January 20 2010 post. Last month, a study, presented at the 2009 American Society of Hematology meeting (see: http://tinyurl.com/yz965fc), was brought to my attention…a study concerning high-risk smoldering patients, i.e., patients who are NOT in the stable “watch and wait” category. This is an important distinction since, according to a 2007 Mayo Clinic NEJM-published study (see my January 11 post: this is an interesting study that, however, examines a relatively small SMM population, so it should be taken with a rather large side dish of caution…), only a small percentage of SMM patients progress to active myeloma every year.
The 2009 ASH study authors declare right at the beginning that Several small studies have explored the value of early treatment with either conventional agents (melphalan/prednisone) or novel drugs (thalidomide, interleukin-1b), with no clear benefit. It should be noted that these trials didn’t focus on high-risk sMM.
Notice these words: No Clear Benefit.
And now let’s see how the authors define a “high-risk” smoldering population:
Criterion A: at least 10% plasma cells in the bone marrow.
Criterion B: an M-component of at least 3 g/dL.
If only one criterion is present, then, according to these authors, a patient must have other “aberrant factors” in order to be classified as “high risk” (see above-mentioned abstract for details). Well, that would have excluded me from participating in this study. Even though I probably still have a decent amount of myeloma cells in my bone marrow, my M-spike has never gone as high as 3 grams/dL, and all my, er, factors are far from…aberrant.
Not that I would ever have accepted to be part of this study, and I will give you a few good reasons why:
- The study lasted from October 2006 to June 2008…not long enough to reach any conclusions, in my opinion, especially given what follows…
- Some of the 40 “high risk” smolderers who were given lenalidomide (=Revlimid) and dexamethasone suffered from severe side effects, as we will see in a second…
- Complete remission or CR was achieved by only 11% of the 40 patients mentioned in the abstract (there was also a 5% of stringent CRs, see http://tinyurl.com/y8ty9vr for more details on this type of remission). Okay, that’s four people, more or less (don’t you just love percentages? 11% of 40: 4.4 people…eh??? I’d be curious to know which part of that 0.4 person was in remission…)…oh let’s be generous, let’s say even five people in complete remission. But let’s look at the other numbers mentioned in the abstract: five patients developed what are called “serious adverse events” or SAE = gastrointestinal bleeding, delirium and glaucoma, two of these SAE patients left the study, in fact…and two other patients left at their own request…no details given as to why. Let’s add this up (math is not my forte, as you know, so you might want to double-check): five patients were affected by severe side effects, two left the study for unknown reasons, and four others were having problems such as asthenia, diarrhea and gastrointestinal bleeding. Now, according to my calculations, that’s eleven people with problems…compare that to the four, perhaps five, who achieved CR…out of a total of only forty patients…I don’t think I need to comment here…
- The abstract concludes that these preliminary results show that in sMM patients at high-risk for progression to active MM, delayed treatment is associated with early progression (median time 17.5 months) with bone disease, while so far Len-dex has been able not only to prolong the TTP (without any progression so far) but also to induce CRs with a manageable and acceptable toxicity profile. How “acceptable” was the “toxicity profile” for the smoldering patients who came down with delirium, glaucoma, gastrointestinal bleeding and infections? Uhm, just wondering…of course…!
- Last but not least. Celgene (the makers of Revlimid) was deeply involved in this study. In the abstract, check out number 21 on the list of hospitals/centers AND also the “Disclosures” section (=bottom of the abstract). You will find a list of 23 names: six, including the main author, are “Celgene Honoraria” recipients; two are Celgene employees (what the haaay???), and one belongs to the Celgene Speakers Bureau. So, let’s see: 9 people out of 23 are closely connected to Celgene…interesting…
This heavy involvement on the part of a pharmaceutical company made me suspicious right off the bat…And the following scenario popped into my head: if you saw a TV ad on a recently developed pesticide, would you trust the safety data provided by the pesticide company’s own spokespeople…enough to begin spraying this pesticide all over your vegetable garden? No, I didn’t think so…nor would I.
