Dr Kunal Jobanputra MD, DM

I know some have become experts at clinical appraisal and clinical trial critique. It’s important to have this dialogue and it helps physicians and patients understand the drawbacks of a given trial. But my advise to young investigators is to best not to make it your primary academic output. Secondly, when critiquing it’s also worthwhile remembering that the investigators of trials may also fully aware of the issues but there are many barriers and often we have to choose between not doing a trial at all versus compromising. Perfect trials are not common; we can usually find some fault with almost all trials. So we must strive to avoid rudeness and condescension. Third, try if possible to lead a clinical trial or at least get engaged with someone who leads trials and get a feel for the various stakeholders who have veto power during trial design, and more importantly the various competing priorities for what the trial seeks to accomplish, it will be easier to understand why a specific control arm was chosen, or a why a specific endpoint was chosen, even though you may think they are the wrong ones.

One of the main goals of our review article in @NEJM on MGUS was to provide clear clarifications on the concept of “monoclonal gammopathy of clinical significance” (MGCS). It’s all very confusing in the literature and can cause problems for patients if we are not totally clear of the concepts. Read on to be 100% sure of the concepts so you can take care of your patients correctly! 1) First key concept: MGUS is a clinically indolent condition that usually remains quiet for an entire lifetime. The problem with MGUS is that it can progress to symptomatic malignancy (like multiple myeloma), or cause a variety of non-malignant, serious, and clinically important diseases that are collectively referred to as “monoclonal gammopathy of clinical significance” (MGCS). 2) Second key concept: MGCS is like the title of chapter in a textbook. It is NOT the name of a disease. Within the term “MGCS” are several distinct diseases, each of which has its own diagnostic criteria, clinical manifestations, and treatment strategies. So you simply cannot diagnose “MGCS” and treat but need to identify the specific disease. All that the term MGCS does is to alert you that MGUS can cause serious non-malignant diseases besides progression to malignancy. 3) Third key concept is: Some of the MGCS conditions are multi-system disorders like light chain amyloidosis and light chain deposition disease. Some MGCS disorders on the other hand are restricted to one organ leading to more confusing terms like “monoclonal gammopathy of renal significance” (MGRS), “monoclonal gammopathy of dermatologic significance” (MGDS), monoclonal gammopathy of neurological significance” (MGNS), and so on. These are also like titles of book chapters NOT the names of a disease. Within each term are specific unique diseases. 4) Fourth key concept is: For taking care of the patient you need to know the name of the exact disease. Not just add an umbrella term like “MGCS” or “MGRS”. So for example instead of diagnosing “MGRS” you need to be clear exactly which kidney disease the monoclonal protein is accused of causing! MGUS is so common and so many people can have a MGUS and a completely unrelated kidney disease. MGUS plus kidney disease doesn’t mean “MGRS”. Most of the time the two have nothing to do with each other. There are specific kidney diseases that are casually related to the monoclonal protein and if we suspect MGRS for some reason we need to work up and make the specific diagnosis which needs a kidney biopsy: proliferative glomerulonephritis with immunoglobulin deposits (PGNMID), C3 glomerulonephritis, and so on. Each of these disease have their unique clinical and lab manifestations, and treatment strategies. 5) Fifth key concept is: with more and more sensitive tests for MGUS and more and more testing done for MGUS we are all going to find M proteins associated with a variety of clinical problems, 99% of which are NOT caused by the M protein. I am hugely concerned with labels like MGCS and MGRS wrongly applied. And the last thing we want is Dara-VRd for a DVT just because there is a paper that says M proteins can cause blood clots! This Review will be a good place to start for getting all the key concepts straight. nejm.org/doi/abs/10.1056/NEJ…