I write on behalf of my wife, diagnosed Sep 2012, auto stem cell transplant (SCT) Feb 2013. She is considered very high risk due to the presence of both the del(17p) and t(4;14) genetic anomalies by FISH.
We would like to get her into a clinical trial with agents that look promising for high-risk disease, such as the anti-CD38 monoclonal antibodies. What we have found is that she is not eligible for any trials at all because she does not (yet) meet the criteria for "relapsed or refractory" disease. She is still quite healthy and meets all other eligibility criteria and has none of the exclusionary factors of any of the trials we've examined.
This seems very unfair. It looks like the trial investigators want either newly diagnosed patients (a blank slate on which to work) or those who have exhausted most approved agents and are now desperate. Anybody in between is left out. It seems to me that the patient should be allowed to determine (in consultation with competent physicians) whether the risk/benefit ratio of a given trial is acceptable to him/her.
Here are other details of my wife's case:
Induction - 3 cycles of Vd followed by 2 cycles of RVd reduced M-spike from 3.33 to 0.46 g/dL (VGPR) and reduced bone marrow plasma cell fraction from 65% to 5%.
Auto SCT - essentially no effect. M spike remained near 0.5 (minimum post-SCT M protein 0.43 g/dL at day +74) and BM plasma cell fraction 3%. Same genetic anomalies by FISH.
Post-SCT - maintenance therapy with Rd then Vd then weekly CyBorD, the latter for 6 months through Jan 2014. Nothing had much effect, with M spike stable near 0.5 g/dL until Nov 2013 (9 months post-SCT).
Recent - Since Nov 2013 (SCT+9 months), M spike has slowly and steadily increased to 0.7 g/dL. In late Jan 2014, switched from weekly CyBorD to VRd (weekly Velcade 1.3mg/m2 and dex 20gm; Revlimid 10mg days 1-14 of 21) with little effect.
She has IgG-lambda myeloma. Uninvolved immunoglobulins always heavily suppressed, with IgM and kappa often undetectable. IgG in normal range since induction, but now increasing slowly. Lambda down from 774 mg/L at dx to 20 mg/L pre-SCT, then 22-37 until SCT+9 months, now rising and currently 52 mg/L.
The problem with the trials is that the M spike has not yet risen by 0.5 g/dL from its minimum, which is the formal criterion for progression. We have had second opinions from two myeloma experts, and they confirm that she is ineligible for trials until passing that mark. The presence of high-risk genetic anomalies is not a consideration for the trial investigators, but it is for us.
Why should we have to wait until the disease becomes more firmly established and difficult to treat to get access to the most promising treatments?
I have read papers reporting on trials that used "relapsed/refractory" patients. The responses are often poor, with a majority having no response at all. Yet when the same drugs are later tried on newly diagnosed patients, nearly all of them respond. Waiting seems like a bad idea.
Thanks for any opinions or different experiences.
Regards,
Larry
Forums
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LarryD - Name: Larry D'Addario
- Who do you know with myeloma?: wife
- When were you/they diagnosed?: September 2012
- Age at diagnosis: 65
Re: Why am I excluded from all clinical trials?
Hi Larry,
I can certainly understand your frustration.
A couple of things occur to me as I read through your note.
1. Have you considered a Pomalyst or Kyprolis-based approach to treatment? There are some encouraging results for high-risk patients that have used these approaches:
https://myelomabeacon.org/news/2013/04/10/pomalyst-low-dose-dexamethasone-high-risk-relapsed-myeloma-imw-2013/
MAB-based approaches aren't the only promising new game in town for high risk patients, although I can understand why you might find them to be appealing.
2. Which specific Anti-CD38 trials are you looking at? I can see that she would be technically disqualified from the SAR650984 trial given the 0.5g/dL M-Spike minimum rqt. But have you looked into the daratumumab trial? It doesn't spell out this same 0.5g/dL M-Spike rqt.
I can certainly understand your frustration.
A couple of things occur to me as I read through your note.
1. Have you considered a Pomalyst or Kyprolis-based approach to treatment? There are some encouraging results for high-risk patients that have used these approaches:
https://myelomabeacon.org/news/2013/04/10/pomalyst-low-dose-dexamethasone-high-risk-relapsed-myeloma-imw-2013/
MAB-based approaches aren't the only promising new game in town for high risk patients, although I can understand why you might find them to be appealing.