My own considerations: how would these patients be doing now if they had been given only curcumin and perhaps some of the non-toxic anti-myeloma plant-derived substances that I and others have been testing? You won’t get delirium or infections or glaucoma from curcumin or ashwagandha…
I rest my case.
Update, January 23 2010 post. At the end of the SMM abstract presented at ASH 2009 (see previous post), the authors write about a manageable and acceptable toxicity profile. I would like to take a closer look at this statement today. Let’s see. Many of these smoldering patients suffered from G3 adverse events…but what exactly does G3 mean?
Well, it just so happens that a fabulous blog reader (merci!) sent me a link to a grade toxicity chart that can help us understand what all these various levels (G1, G2, G3 and G4) mean: http://tinyurl.com/yfohksl
However, based on the way the ASH abstract is worded, I found it very difficult to figure out exactly how many patients experienced side effects. I am still not sure if I have counted them correctly, since there could be some overlap between the groups.
Well, let’s try to go through the abstract carefully:
- 7 patients experienced G3 side effects, such as G3 asthenia, which, incidentally, means that they were not able to work (=normal activity reduced by 50%)…
- 5 patients had severe (=G3) dexamethasone or lenalidomide-related symptoms. Of these, 3 patients developed gastrointestinal bleeding, glaucoma and infections from dexamethasone, the other 2 had infections from lenalidomide (no details provided). Since these patients had different G3 symptoms from the above-mentioned 7 patients, I presume that they are not the same patients. No overlap. Presumably.
- 4 patients had to reduce their dose of lenalidomide because of side effects such as fatigue, diarrhea and gastrointestinal bleeding. I don’t think this number includes the two patients who developed G3 infections (see previous point), since the infections experienced in this group do not appear to be so severe…Not super clear, though.
- 2 patients left the study at their own request: they were probably among the above-mentioned G3 sufferers. Again, this is not clearly stated. But let’s say that that is the case…I won’t include them in my head count.
Boy, what a sloppy bit of writing. I am NOT impressed!
Anyway, trying to add all this up…it appears to me that the number of patients who suffered from a variety of side effects, some serious, some not so serious, is a whopping 16 (7+5+4). Hmmm, I don’t suppose anyone could help me figure this out? Or is it impossible, given the hazy details provided in the abstract? It is, most likely, the latter case…
Well, what is clear is that the side effects experienced by 16 patients or even 14 out of a total of 40 CANNOT be ignored.
Manageable and acceptable…for whom???!!!
Update, May 11 2010 post. Remember the post I wrote back in January on a Spanish study concerning “high risk” smoldering myeloma patients? (I use quotation marks because the “high-risk” criteria were established by the study authors themselves…not by an independent group of myeloma specialists…as far as I can tell, anyway.) If this study doesn’t ring a bell, click here to read about it: https://margaret.healthblogs.org/2010/01/20/a-high-risk-smm-study-presented-at-ash-2009/
Relevant to today’s topic: in January, I found out that 9 of the 23 study authors are closely connected to Celgene, the makers of lenalidomide; indeed, two of the authors were Celgene EMPLOYEES (hello???)…these titbits made me suspicious, to put it mildly…anyway, I made my position clear in my post…no need to vent here, too…
Ah, before I continue: out of curiosity, just now I checked the Clinical Trials website and, yes, the Spanish study is still recruiting participants…(I am sure you can imagine what I think about that…but I prefer not to comment…oh okay, just one teeny tiny growl: grrrr…!).
And now we get to the point of this post. Today I feel vindicated…you see, I just finished reading a Science Daily article on how pharmaceutical companies influence and manipulate clinical trials: http://tinyurl.com/355lqwk Bloody hell!!! For more information, here is the link to the original article, printed in “Deutsches Aerzteblatt International”: http://tinyurl.com/2bw2xr6
This bit of news really came as no surprise to me (remember Vioxx?)…but I admit, it is very very frustrating. I mean…
…whom can we trust?