Multiple myeloma: A saga of discoveries

EARLY CASES

THE FAMOUS CASE OF MR. ALEXANDER MCBEAN AND DISCOVERY OF BENCE JONES PROTEIN

“Saturday, Nov. 1^st 1845

Dear Dr Jones,

The tube contains urine of very high specific gravity.

When boiled, it becomes slightly opaque. On the addition of nitric acid, it effervesces, assumes a reddish hue, and becomes quite clear; but as it cools, it assumes the consistence and appearance which you see. Heat reliquifies it. What is it?”

Dr. Thomas Watson, a well-known general practitioner in London, submitted Mr. McBean’s [Figure 1] urine sample along with this note to Henry-Bence Jones, a 31-year-old physician at St. George’s Hospital. At the time, he had already established himself as a chemical pathologist.^[3]

Close

Figure 1:

Henry-Bence Jones (source Wikipedia).

Export to PPT

Mr. McBean was sent to MacIntyre in 1845 with vague but persistent chest, back, and pelvic pain. Bence Jones analyzed this patient’s urine and observed that by adding nitric acid, a substance precipitated. The precipitate was soluble in boiling water but dispersed as the urine cooled. He called this disorder “albumosuria.” Jones determined that the protein was a “oxide of albumen” and, after more investigation, the “hydrated deutoxide of albumen.” He stressed its role in myeloma diagnosis, noting, “I need hardly remark on the importance of seeking for this oxide of albumen in other cases of mollities ossium.”^[5-7]

Thus, Bence Jones Protein was discovered. But it is Fleischer who was the first to use the term ”Bence Jones protein.“^[4,8]

Mr McBean succumbed to his illness in 1846.

John Dalrymple performed an autopsy. He observed that the sternum, cervical, thoracic, and lumbar vertebrae were soft, fragile, and readily broken, and could be sliced with a knife. He also found many hemorrhagic cavities in bones across the body. Dalrymple detailed the key postmortem results, saying that the illness started in the cancellous bone and advanced to the periosteum.^[9]

The cancellous cavities were filled with gelatiniform material constituted primarily of nucleated cells. The major portion of these cells was round or oval, about half to twice the size of a typical blood cell. The cells featured one or two nuclei, each with a bright, visible nucleolus. Wood engravings based on Dalrymple’s realistic drawings resemble myeloma cells.^[7]

In the coming years, a number of landmark papers on findings of the McBean case were published, which forged the path of new discoveries on MM.

In 1847, Bence Jones published a short observational note in the Lancet detailing his premortem observations.^[6] The following year, he released a comprehensive study on the laboratory findings, including a thorough explanation of the technique he used to examine the urine.^[5] The clinical aspect of the very same case was addressed in a report published by MacIntyre in 1850.^[10]

WHAT’S IN A NAME? TERMINOLOGY OF MM

While doing an autopsy, von Rustizsky noted eight separate tumors of bone marrow which he described as “multiple myeloma.” Thus, in 1873, the term “Multiple Myeloma” first came into use. In Russia, the term “Rustizky’s disease” is often used for MM.^[7,11]

Kahler disease

In 1889, Professor Otto Kahler [Figure 2] published a review that described a case with skeletal pain, albuminuria, pallor, anemia, precipitable urinary protein, and autopsy findings as part of a clinical syndrome known as Kahler disease, also known as MM.^[12]

Close

Figure 2:

Otto Kahler (Source: Wikipedia).

Export to PPT

At this point of this discussion, it would be pertinent to mention with great surprise as well as dismay that the landmark contributions of Henry-Bence Jones and Otto Kahler on MM were not recognized during their lifetime.^[4]

MORE REVELATION ON BENCE JONES PROTEIN

In the years following the discovery of Bence Jones protein, many researchers put forward their meaningful observations, corroborating as well as adding to the findings. J. F. Heller, Kühne and Huppert, to name a few of them.^[4] One important addition to the findings was by Bradshaw. He observed that meals had minimal to no effect on Bence Jones proteinuria levels, and he stated there was no nocturnal fluctuation and the rate of excretion remained somewhat consistent throughout the day.^[4,19]

Jacobson made another key observation in 1917. He discovered Bence Jones protein in the blood of a patient with bone pain, lytic lesions, anemia, Bence Jones proteinuria, and renal failure. A significant number of plasma cells in the bone marrow were also found postmortem. He suggested that renal failure caused the Bence Jones protein to be “dammed back” into circulation.^[20]

Walters proposed in 1921 that the Bence Jones protein was produced endogenously from blood proteins by abnormal bone marrow cells.^[7]

In 1922, Bayne-Jones and Wilson showed that the Bence-Jones proteins were composed of a number of related but not identical proteins. They identified two distinctly separate groups: Group I and Group II.^[7]

In 1956, Korngold and Lipari identified a link between Bence-Jones protein and serum proteins in patients of MM. The two Bence-Jones protein classes, kappa and lambda, are named after Korngold and Lipari.^[21]

Two years later, Harold Porter of England separated the antibody into two main parts: Heavy chains and light chains.^[3]

In 1962, Edelman and Gally analyzed the light chains of a patient with MM and a characteristic M-spike in the blood. The M-spike of this patient had been split into heavy and light chains. The properties of light chains derived from monoclonal immunoglobulin molecules in the spike were absolutely identical to those of the Bence-Jones protein from the same patient’s urine.^[22]

It took almost 115 years to solve the riddle of the origin of Bence-Jones protein after it was reported in 1848.