2. Which specific Anti-CD38 trials are you looking at? I can see that she would be technically disqualified from the SAR650984 trial given the 0.5g/dL M-Spike minimum rqt. But have you looked into the daratumumab trial? It doesn't spell out this same 0.5g/dL M-Spike rqt.
Last edited by Multibilly on Sun Apr 06, 2014 10:02 pm, edited 1 time in total.
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Multibilly - Name: Multibilly
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: Smoldering, Nov, 2012
Re: Why am I excluded from all clinical trials?
Hello from gray Seattle Larry,
Great question and one that I am sure many myeloma patients (and their doctors) have stuggled with.
I think the key issue is that most studies are designed to prove (answer) a specific hypothesis (question). In studies regarding treatments for relapsed and refractory (RR) myeloma, there must be very specific rules as to what defines a patient who has RR myeloma. Guidelines for the definition of RR myeloma have been defined by international groups of expert myeloma doctors. I will put one of the current guidelines at the end of this post.
If researchers dont use the same rules for what constitutes relapse and what does not, then research results cannot be compared or fairly analyzed alongside other studies. For purposes of getting a new drug approved, the FDA requires these rules be incorporated into all studies. Some studies require an M-spike of 0.5 and others require 1.0 to meet the RR criteria. The entry criteria for a study are always strictly followed. If an investigator was caught "bending" the rules, he/she could be jailed and the research center could be closed down or severely punished by the federal government.
2011 International Myeloma Working Group (IMWG) Definition of Clinical Relapse of Myeloma
Clinical relapse is defined using the definition of clinical relapse in the IMWG criteria.. In the IMWG criteria, clinical relapse is defined as requiring one or more of the following direct indicators of increasing disease and/or end-organ dysfunction that are considered related to the underlying plasma cell proliferative disorder:
1. Development of new soft tissue plasmacytomas or bone lesions on skeletal survey, magnetic resonance imaging, or other imaging
2. Definite increase in the size of existing plasmacytomas or bone lesions. A definite increase is defined as a 50% (and at least 1 cm) increase as measured serially by the sum of the products of the cross-diameters of the measurable lesion
3. Hypercalcemia ( >11.5 mg/dL; > 2.875mM/L)
4. Decrease in hemoglobin of more than 2 g/dL (1.25mM) or to less than 10 g/dL
5. Rise in serum creatinine by more than or equal to 2 mg/dL (> 177mM/L)
6. Hyperviscosity
In patients who do not have clinical relapse, a significant paraprotein relapse is defined as doubling of the M-component in 2 consecutive measurements separated by less than or equal to 2 months; or an increase in the absolute levels of serum M protein by more than or equal to 1 g/dL, or urine M-protein by more than or equal to 500 mg/24 hours, or involved FLC level by more than or equal to 20 mg/dL (plus an abnormal FLC ratio) in 2 consecutive measurements separated by less than or equal to 2 months. This definition of “paraprotein relapse” represents the rate of rise or absolute level of increase in M protein at which the panel considered that myeloma therapy should be restarted in relapsing patients in clinical practice, even if signs and symptoms of new end-organ damage are not yet apparent.
Rajkumar. Blood. 2011;117(18):4691-4695)
*Durie BGM, Harousseau J-L, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20(9):1467-1473.
Great question and one that I am sure many myeloma patients (and their doctors) have stuggled with.
I think the key issue is that most studies are designed to prove (answer) a specific hypothesis (question). In studies regarding treatments for relapsed and refractory (RR) myeloma, there must be very specific rules as to what defines a patient who has RR myeloma. Guidelines for the definition of RR myeloma have been defined by international groups of expert myeloma doctors. I will put one of the current guidelines at the end of this post.
If researchers dont use the same rules for what constitutes relapse and what does not, then research results cannot be compared or fairly analyzed alongside other studies. For purposes of getting a new drug approved, the FDA requires these rules be incorporated into all studies. Some studies require an M-spike of 0.5 and others require 1.0 to meet the RR criteria. The entry criteria for a study are always strictly followed. If an investigator was caught "bending" the rules, he/she could be jailed and the research center could be closed down or severely punished by the federal government.
