Q. Here’s a question from Twitter: Can you explain to me what the M protein in multiple myeloma is?

A. Multiple myeloma is a malignant, clonal disorder of plasma cells that originates in the bone marrow. It’s a relatively common disorder, accounting for 1% of all malignancies and 10% of all hematologic malignancies in adults. Patients present with painful, lytic lesions of the bones, recurrent and persistent infections, weakness, renal failure, and hypercalcemia. The prognosis is generally not great, but new chemotherapeutic agents seem to hold some promise.

Patients with myeloma have a monoclonal proliferation of plasma cells in the bone marrow, meaning that there are a ton of malignant plasma cells that all originated from the same initial cell. In the bone marrow aspirate above, you can see tons of malignant plasma cells. A few look a lot like plasma cells, with clock-face chromatin and a hof and everything, but others look for all the world like blasts. That’s one thing to remember about myeloma – malignant plasma cells don’t always resemble their nice little benign counterparts.

The malignant plasma cells almost always secrete immunoglobulin, and because they are monoclonal, they all secrete exactly the same form of immunoglobulin. This is very different than what you see in a patient without myeloma, where there are a bazillion different types of plasma cells, all making different types of immunoglobulin molecules.  This huge  mass of all-the-same immunoglobulin secreted by myeloma cells is called a “monoclonal gammopathy;” the normal immunoglobulins are called “polyclonal.”

Monoclonal gammopathy is so characteristic of myeloma that you can use it for both diagnosis of disease and follow-up of patients. You can detect the monoclonal immunoglobulin using serum electrophoresis (which separates the blood proteins into groups based on charge and size).  There’s a predictable pattern of proteins in normal serum: albumin (the most abundant protein in the blood) migrates to a certain predictable point; other proteins migrate to different places (which are given different names – the alpha 1 region, the alpha 2 region and the beta region). Immunoglobulins migrate to a unique place called the gamma region, and because they are all different (in normal patients), they migrate to slightly different places within that region, giving a gentle bell-shaped curve or smear (depending on whether you’re looking at a tracing or the actual bands on the gel). In myeloma, the immunoglobulin is monoclonal, so it all migrates to exactly the same spot on the gel! Which gives you a big spike (if you’re looking at a tracing) or a very distinct, crisp, strong band (if you’re looking at the gel itself). This spike is called an M-spike (you could remember M for either monoclonal or myeloma), and the corresponding monoclonal protein that it represents is called an M protein.

A few other things to note about this M protein:

1. You need to do electrophoresis on urine too, not just serum. Some cases of myeloma secrete only light chains (these are called Bence-Jones proteins), which are so small that they are passed in the urine (so if you only looked at the blood, you’d miss them).

2. While patients with myeloma have an increase in the total amount of immunoglobulin present in the blood (due to the large monoclonal immunoglobulin spike), they also have a decreased amount of normal, polyclonal immunoglobulins. So when you look at an electrophoresis, you’ll see this huge spike in the gamma region, but also a noticeable depression in the amount of the background normal immunoglobulins.

3. A little trivia regarding the kinds of immunoglobulin expressed by myeloma cells. The most common heavy chain expressed in myeloma is IgG (60%); next is IgA (20%). Rare cases express IgD or IgE, and IgM myeloma is virtually nonexistent (most cases of plasma cell lesions that express IgM turn out to be Waldenström macroglobulinemia). Almost one-fifth of all cases of  myeloma secrete only light chains. And somewhere between 1 and 5% of all cases of myeloma secrete no detectable immunoglobulin at all! Which, without the familiar M-spike, would make for a pretty difficult diagnosis.