March 14 2010 post. Part I. This two-part post concerns a study on smoldering (asymptomatic) multiple myeloma published last month in the “Journal of Clinical Oncology”…Sherlock, grazie!, sent me the full text…

In the abstract (see: http://tinyurl.com/ybwtzke), there is a list of some of the risk factors for progression to full-blown myeloma, nothing new, here—M-protein size, percentage of bone marrow neoplastic cells, etc.

Interesting excerpt: Immediate therapy with cytotoxic agents, such as melphalan/prednisone has not resulted in improved outcome = this bit is explained more in detail in the full study, so we will get to it later. The following excerpt simply confirms what we already know: Patients should not be treated until progressive disease with end-organ damage occurs. There are so many things to keep in mind with myeloma…but this one is certainly NUMERO UNO: no CRAB, no treatment.

Now for the full study. Something I didn’t know (or didn’t remember…) is that smoldering myeloma was first described in 1980 by Drs. Kyle and Greipp, as follows: a distinct clinical entity characterized by the presence of a serum M-protein value higher than 3 g/dL, bone marrow clonal plasma cells (BMPC) involvement of 10% or higher, and no bone lytic lesions or clinical manifestations attributable to the monoclonal plasma-cell proliferative disorder. A distinct…er… “entity”? I’m walking around with an entity inside of me??? Hehe, that gave me a bit of a chuckle…

Problem: the diagnostic criteria have not been uniform, thus resulting in important differences in time to progression and in a lack of consistent predictors of outcome between the different series. (The “different series” bit refers to the different classifications of asymptomatic myeloma: SMM, indolent myeloma, asymptomatic myeloma or low tumor mass myeloma.)

Before 2003, there was no real consensus on how to define smoldering myeloma, or SMM. In 2003, the International Myeloma Working Group agreed on a new definition of SMM consisting of a serum M-protein of > 3 g/dL and/or > 10% bone marrow plasma cells with no evidence of end-organ damage (hypercalcemia, renal insufficiency, anemia or bone lesions [CRAB]).

The study then spells out the differences between MGUS and SMM, but I won’t focus on that, since we know them, or should know them! , by now. The following, however, was new to me: When the M-protein size and the proportion of bone marrow plasma cells are consistent with MGUS but there is substantial albuminuria, congestive heart failure, renal failure, peripheral neuropathy, orthostatic hypotension, carpal tunnel syndrome, massive hepatomegaly, malabsorption syndrome, or any combination of the above, the most likely diagnosis is primary systemic amyloidosis (AL) […]. Something to keep in mind…

…as well as a few other things: elderly folks can have diseases that mimic myeloma, for instance an increase in serum creatinine, anemia, diffuse osteoporosis and so on. Even patients with a single asymptomatic lytic bone lesion, the possibility of an associated benign bone cyst or a bone angioma should be considered […]. So ONE bone lesion doesn’t necessarily mean that you have developed active myeloma…interesting…my notes are filling up my…mental pad!

Risk factors for progression: M protein > 30 g/L, bone marrow plasma cells > 20%, haemoglobin > 12 g/L, light chain proteinuria (Bence Jones) > 50 mg/24 hours and an IgA monoclonal heavy chain. And lytic bone lesions. And, going down the list, also the presence of MRI abnormalities. A personal note: at times, my M protein has gone above 30 g/L, in fact in May 2009 it went as high as 39.9 g/L (eek!)…then it went back down to 29.7 g/L in September 2009…so I am still smoldering…what I mean to say is: please don’t freak out if your M protein surpasses the 30 g/L limit…first look at the context and the trends…

An interesting paragraph is titled “Pattern of evolution.” According to a group of researchers, there are two kinds of SMM: 1 evolving and 2 non-evolving. Patients who fall into group 1 had an increase in M-protein levels in two follow-up consecutive visits. Group 2 was instead stable and had a longer time to progression (3.9 years versus 1.3 years).