2011 International Myeloma Working Group (IMWG) Definition of Clinical Relapse of Myeloma
Clinical relapse is defined using the definition of clinical relapse in the IMWG criteria.. In the IMWG criteria, clinical relapse is defined as requiring one or more of the following direct indicators of increasing disease and/or end-organ dysfunction that are considered related to the underlying plasma cell proliferative disorder:
1. Development of new soft tissue plasmacytomas or bone lesions on skeletal survey, magnetic resonance imaging, or other imaging
2. Definite increase in the size of existing plasmacytomas or bone lesions. A definite increase is defined as a 50% (and at least 1 cm) increase as measured serially by the sum of the products of the cross-diameters of the measurable lesion
3. Hypercalcemia ( >11.5 mg/dL; > 2.875mM/L)
4. Decrease in hemoglobin of more than 2 g/dL (1.25mM) or to less than 10 g/dL
5. Rise in serum creatinine by more than or equal to 2 mg/dL (> 177mM/L)
6. Hyperviscosity
In patients who do not have clinical relapse, a significant paraprotein relapse is defined as doubling of the M-component in 2 consecutive measurements separated by less than or equal to 2 months; or an increase in the absolute levels of serum M protein by more than or equal to 1 g/dL, or urine M-protein by more than or equal to 500 mg/24 hours, or involved FLC level by more than or equal to 20 mg/dL (plus an abnormal FLC ratio) in 2 consecutive measurements separated by less than or equal to 2 months. This definition of “paraprotein relapse” represents the rate of rise or absolute level of increase in M protein at which the panel considered that myeloma therapy should be restarted in relapsing patients in clinical practice, even if signs and symptoms of new end-organ damage are not yet apparent.
Rajkumar. Blood. 2011;117(18):4691-4695)
*Durie BGM, Harousseau J-L, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20(9):1467-1473.
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Dr. Edward Libby - Name: Edward Libby, M.D.
Beacon Medical Advisor
Re: Why am I excluded from all clinical trials?
Multibilly wrote: "2. Which specific Anti-CD38 trials are you looking at? I can see that she would be technically disqualified from the SAR650984 trial given the 0.5g/dL M-Spike minimum rqt. But have you looked into the daratumumab trial? It doesn't spell out this same 0.5g/dL M-Spike ."
Dear Multibilly,
The published trial descriptions (e.g., at clinicaltrials.gov) usually don't give specific numbers in the eligibility criteria, but when they say "relapsed/refractory," what they actually use are the IMWG critera for relapse or progression. I have telephoned a couple of them and that's what I've been told.
I was told by a myeloma expert that this is true for virtually all trials, so my wife is not eligible for any of them. This also agrees with Dr. Libby's response to my post. My wife is obviously not eligible for those trials that want newly diagnosed patients. The problem is that I can't find anything that accepts people who are in between.
Dr. Edward Libby wrote: "I think the key issue is that most studies are designed to prove (answer) a specific hypothesis (question). In studies regarding treatments for relapsed and refractory (RR) myeloma there must be very specific rules as to what defines a patient who has RR myeloma."
Dear Dr. Libby,
Thanks very much for your response. Yes, I'm familiar with the IMWG criteria and I understand the need to standardize response measurements and to a lesser extent selection criteria in clinical trials. My question was far more basic: WHY are nearly all trials seeking only relapsed/refractory patients or newly diagnosed patients?
For those that want only newly diagnosed patients, I can see a benefit to the research from having a "clean slate," avoiding confusion from treatments not being studied. But what could possibly be the benefit of restricting enrollment only to relapsed/refractory patients? Even if there is *sometimes* a good reason for this, why does there *never* seem to be any interest in studying those who have measurable disease but are not yet in strong progression? From my searches, this seems to be true for trials at all phases.
Regards,
Larry
Dear Multibilly,
The published trial descriptions (e.g., at clinicaltrials.gov) usually don't give specific numbers in the eligibility criteria, but when they say "relapsed/refractory," what they actually use are the IMWG critera for relapse or progression. I have telephoned a couple of them and that's what I've been told.
I was told by a myeloma expert that this is true for virtually all trials, so my wife is not eligible for any of them. This also agrees with Dr. Libby's response to my post. My wife is obviously not eligible for those trials that want newly diagnosed patients. The problem is that I can't find anything that accepts people who are in between.
