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How I treat multiple myeloma in younger patients…

Posted Jan 11 2010 12:00am

At the end of my December 17 2009 post, I mentioned a study that I was reading. It is titled “How I treat multiple myeloma in younger patients” and was published in “Blood” in October 2009. It doesn’t have an abstract, but here is the link: http://tinyurl.com/yan57ow (By the way, many thanks to Sherlock for sending me the full study…)

Before we begin, let me just say that there now seems to be a trend against treating stable smoldering patients too early. Last fall, for example, I heard Dr. Durie speak of the potential dangers of prematurely treating stable asymptomatic patients, and this is confirmed by the authors of the above-mentioned study, three well-known MM specialists who, incidentally, openly declare their general propensity for very aggressive treatments in the case of younger myeloma patients (=full-blown MM, not SMM, patients, mind you). 

I thought that the following paragraph was rather extraordinary, especially when you consider that these three specialists do not believe in “saving drugs for later” but prefer, whenever possible, the gung-ho “throw everything but the kitchen sink” approach: Although the activity of novel agents has advanced to the point that early interventions are now being explored in clinical trials for smoldering myeloma, there is still no evidence that early treatment will improve survival in asymptomatic and biochemically stable patients. A critical point is that up to 25% of smoldering myeloma patients will not require active treatment for 10 to 15 years, although the majority will in fact progress during that time.

As far as I am concerned, the key point in this paragraph is: [...] there is still no evidence that early treatment will improve survival in asymptomatic and biochemically stable patients. But what about that “critical point,” indicating that the majority of SMM patients will progress to active MM within 10-15 years? On what is that statement based?

Well, it turns out to be based on the 2007 New England Journal of Medicine study that we have already discussed here (see my Page titled “SMM-MM risk of progression” on the right-hand side of this page). If you would like to see the full NEJM study, click here: http://tinyurl.com/c9f8lb

Without repeating what has already been discussed on my blog, I would like to go over a few points:

1. the NEJM study looked only at 276 smolderers, which is hardly a huge number, when you consider how many smolderers there must be…on a world scale, that is.

2. the average age of this group of SMM patients at the time of diagnosis was 64 (the range was 26 – 90). Now, while I have the utmost respect for the person or people who was/were 90 years old (at the time of diagnosis), I would have liked to have seen some data on the younger patients, for example the eight patients (3%) who were younger than 40. What has happened to them? Have they progressed to active myeloma? No such data is provided.

3. the risk of progression to myeloma, according to the Mayo study, is approximately 10% per year in the first five years…let me emphasize the adverb: APPROXIMATELY. That percentage goes down to APPROXIMATELY 3% per year in the next five years, then to APPROXIMATELY 1% per year after ten smoldering years. These percentages, therefore, should be taken for what they are: estimates…nothing more…

Now for my own conclusions. A sweeping statement similar to “most SMM patients will progress to MM within 15 years” and based on a sample of only 276 people is simply astounding. Unacceptable, in my view. Nobody, with the possible exception of Harry Potter, has the ability to predict that most of us, those taking curcumin, those taking resveratrol, those on the Gerson protocol, those laughing at comedies all day, those climbing mountains, etc. etc. etc., will progress some day to active myeloma…there are just too many variables involved (and I didn’t even mention DNA…!).

Back to the “Blood” study…Even though, I repeat, the three authors favour extremely aggressive myeloma treatments, they do point out that The clinician should therefore avoid treating asymptomatic and biochemically stable patients with active therapy, allowing current drug development efforts to mature to their maximal efficacy at a time when systemic treatment does become a necessity. Indeed, early intervention may only serve to identify those patients at early risk for progression, or worse, theoretically to select out more aggressive genetic subclones of myeloma.

Now, the underlined (by me, of course) bit is not the most comprehensible string of words ever written in the English language, but I think it means that early intervention might turn a not-so-aggressive type of myeloma into an aggressive type. This happened to a couple of friends of mine…and, in fact, it could easily have happened to me: when my former haematologist advised me to begin chemotherapy in the fall of 2005, I declined (based on a gut feeling) and sought the opinion of three well-known MM specialists who confirmed that I had done the right thing, that I was still in the “watch and wait, no CRAB symptoms” category. Let us never underestimate the importance of getting a second, even third (etc.), medical opinion…!

Sorry for going off on a tangent. From now on I will try to stick to the study. It’s just that I have strong opinions…in case you hadn’t noticed! ;-)

The authors also say that smoldering patients should be carefully monitored. I couldn’t agree more. In fact, if I were a biologist and had a lab in my cellar, I would be monitoring my blood almost daily!

Which tests do they recommend for newly diagnosed myeloma patients? Well, in addition to the classical CRAB measurements of calcium, renal function, haemoglobin level, and skeletal survey, the Beta 2-microglobulin, albumin and lactate dehydrogenase (LDH) should be measured, as these latter tests impart prognostic significance. Investigations for the monoclonal protein (M) require both serum and urine (24 hour) samples and today could include the serum free light chain (sFLC) assay, which has become mandatory in non-secretory or oligosecretory MM and is often the first marker of response and progression. SFLC is also of value in solitary plasmacytoma, amyloidosis and in initial evaluation of MGUS to predict risk of progression to symptomatic MM.

They also recommend having a bone marrow biopsy to check for any abnormalities that would put the patient into a high-risk category.

And here is another important point: although the conventional skeletal survey remains the standard method for evaluation of bone lesions, magnetic resonance imaging (MRI) is more sensitive and is recommended to exclude spinal cord compression, soft tissue mass in a localized painful area or for assessing BM involvement in patients with solitary plasmacytoma and smouldering myeloma. The role of PET-CT is less well defined in MM, but can be useful for detecting extramedullary disease, unsuspected bone lesions and evaluating patients with plasmacytoma as well as non or oligo-secretory MM.

Quick aside (sorry, can’t help it!): after reading the vitamin D and myeloma study (see my Page on “Myeloma and vitamin D”), I am absolutely convinced that we should all have this simple test done on a routine basis…regardless of our stage (MGUS, SMM or MM). Please add it to your list.  

At any rate, these are the parts of the study dealing with asymptomatic (smoldering) myeloma. The rest focuses on ASCTs and on the authors’ personal predilection for aggressive treatments, via the use of multiple chemo drugs…especially with younger patients who are able to tolerate toxicities and pursue high dose therapy approaches. If my myeloma were to turn aggressive some day, I suppose I might consider such an approach. But for now my goal is to keep the tiger dormant…(see: http://tinyurl.com/yldk5y9).

P.S. Curiosity: since the authors of this study were more than one, shouldn’t the title have been “How we treat multiple myeloma in younger patients”? Hmmm…

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