The 1990s marked an important milestone in the treatment of multiple myeloma. From melphalan, prednisone, and combined alkylating agents for decades to autologous stem cell transplantation and thalidomide.

As the complex biology and clinical diversity of myeloma became better understood, new attempts were made to find a definite cure. Years of observation and trials yielded the medications that remain a pillar of therapy for myeloma to this day: immunomodulatory drugs. 

Understanding Myeloma Treatment Before the 1990s: Decades of Melphalan and Prednisone

Multiple myeloma has been around since ancient times and from its initial characterization, attempts have been made to find a cure. Even though the first well-documented cases were published around the year 1840, paleopathologists have described cases that morphologically resemble myeloma dating from 3200 BC to AD 1800. 

By early 1900, a wide variety of substances, roots, beverages, and procedures had been tried as remedies for myeloma. Compounds and medications such as quinine and urethane were administered as well.

Quinine and urethane were introduced purposely for myeloma treatment in 1947 and used for several years before it was proved to cause toxicity or shortened survival rather than improvement in controlled clinical trials. Thus, median overall survival around 1950 for multiple myeloma patients was around 6 months. 

It wasn’t until the 1960s that effective medical treatments were introduced, when melphalan and dexamethasone were demonstrated to improve overall survival to 3-4 years, with the “little cost” of causing mild myelosuppression, that is, low blood cell counts, especially platelets. 

Different combinations of alkylating agents (cyclophosphamide, carmustine, melphalan) were also tried with some favorable results but not an improvement in overall survival. Melphalan and prednisone remained the standard of therapy for decades. 

The Innovation of Myeloma Treatment in 1990s: A Nobel Prize for Discoveries Concerning Stem Cell Transplantation

At the beginning of the 1990s, myeloma treatment started to grow exponentially. In the early 1980s, in the context of melphalan's demonstrated efficacy, the administration of high-dose melphalan was proposed in the pursuit of longer, deeper remissions in myeloma. 

Tim McElwain, professor of medical oncology at the Institute for Cancer Research and the Royal Marsden Hospital in London, published the first report of this approach in 1982.

They demonstrated that a single high-dose melphalan infusion could achieve complete remission in patients with high-risk disease; nonetheless, the myelosuppression caused by high-dose melphalan was life-threatening, and some patients would die from severe infections.  

To overcome this profound and prolonged blood cell deficiency, autologous stem cell transplant was introduced as a support measure. 

From the mid-1950s, E. Donall Thomas, an American physician with extensive interest and work in hematology had been investigating methods of providing new bone marrow cells for people through transplants as a cure for hematologic diseases.

In the 1960s, Donall established his program at the Seattle Public Health Hospital and continued to study and try approaches to stem cell transplantation, which ultimately led to his Nobel Prize in 1990. 

Bart Barlogie, a University of Arkansas for Medical Sciences (UAMS) dedicated professor of medicine and pathology and distinguished clinical scholar who founded the UAMS myeloma program in 1989, was the one to propose systematic autologous stem cell support to overcome the prolonged myelosuppression induced by high-dose chemotherapy.

Stem cells were obtained from the patient’s bone marrow and preserved,high-dose chemotherapy with melphalan was given in the interim to destroy cancer cells, and reinfusion of stem cells would rebuild blood and the immune system.

High-dose therapy and stem cell rescue eventually became the standard therapy for myeloma.

Initially, this approach was explored in a relapse setting but was later introduced as initial therapy for newly diagnosed myeloma patients with promising results. With a single high-dose chemotherapy followed by a stem cell transplant, 20-50% of patients achieved complete remission.

However, relapse was reported in the majority of patients after some months. 

End of 1990s: The Emergence of Immunomodulatory Drugs for Myeloma

The decade of the 1990s ended with the interesting and eventually groundbreaking use of thalidomide as a multiple myeloma treatment.

This drug, an anti-angiogenic agent (which prevents the formation of new blood vessels), had been on the market since the late 1950s and it was used as a sedative and to treat pregnancy morning sickness.

Unfortunately, in 1961, a German genetist reported that in utero exposure to thalidomide was associated with severe fetal malformations. Then, thalidomide was withdrawn in several countries. 

Despite removal as a sedative, thalidomide was still used as a treatment for leprosy and some autoimmune conditions, of course, precluding pregnant women. As the pathogenesis and biological bases of cancer were better understood, the potential role of thalidomide as an antiangiogenic agent for treating myeloma began to be explored. 

It was a “compassionate use trial” by Barlogie et al. at the University of Arkansas the first approach of thalidomide as myeloma therapy.

A patient with non-responsive myeloma was treated with unfavorable results, but then a second one who received the same treatment went into complete remission.

Soon after this, Dr. Barlogie conducted a trial with 84 patients enrolled and surprisingly, 32% of patients showed a response to thalidomide as a single agent. 

In the majority of patients, the decline in m-protein levels was associated with a lower percentage of plasma cells in the bone marrow and an increase in hemoglobin levels, making this consistent with a reasonable antimyeloma response, with 10% of patients reaching complete or near-complete remission.

These findings made thalidomide the first new single anti-imyeloma agent in three decades.

A Brief Glimpse into the Future of Myeloma After the 1990s 

Only a few years of intensive clinical research passed before new drugs were introduced.

Bortezomib, a proteasome inhibitor approved by The US Food And Drug Administration for myeloma treatment in 2003; lenalidomide, a second-generation drug following thalidomide approved by The US Food And Drug Administration for myeloma treatment in 2006; carfilzomib, a second generation proteasome inhibitor approved in 2012, are only some examples of the many agents that in combination or by itself began to demonstrate promising results in the treatment of myeloma. 

Nowadays, multiple myeloma has more than a dozen Food and Drug Administration medications approved for treatment.

Since myeloma is a very diverse entity, drugs are used in a variety of combinations, dosing, and regimens depending on each individual case. The horizon for multiple myeloma patients undoubtedly has evolved massively in the last 40 years.

Observation of a single case is the base of every science. By observing a series of cases scientists detect trends, formulate hypotheses, and eventually experiment to prove these hypotheses.

The more cases observed, the more available real-life information and feedback about the many treatments in the market today, so better solutions, medications, and technologies are developed. 

Since the 1990s, research in multiple myeloma has incredibly speeded up and to this day, it continues to grow at a great pace. 

Join Us to Build the Future of Myeloma Treatment Now! 

Myeloma innovation didn't stop in the 1990s, and it's not stopping today! HealthTree is excited about the myeloma innovation happening today that's accelerating toward a cure. You can be part of this acceleration and innovation! 

Join us for an exciting journey through the history of myeloma care and the launch of HealthTree 2.0, a revolutionary platform designed to empower myeloma patients and caregivers.

We invite you to participate in this momentous occasion and make it even more special by hosting a virtual watch party with your friends, family, or support group.

Let's come together to celebrate the progress we've made in myeloma treatment and explore the promising future that lies ahead.

Register for our virtual launch today! 

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References for this article: 

• A historical perspective on milestones in multiple myeloma research. Review Article. European Journal of Hematology, 2017.
• History of multiple myeloma. RA Kyle. Recent Results in Cancer Research 183, DOI: 10.1007/978-3-540-85772-3_1, 2011.
• High-dose melphalan with autologous bone marrow transplantation for multiple myeloma. Barlogie, et al 1986
• Antitumor Activity of Thalidomide in Refractory Multiple Myeloma. NEJM, Singhal et al, 1999
• https://www.nobelprize.org/prizes/medicine/1990/summary/

Thanks to our event sponsors, Bristol Myers Squibb, Amgen and Genentech, for making this event possible.