Dr. Edward Libby wrote: "I think the key issue is that most studies are designed to prove (answer) a specific hypothesis (question). In studies regarding treatments for relapsed and refractory (RR) myeloma there must be very specific rules as to what defines a patient who has RR myeloma."
Dear Dr. Libby,
Thanks very much for your response. Yes, I'm familiar with the IMWG criteria and I understand the need to standardize response measurements and to a lesser extent selection criteria in clinical trials. My question was far more basic: WHY are nearly all trials seeking only relapsed/refractory patients or newly diagnosed patients?
For those that want only newly diagnosed patients, I can see a benefit to the research from having a "clean slate," avoiding confusion from treatments not being studied. But what could possibly be the benefit of restricting enrollment only to relapsed/refractory patients? Even if there is *sometimes* a good reason for this, why does there *never* seem to be any interest in studying those who have measurable disease but are not yet in strong progression? From my searches, this seems to be true for trials at all phases.
Regards,
Larry
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LarryD - Name: Larry D'Addario
- Who do you know with myeloma?: wife
- When were you/they diagnosed?: September 2012
- Age at diagnosis: 65
Re: Why am I excluded from all clinical trials?
Larry,
I see your point and I appreciate the education on the IMWG criteria for R/R patients in a trial setting. It has to be frustrating for you and your wife.
I see your point and I appreciate the education on the IMWG criteria for R/R patients in a trial setting. It has to be frustrating for you and your wife.
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Multibilly - Name: Multibilly
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: Smoldering, Nov, 2012
Re: Why am I excluded from all clinical trials?
Hi LarryD,
I am sorry to hear about the troubles your wife is having. Dr. Libby hit on the important points but I think you are overlooking an obvious point. The type of trials you are discussing get the drugs from the biotech/pharma companies. They are typically providing the drugs free of charge. Insurance companies/Medicare do not pay for the experimental drug.
"It seems to me that the patient should be allowed to determine (in consultation with competent physicians) whether the risk/benefit ratio of a given trial is acceptable to him/her."
Biotech/Pharma companies first responsibility is to make money for their shareholders/owners. It is difficult to expect them to provide a drug/therapy to any patient/doctor that wants to use it without getting compensated. Providing drugs free of charge is not in the best interest of their shareholders. I am not saying it is a perfect system or that I like it as a cancer patient. I have also heard antibodies are more expensive to manufacture than the typical drug like Revlimid.
The trials are designed to provide data to get the drug approved for a specific use and to test for safety issues. It is common for drug companies to get drugs approved for R/R patients in the US because they know once they are approved they will be prescribed off-label. There is a lesser standard provided for drugs that are approved for R/R patients. A good example was when carfilzomib was approved. There were/are questions about how much cardio toxicity there is associated with the drug but it was approved because the patient population for whom it was approved for had no other options. Giving the drug to a patient to help prevent relapse will not help the drug firm to get data for approval for use in R/R patients.
There was a case in the news relating to a small biotech firm called Chimerix recently. They are currently testing an antiviral drug to prevent a certain virus. A young leukemia patient already has the virus and his doctors wanted to try the drug as he had no other options. Fortunately he ultimately received the drug due to all the publicity the case received, but after reading the story I do understand why a small biotech cannot just provide a drug free of charge to anyone that wants to use it for a use they are not even trying to get the drug approved for.
It is a very complex issue. As a cancer patient I wish there was a perfect system but we have to try and do the best we can in the one we have. In the US patients have access to more drugs than patients in other countries do so it is hard to argue that our system is particularly bad for patients trying to access newer drugs/therapies.
Mark
I am sorry to hear about the troubles your wife is having. Dr. Libby hit on the important points but I think you are overlooking an obvious point. The type of trials you are discussing get the drugs from the biotech/pharma companies. They are typically providing the drugs free of charge. Insurance companies/Medicare do not pay for the experimental drug.
"It seems to me that the patient should be allowed to determine (in consultation with competent physicians) whether the risk/benefit ratio of a given trial is acceptable to him/her."
