By Marty Vanderlaan
I spent my career developing monoclonal antibody (Mab) therapeutics. One of our standard tests was to quantify noncovalently linked light chains that can be dissociated from the antibodies, the result of failure to form critical S-S bonds linking the light chain to the heavy chain.
Turns out that “normal” immunoglobulins in patient serum also contain free light chains at a low level—in most people, but not all. These noncovalent light chains can have the propensity to separate from the antibody, precipitate in tissues, and form amorphous protein aggregates termed amyloid AL. Myelomas and other plasma cell lymphomas can produce high levels (100x normal) of free light chains, which form tissue-damaging amyloid plaques. Readers might be familiar with the neural amyloid plaques associated with loss of brain function in Alzheimer Disease. Different proteins (A-beta and Tau) form those plaques in the brain, but the concept of precipitated protein-forming tissue-damaging plaques is the same. Light chain amyloid plaques lead to heart, kidney, and liver damage, and precipitate can be found throughout the body from fat tissue to bone marrow. Free light chain levels in serum, however, can be assessed by a simple clinical assay of human serum.
My wife complained for a couple of years about “not feeling right” and was breathless doing even mild exercise, like walking a few blocks. Panels of serum tests were run by her internist, but never a test for free light chain and she was not referred to a cardiologist. In retrospect, she had many symptoms of cardiac insufficiency and eventually was hospitalized with fluid in her lungs. Amyloidosis was not suspected. What frustrates many in the amyloid patient advocacy community is that the disease is so often not diagnosed until it too late.
She was in and out of the hospital over the next four months before a diagnosis of cardiac amyloidosis was made. The best description I heard of her heart at that point was that it was “starched”—rendered so rigid with excess precipitation of proteins that her beating heart no longer moved much blood. The recommended therapy at that point was a heart transplant, followed by chemotherapy to kill the myeloma cells. Without the post-transplant treatment for multiple myeloma, the malignant cells would starch the new heart, too. It is likely that the amyloid had damaged other organs, too, so she might have been looking at multiple organ failures/transplants. Because I worked in biotech and had access to extensive medical literature online, I searched “cardiac amyloidosis” and saw sobering survival curves (for patients with advanced disease, it is 100% lethal within six months).
She was dead six weeks after we got the diagnosis. Just before Christmas she went into the cardiac intensive care unit at UCSF. On New Year’s Day, our daughter and I made the decision to discontinue treatment and we watched her cardiac monitor flat-line. Even with the many advances in medical and pharmaceutical science today, her cardiac amyloidosis was not detected soon enough to allow for an optimal line of treatment.
Who knew at that time that I, too, would have an amyloid-related disease, which will be discussed in my next post.