SERUM GLOBULIN

In 1928, Perlzweig et al., reported hyperproteinemia in a MM patient who had 9–11 g of globulin in his serum.^[23]

In 1937, Tiselius utilized the moving boundary method of electrophoresis to separate serum globulins into three components, which he designated: α, β, and γ.^[24]

It would not be out of context to highlight an intriguing fact here that the article, which led Tiselius to win the Nobel Prize and later to his presidency of the Nobel Foundation, had been initially rejected by the Biochemical Journal.^[7]

Longsworth et al., utilized electrophoresis to analyze MM cases in 1939, revealing the tall, narrow-based “church-spire” peak.^[25]

Grabar and Williams’ 1953 breakthrough of immunoelectrophoresis made it simpler to diagnose MM. Immunofixation is useful when immunoelectrophoresis findings are inconclusive. When immunoelectrophoresis fails to identify very small monoclonal light chains, immunofixation might be employed instead.^[4,26]

In 1982, a study by Reichert et al. revealed that, combined with immunofixation, high-resolution agarose gel electrophoresis is more sensitive than immunoelectrophoresis for identifying very small monoclonal proteins. Even though immunofixation has benefits, immunoelectrophoresis is a suitable first step since it is less technically complex and usually produces excellent results.^[4,27]

MONOCLONAL VERSUS POLYCLONAL GAMMOPATHIES AND WALDENSTRÖM

Waldenström [Figure 3] proposed the groundbreaking notion of monoclonal versus polyclonal gammopathies in 1961’s renowned Harvey Lecture series.^[28]

Close

Figure 3:

Jan Waldenström [Source: Wikipedia].

Export to PPT

He diagnosed individuals with a narrow band of hypergammaglobulinemia on electrophoresis as having a monoclonal protein. Some had MM or macroglobulinemia; others had “essential hypergammaglobulinemia” or a “benign monoclonal protein.”

Eventually, the entity becomes known as monoclonal gammopathy of undetermined significance (MGUS), which may progress to MM, macroglobulinemia, light-chain (AL) amyloidosis, or other comparable illnesses.^[29]

Waldenström referred to the wide band in hypergammaglobulinemia as a polyclonal protein increase. Patients with monoclonal gammopathies may develop a neoplastic process or malignancy, whereas those with polyclonal gammopathies may have an inflammatory or reactive condition. It’s critical to distinguish between the two.^[28]

ARE MONOCLONAL PROTEINS “ABNORMAL”?

Monoclonal proteins were considered abnormal due to their homogeneity that presents as a sharp band or a narrow spike on electrophoresis. Kunkel argued that malignant plasma cells generated monoclonal proteins, which were comparable to normal antibodies produced by normal plasma cells. Thus, monoclonal proteins were thought to represent an assortment of gamma globulins. He established that each heavy chain subclass and light chain type in monoclonal proteins has a corresponding equivalent in normal immunoglobulins and antibodies.^[30]

SERUM FREE LIGHT CHAINS (FLCS): CONCEPTS AND UTILITY

The major portion of immunoglobulin light chains is integrated into complete immunoglobulins through interacting with heavy chains. Nevertheless, even under physiological circumstances, unbound κ and λ light chains are secreted in modest amounts. For many years, the development of accurate serum tests for FLCs was hindered by the difficulty in producing antibodies that could distinguish between FLCs and those integrated into intact immunoglobulin. This issue was resolved in 2001 with the advent of immunoassays using polyclonal antibodies, which allowed for precise detection of FLCs within the normal physiological range.^[31]

These assays have thus far enabled a variety of diagnostic and monitoring applications in plasma cell dyscrasias, including MM, AL amyloidosis, and MGUS.^[32] In 2014, the International Myeloma Working Group (IMWG) amended the MM diagnosis criteria to include serum FLC testing. These guidelines suggest that an abnormal κ:λ ratio may indicate the presence of an M protein in circumstances when traditional approaches cannot be used to diagnose the condition. Furthermore, measurable illness is defined as an involved FLC concentration of >100 mg/L with an abnormal ratio.^[33]

The combination of serum protein electrophoresis (SPEP) or immunofixation with serum FLC testing improves the first evaluation of monoclonal gammopathies and has significantly decreased the need for preliminary urine studies.^[34] While SPEP alone detects around 80% of M-proteins, adding serum FLC testing raises the detection rate to 99.3%. Despite these advancements, SPEP remains the more sensitive method for detecting intact immunoglobulin myeloma.^[32,35]

Non-secretory myeloma, which accounts for 1–3% of all cases, is typically identified by the lack of detectable monoclonal immunoglobulins in both serum and urine electrophoresis. However, FLC test results show that <25% of these instances are actually non-secretory, with almost 75% exhibiting low but measurable amounts of monoclonal FLCs.^[35]

SFLC has also established its role as a prognostic marker in MGUS and SMM; it is also a standard marker of disease monitoring in MM. These aspects will not be covered in this review.

