinical trial were hardly negligible. Some rather uncomfortable, even serious, side effects were experienced by relatively large numbers of patients. Are those side effects worth the (marginally) statistically significant improvement in overall survival that has appeared in the trial results Dr. Mateos presented? Would there still be a benefit to treatment with Revlimid if patient quality of life also was tracked in the trial, not just progression and overall survival?
To bolster his argument, Dr. Lonial noted that consensus guidelines for the treatment of smoldering myeloma clearly state that no smoldering myeloma patients should be treated before their disease progresses. These guidelines were developed even though physicians have long been aware that not all smoldering myeloma patients are alike; that is, that some smoldering patients have a considerably higher risk of progressing to active disease than others.
Finally, Dr. Lonial noted the trial Dr. Mateos described is probably flawed because of the inclusion of dexamethasone in the treatment given to the treated patients. The dexamethasone, in particular, causes many undesirable side effects.
Thus, Dr. Lonial feels a better trial would be one that has only Revlimid as the tested treatment, and he also believes the trial should include both high-risk as well as medium-risk patients.
And, in fact, Dr. Lonial is currently leading a trial that has exactly this kind of design. Moreover, the trial is tracking measures of patient quality of life.
It was not entirely clear in the discussion that followed the debate if the audience was swayed by the data presented by Dr. Mateos. The data certainly seemed to make many in the audience receptive to her position. It may take more data from the Spanish trial, however, to actually change standard treatment practices.
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Boris Simkovich - Name: Boris Simkovich
Founder
The Myeloma Beacon
7 posts
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