Biotech/Pharma companies first responsibility is to make money for their shareholders/owners. It is difficult to expect them to provide a drug/therapy to any patient/doctor that wants to use it without getting compensated. Providing drugs free of charge is not in the best interest of their shareholders. I am not saying it is a perfect system or that I like it as a cancer patient. I have also heard antibodies are more expensive to manufacture than the typical drug like Revlimid.
The trials are designed to provide data to get the drug approved for a specific use and to test for safety issues. It is common for drug companies to get drugs approved for R/R patients in the US because they know once they are approved they will be prescribed off-label. There is a lesser standard provided for drugs that are approved for R/R patients. A good example was when carfilzomib was approved. There were/are questions about how much cardio toxicity there is associated with the drug but it was approved because the patient population for whom it was approved for had no other options. Giving the drug to a patient to help prevent relapse will not help the drug firm to get data for approval for use in R/R patients.
There was a case in the news relating to a small biotech firm called Chimerix recently. They are currently testing an antiviral drug to prevent a certain virus. A young leukemia patient already has the virus and his doctors wanted to try the drug as he had no other options. Fortunately he ultimately received the drug due to all the publicity the case received, but after reading the story I do understand why a small biotech cannot just provide a drug free of charge to anyone that wants to use it for a use they are not even trying to get the drug approved for.
It is a very complex issue. As a cancer patient I wish there was a perfect system but we have to try and do the best we can in the one we have. In the US patients have access to more drugs than patients in other countries do so it is hard to argue that our system is particularly bad for patients trying to access newer drugs/therapies.
Mark
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Mark
Re: Why am I excluded from all clinical trials?
Yet another interesting discussion. Thanks for all the informative postings everyone. And sorry about the challenges you and your wife are facing, Larry.
Here are my two cents ...
Isn't the key question really: When do most myeloma specialists feel it is appropriate to start new treatment, or alter existing treatment, when a patient seems to be relapsing?
Do most wait until the patient has met the official criteria for relapse, as defined in the postings above, or do many change patients' treatments before they have officially relapsed?
If most myeloma specialists wait until a patient has officially relapsed to alter the patient's treatment, then the clinical trial rules simply reflect that approach. It may not be the approach that some specialists, and some patients, prefer. But it would be in line with the usual approach to treatment at or close to the time of relapse.
If, however, "standard" practice is different, and many specialists are changing patients' treatments as they are first showing signs of relapse, but before an official relapse has occurred, then perhaps the definition of relapse needs to be revisited.
Here are my two cents ...
Isn't the key question really: When do most myeloma specialists feel it is appropriate to start new treatment, or alter existing treatment, when a patient seems to be relapsing?
Do most wait until the patient has met the official criteria for relapse, as defined in the postings above, or do many change patients' treatments before they have officially relapsed?
If most myeloma specialists wait until a patient has officially relapsed to alter the patient's treatment, then the clinical trial rules simply reflect that approach. It may not be the approach that some specialists, and some patients, prefer. But it would be in line with the usual approach to treatment at or close to the time of relapse.
If, however, "standard" practice is different, and many specialists are changing patients' treatments as they are first showing signs of relapse, but before an official relapse has occurred, then perhaps the definition of relapse needs to be revisited.
Re: Why am I excluded from all clinical trials?
Thanks for the interesting discussion, and for the description of the criteria for clinical relapse, Dr. Libby. We have discussed this same set of guidelines with my doctor, and it's interesting to see that they are also used in the US.
I think that one reason why these trials are reserved for relapsed/resistant patients is that they are inherently risky for the patient. There is no guarantee that a clinical trial drug would be better for the patient than an already approved drug would be. Thus, the new drug testing is more reserved for people who really need to try a new drug.
That is a different scenario than for newly diagnosed multiple myeloma (NDMM) patients though, I guess.
I think that one reason why these trials are reserved for relapsed/resistant patients is that they are inherently risky for the patient. There is no guarantee that a clinical trial drug would be better for the patient than an already approved drug would be. Thus, the new drug testing is more reserved for people who really need to try a new drug.
That is a different scenario than for newly diagnosed multiple myeloma (NDMM) patients though, I guess.
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Nancy Shamanna - Name: Nancy Shamanna
- Who do you know with myeloma?: Self and others too
- When were you/they diagnosed?: July 2009
8 posts
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