IMAGING IN MM: ARE YOU OBSERVING CLOSELY ENOUGH?

The initial documentation of bone disease in MM may be traced back to McIntyre’s autopsy, which found several rib fractures, barring the prehistoric cases.^[4] It has since become widely recognized that up to 90% of myeloma patients develop osteolytic lesions during the course of the disease.^[37] Radiographic imaging began in 1895, when the physicist Wilhelm Conrad Röntgen, working in a small German village, developed the first radiographic image with his newly discovered rays. To demonstrate their penetrative characteristics, he photographed his wife’s hand, revealing skeletal structures. Because their qualities were unknown, he referred to them as “X-rays.” The image, which was sent globally on Christmas Day 1895, heralded the clinical radiology.^[38]

In 1903, Weber reported the first radiographic detection of myeloma lesions. Since then, X-rays have become the central diagnostic technique for identifying myeloma-related skeletal lesions, both at the time of diagnosis and as the disease progresses.^[39] The presence of lytic lesions was subsequently incorporated into the diagnostic criteria for myeloma, and the extent of lytic involvement was included in the Durie-Salmon staging system, which debuted in 1975.^[40] However, one major drawback with conventional radiography is that lytic lesions are only detectable when 30–50% of bone mineral density has been lost.^[41]

Advances in imaging technology provided alternatives to plain radiography. In 1985, Horger et al. compared radiographic images of 32 myeloma patients to computed tomography (CT) and reported that CT revealed more lesions than conventional skeletal surveys. Nonetheless, radiation exposure from standard-dose CT was significant, with effective doses ranging from 25.5 to 36.6 mSv. This concern prompted the emergence of low-dose imaging methods. Horger et al. invented whole-body low-dose CT (WBLDCT) in 2005, which uses a conventional tube voltage (120 kV) but a lower tube current (40–70 mAs), resulting in much decreased radiation exposure (4.1–7.5 mSv) while preserving diagnostic performance.^[42] WBLDCT was subsequently integrated into the 2014 IMWG diagnostic criteria.

Given that bone marrow infiltration in myeloma is usually patchy rather than homogeneous, sophisticated imaging methods have become critical for detecting both diffuse and focal involvement. Functional modalities like Fluorine-18 fluoro-deoxy-glucose positron emission tomography/CT (¹⁸FDG PET/CT) and whole-body magnetic resonance imaging (MRI) provide information on skeletal destruction, tumor burden, and disease activity across extensive marrow regions.^[33] MRI was brought into clinical practice in the early 1980s, with early investigations proving its importance in detecting bone marrow involvement in MM.^[43,44] Its diagnostic relevance was explicitly recognized in 2014, when MRI was integrated into the IMWG criteria.^[33]

The introduction of PET/CT furthered the combination of functional and anatomical imaging. R. Raylman presented the idea of merging both modalities in his 1991 Ph.D. Thesis,^[45] and the National Cancer Institute sponsored the first clinical PET/CT prototype, which was placed at the University of Pittsburgh Medical Center in 1998.^[46] The clinical use of PET/CT in MM developed in the late 1990s,^[47] and it was later integrated into the 2014 IMWG diagnostic framework.^[33]

More recent research, such as the study by Rasche et al. in 2017, has highlighted biological limitations of FDG-PET in MM, noting that reduced expression of hexokinase 2, a glycolytic enzyme, may lead to false-negative results and consequent underestimation of disease burden.^[48]

To address the individual limitations of PET/CT and MRI, hybrid PET-MRI technology is currently under investigation. This modality allows simultaneous assessment of osseous, extra-medullary, and spinal lesions within a single examination, combining the metabolic sensitivity of PET with the superior soft-tissue contrast of MRI, and importantly, without additional radiation exposure. Baseline PET imaging also offers valuable prognostic insights.^[49,50]

Figure 4 highlights the landmark events in the history of multiple myeloma spanning over 150 years.

Close

Figure 4:

Important events in the history of multiple myeloma spanning 150 years.

Export to PPT

CONCLUSION

The story of MM is not only a success story, but also an exciting one. The best of the brilliant minds of centuries are working on different aspects of this intriguing disease and throwing light on its different facets, leading to ever-growing understanding of the disease. And that is why, what started with clinical description of disease, postmortem findings, and so-called “simple” biochemical analysis of urine, after almost 150 years, delves into proteogenomic landscapes. And without any doubt, it is the beginning.