What Is Bence-Jones Protein, and Where Does Its Name Come From?

What Is Bence-Jones Protein?

Bence-Jones protein is a small protein made by plasma cells, which are antibody-producing white blood cells. A hematological cancer starting in plasma cells is multiple myeloma, and this protein is present in large quantities in the urine of most people with it.

In other words, Bence-Jones proteins are monoclonal free light chains of immunoglobulin.

An increased Bence-Jones protein level is usually seen in cancer. In addition to multiple myeloma, urinary Bence-Jones proteins are also observed in patients with Waldenstrom macroglobulinemia, chronic lymphotic leukemia, and other B-cell cancers.

Where Does the Name Bence-Jones Protein Come From?

The namesake of Bence-Jones protein, Henry Bence Jones, was born in Suffolk, England, in 1813. He completed his undergraduate, postgraduate, and medical education at Cambridge University.

In 1845, Dr. Bence Jones was appointed a resident physician and faculty member at St. George Hospital. That same year, he was asked to analyze a urine sample from Thomas Alexander McBean, a London grocer experiencing sudden and persistent chest pain.

Dr. William MacIntyre, who treated McBean, had noted peripheral edema. Suspecting nephrotic syndrome, MacIntyre tried to precipitate albumin by heating and cooling the patient’s urine and adding nitric acid. Heating the sample isolated albumin, but adding nitric acid caused the precipitate to disappear. The urine became clear and remained so for 1-1.5 hours. When the sample was reheated, the dissolved solid turned into a yellow substance.

Unable to identify the cause of this thermolability, Dr. MacIntyre sent a urine sample to Dr. Bence Jones. He concluded that this heat-precipitated protein, which would later bear his name, was a protein different from albumin.

McBean died in 1846, and his autopsy revealed soft, fragile ribs. In 2 articles subsequently published on the urinary findings, Dr. Bence Jones advised readers to look for this protein in cases of “mollities ossium,” now known as multiple myeloma.

The term “Bence-Jones protein” was first used by Dr. Richard Fleischer in 1880. Because he emphasized the urinary findings, Dr. Bence Jones was honored as the discoverer of the protein.

Dr. Bence Jones died of heart failure in 1873 at age 60. The announcement of his death did not mention his work on the urinary proteins later named after him.

Years after Dr. Bence Jones, in 1956, Leonard Korngold and Rose Lipari discovered the monoclonal nature of Bence-Jones proteins after finding them in the serum of patients with multiple myeloma.

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The Current State of Multiple Myeloma Treatment – Summary

Confirming the Diagnosis: The first step in evaluating a new patient with multiple myeloma (MM) is to confirm the diagnosis, because premalignant stages of myeloma, namely monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), can easily be misdiagnosed as MM.

• Management of SMM depends on risk stratification.
• Patients with end-organ damage attributable to the underlying plasma cell disorder or other myeloma-defining biomarkers require treatment.
• All patients with confirmed MM should start treatment immediately. Without effective treatment, symptomatic patients have a life expectancy of less than one year.

Risk Stratification: Cases are divided into risk strata based on fluorescence in situ hybridization (FISH) results for specific translocations and certain other tests. This risk classification has important prognostic value and also helps guide the choice of initial treatment.

• High-Risk Myeloma: Includes patients with FISH evidence of t(4;14), t(14;16), t(14;20), del17p13, or addition of 1q; those with lactate dehydrogenase (LDH) ≥2 times the upper limit; and those with features of primary plasma cell leukemia.
• Standard-Risk Myeloma: Includes patients without any of the high-risk cytogenetic abnormalities or features. This includes patients with trisomy, t(11;14), and t(6;14).

Determining Transplant Eligibility: All patients are evaluated for eligibility for autologous hematopoietic cell transplantation (HCT), which appears to prolong both event-free and overall survival compared with nontransplant strategies. Eligibility for HCT varies among institutions. Although guidelines exist, eligibility should take account of a risk-benefit assessment and the patient’s needs and wishes.

HCT-eligible patients receive induction treatment for three to four months before stem cell collection to reduce the number of tumor cells in the bone marrow and peripheral blood, relieve symptoms, and reduce end-organ damage. After recovering from stem cell collection, patients may proceed directly to autologous HCT (an early transplant strategy) or continue treatment, usually with the induction regimen, reserving autologous HCT until the first relapse (a delayed transplant strategy).

In Standard-Risk Myeloma Treatment Approach: Treatment of standard-risk MM depends on HCT eligibility and comorbidities.

• HCT-eligible patients with standard-risk MM receive a triplet regimen for three to four months before stem cell collection.
  • After stem cell collection, early or delayed autologous HCT is recommended rather than chemotherapy alone or allogeneic HCT (Grade 1B).
  • Studies comparing early and delayed transplant strategies have shown similar survival rates, so either option is acceptable for most patients. The decision is individualized according to patient preference, age, response and tolerance to initial chemotherapy, and logistical factors. Importantly, patients choosing to delay transplantation may experience an event or complication that makes them ineligible in the future.
  • Those proceeding with early transplantation are offered maintenance treatment for at least two years afterward. Those choosing to defer HCT until the first relapse complete a total of 8 to 12 cycles of triplet therapy followed by lenalidomid-based maintenance until relapse.
• Most HCT-ineligible patients are recommended a bortezomib-based triplet regimen for 8 to 12 cycles, followed by lenalidomid-based maintenance. For frail patients considered unsuitable for triplet treatment, dual treatment with lenalidomid and low-dose deksametazon is recommended, switching to single-agent lenalidomid after 9 cycles.

High-Risk Myeloma: Patients with high-risk MM should be encouraged to participate in a clinical trial investigating new therapeutic strategies because all conventional treatment options fail in these patients. Outside a clinical trial, data are limited and experts differ in their approaches. For transplant-eligible patients, induction therapy followed by early autologous HCT and proteasome inhibitor-based maintenance is recommended. Transplant-ineligible patients are offered 8 to 12 cycles of triplet-based induction therapy followed by proteasome inhibitor-based maintenance.

Supportive Treatment: In addition to treatment directed at the malignant clone, management of most patients with MM includes preventive measures to reduce skeletal events, kidney injury, infections, and thrombosis. Patients may also need specific interventions for hypercalcemia, anemia, and neuropathy.

Assessing Response: Patients should be assessed before each treatment cycle to determine how their disease is responding.

Relapsed Disease: Relapsed or refractory MM is usually identified during routine surveillance. Treatment is individualized according to prior therapy, response, and the likelihood that the disease is sensitive or resistant to previous agents.