Myeloma’s First Promising Treatment
Randomness is built into planning these myeloma history Substack articles. That’s because I think sequential learning is overrated. It’s not how most of us learn, especially for those who finished school decades ago and just been told they have a disease they’ve never heard about before.
Just as we learn in different ways, we begin to learn about the stories that interest us in unplanned chronologies. We can’t always begin with chapter one when learning. It can be disconcerting, but I’m doing my best to make readers comfortable with this approach over time.
In the past few articles, some of the subjects I’ve focused on have included thoughts about the impact of Mike Katz, the birth of disease advocacy, how bisphosphonates changed myeloma in differing ways, and the crucial role the International Myeloma Foundation played in creating a myeloma community.
First we’ll detour to the 1960s and make a slight detour to the World Wars.
It’s one thing to know the theory, it’s quite another when “practice” translates into an actual patient, or when you are the patient. Going from one to the other often comes at the cost of time and frustration. It’s been the only way science has worked in recorded history. As a Canadian in Texas learned more than sixty years ago.
Three years before Robert Kyle’s birth, another key player in myeloma, Daniel Bergsagel (BERG-sah-gel), was born about 350 miles northwest of Bottineau, in Outlook, Saskatchewan, Canada before moving and growing up in Manitoba. Officially he financed his medical school education working for the Canadian Pacific Railroad at a time when jilted war brides from World War II were returning to their European homes.
Unofficially, most of the money came from playing poker during his free time on the rails – a secret he kept from his Lutheran pastor father. After medical school, he went to northern Canada treating mostly miners, where he soon tired of “pulling teeth.”
His interest in hematology led him to Salt Lake City and Wintrobe, the hematology guru Kyle wanted to avoid. Later Wintrobe recommended Bergsagel for a doctoral program in Oxford, England, where he earned his doctorate for innovative research on blood coagulation, on how “sticky” blood cells had to be in order to work effectively.
By the mid-1950s, MD Anderson Cancer Center in Houston, Texas, recruited him for their hematology department, which was investing more resources to treat leukemia and lymphoma with new chemotherapies. Myeloma patients were generally turned away because there were no proven treatments available to extend lives. Bergsagel’s growing interest in blood proteins and electrophoresis, the same procedure that produced the “M” pattern that was to get Kyle’s attention at Mayo a few years later, would inevitably lead to more professional curiosity in myeloma.
New chemotherapies were feeding MD Anderson’s interest in leukemia and lymphoma, so when Bergsagel found out about a promising new one developed in the Soviet Union around the same time Sputnik circled the globe in 1957, he thought it had promise. Unfortunately, Cold War politics effects on everything made it difficult for anything on the “wrong” side of the Iron Curtain.
That’s why it wasn’t until 1962 that Bergsagel became the first physician in the nation to use melphalan in myeloma patients and MD Anderson let him do so. What did they have to lose in possibly being first in something big? Especially when six months survival was the myeloma norm. Even a little progress would be a big deal.
Still, nothing prepared him for the shock of seeing unprecedented, immediate, significant drops in myeloma cell numbers. He thought for a short time he might even have cured the disease. Could he dare to dream that he might be a modern-day Prometheus, curing a once hopeless cancer?
It turned out to be somewhat of a mirage. A hopeful pause before the inevitability of disease relapse. Rather than being like the hero who brought people fire, he was starting to resemble Icarus, flying close enough to the sun to think he was unlocking its secrets, but with too much uncertainty of heat for the wax to hold together before tumbling back to the reality of myeloma.
The dream was short-lived. It was significant but not what it seemed. Big questions remained. Excitement about the success of melphalan was still being offset by the disappointment and human cost of eventual relapse sooner or later. Like all chemotherapies, the toxicity of melphalan eventually took its toll, forcing physicians to curtail its prolonged use.
Bergsagel realized melphalan slowed myeloma down for a while in some patients, but not permanently. Relapse was inevitable. More toxic load had to be delivered to kill malignant cells while, at the same time, not killing too many of the healthy ones.
Nonetheless, melphalan became essential to treat myeloma, even if it was not a cure. It was, however, a significant step for myeloma, one that ranked as highly as any that would come decades later.
Chemotherapies like melphalan were two-sided weapons; using them was like betting on the hope that the poison-like toxicity of the therapy would kill cancer cells before there was too much collateral damage done to healthy cells. As people saw what chemotherapies did to patients – lost hair, rapidly declining weight, nausea, and numerous other side effects – many wondered which was worse, the cancer or its treatment?
Why would anyone even consider it to treat disease? The answers to those questions seemed obvious once one learned that chemotherapy has roots in sulfur mustard, better known by the misnomer mustard gas for its garlic-like smell, in World War I.
Clouds of deadly gas created indelible memories that still haunt the world, demonstrated by the fact that just one percent of World War I combat deaths were due to mustard gas. A scientific paper in 1919 explained why it was an effective executioner and propagandist.
Not only did mustard gas induce rapid respiratory failure and skin blistering of the skin that often led to death, but autopsies revealed no evidence of white blood cells, essential for immune systems to function to eliminate disease. Had the victims survived the first symptoms, a lack of an immune system would have finished them off quickly. Nonetheless, scientists started to reason, if mustard gas killed white blood cells, could it be harnessed to kill malignant white blood cells as therapy for diseases?
By the advent of World War II, American cancer researchers were looking into nitrogen sulphur (mustard gas) reserves to study, including William Damashek, who led a consortium of institutions in a clinical trial studying its use in Hodgkin lymphoma and a was later a mentor to Robert Kyle. We’ll meet him again soon.
The biggest breakthrough didn’t happen in labs, though. It was a war tragedy.
Nineteen U.S. ships docked in Bari, Italy attracted a squadron of German bombers. Unknown to virtually everyone in the fleet, a merchant marine ship, the S.S. John Harvey, was loaded with at least 2,000 bombs filled with 100 tons of mustard gas, was hit, sank, and killed all on board. Speculating why it was there in the first place would be debated in the future, not while surviving sailors from other ships were pulled out of the water.
Symptoms that hadn’t been seen in decades led to the deaths of 83 of the 617 hospitalized. Autopsies on 53 of them revealed the secret military leaders were still withholding. Each death confirmed the presence of mustard gas in one of those ships.
Just like the victims in the 1919 study, white blood cells in every victim were gone. Theirs would be the only deaths due to mustard gas in World War II.
The Bari tragedy advanced cancer treatment for generations to come; Bergsagel and melphalan are included in this legacy. Derivatives of these drugs continue to be widely used today in cancer treatment.
Although Bergsagel didn’t realize it at the time—nor did anyone else—he was scouting a path that would be cleared further by colleagues who made myeloma a key part of building MD Anderson’s reputation into one of the top cancer centers in the world. In the next article, we’ll take a look at part of that story in the 1960s and 70s.
Photo: Detail, Michelangelo Merisi de Caravaggio, The Cardsharps (ca. 1594), Kimball Art Museum, Ft. Worth, Texas