And here we get to a very useful item that was mentioned in the abstract, too: Most patients with SMM progress with increasing anemia and/or skeletal involvement consisting of bone lytic lesions and/or diffuse osteoporosis. Anemia is defined as having a haemoglobin lower than 10g/dL…but hey, read this and breathe a sigh of relief: the authors of this review have seen patients with SMM with a Hb level between 9 and 10 g/dL with no need for cytotoxic therapy for several years. It must be considered that in patients with a high serum M-protein there is also a component of hemodilution, and so the severity of anemia may be overestimated.

Wow, now this bit of news is very very important…it proves that treatment protocols should not be applied too rigidly, as happens all too often!!!, but that each case should be evaluated carefully…in its own context. In other words, just because your Hb has dipped below 10 g/dL doesn’t necessarily mean that you should undergo immediate treatment…that number could in fact remain stable or even go up…So this is another thing for us to keep in mind…

March 15 2010 post. Part II. I looked up the three small melphalan-prednisone studies on SMM patients mentioned in the abstract. Here are the links: 2009 abstract: http://tinyurl.com/ygnlwr5; 2000 full study: http://tinyurl.com/yjfneba, and 1996 full study: http://tinyurl.com/yhogw2y). A cursory glance shows that there was no difference in survival…indeed, a couple of patients in the first study developed acute leukemia during treatment. Unfortunately, I don’t have time now to read the studies in great detail, but the upshot seems clear: there is absolutely no benefit in administering early treatment to SMM patients. Case closed…as far as I am concerned, anyway.

The study goes on to discuss the administration of thalidomide to SMM patients and concludes that this drug cannot be recommended for the treatment of SMM until a benefit is shown in prospective randomized trials. Caution happens to be my middle name (well, okay…not really! ). Personal note: in 2007, when my hematologist suggested that I take some thalidomide to zap the cancer cells lurking in my bone marrow (=50% at the end of 2005…down to less than 40% at the beginning of 2007 after one year on curcumin), I said no. She tried to insist, but I was adamant. I want my “tiger” to remain dormant for as long as possible…so, no CRAB, no treatment. Period.

As for bisphosphonates, the study states that data from a few SMM trials shows that they might be beneficial for those who have early bone disease, but the potential toxicities of bisphosphonates, such as renal injury and osteonecrosis of the jaw, should be taken into account […]. Wait a sec. I read something recently about bisphosphonates, but can’t recall what, exactly…hmmm…was it good or bad? Oh I know, I read about it on the MMA patient list. I don’t think list members will mind if I post the link, provided by a list friend (thanks!), to this “USA Today” article: http://tinyurl.com/ykguaxm If you are currently taking bisphosphonates, please read this article and ask your doctor about it…

Another thing that we should all keep in mind if some day we face the choice of undergoing conventional treatment: In patients with SMM who then evolve into symptomatic MM the response rate to chemotherapy has ranged from 52% to 64%. I was actually surprised to read that there was such a low response…

Well, okay, so what do we, SMM folks, need to do? The study offers a useful Table outlining the tests that should be done right after we have been diagnosed with smoldering myeloma:

• Medical history and physical examination
• Complete blood count
• Serum calcium and creatinine
• Protein studies
• Total serum protein and serum electrophoresis (serum M-protein quantitation)
• 24-h urine protein electrophoresis (urine M-protein quantitation)
• Serum and urine immunofixation
• Serum free light chain measurement (FLC ratio)
• Beta-2 microglobulin
• Bone marrow aspirate
• Skeletal survey
• MRI of thoracic-lumbar spine and pelvis

After three months, we should have our blood and urine tests repeated…then, if our markers remain stable, we should continue to be checked every 3 months for the first year in order to establish the pattern of evolution (evolving vs nonevolving). If the markers do not remain stable, however, then a full evaluation should be done again, including a bone marrow biopsy. However, SMM folks should not be treated, the authors repeat, until progressive disease with end-organ damage is evident. Especially those who are in the nonevolving category! I couldn’t agree more…

IMPORTANT: A progressive decrease in the Hb level is the most frequent and reliable indicator of progression. Other indicators of progression that mandate treatment are the development of soft-tissue plasmactyotmas or significant skeletal involvement as well as increased serum calcium or a rise in the serum creatinine level.

So please keep an eye on your hemoglobin, in particular…and take action immediately if that number shows any signs of decreasing!