We tried, myeloma world, but we couldn't come up with a short title for today's report.

There were just too many words needed to describe the three research articles that we plan to review with you in this edition of Myeloma Morning.

First, we have an important new study out of Spain that in­ves­ti­gates the sig­nif­i­cance of Bence Jones protein in smol­der­ing multiple myeloma patients.

Next, we turn to a study by researchers in Japan. They in­ves­ti­gate different methods for measuring a person's bone marrow plasma cell per­cent­ages, and how those methods can lead to different results.

Finally, we wrap up today's report with a look at an important study about a protein known as TJP1. Levels of the protein in a patient's myeloma cells may predict how well the patient will respond to treat­ments in the pro­te­a­some inhibitor class of ther­a­pies, which in­cludes Velcade (bor­tez­o­mib), Kyprolis (car­filz­o­mib), and Ninlaro (ixazomib).

Bence-Jones Protein In Smoldering Multiple Myeloma

We start our research summaries today with a study by a group of well-known myeloma researchers based in Spain. One of the lead authors of the study is Dr. María-Victoria Mateos, and the study concerns a subject that Dr. Mateos has in­ves­ti­gated in the past: smol­der­ing multiple myeloma.

In the current study, the authors in­ves­ti­gate Bence Jones protein and whether its presence in a patient's urine is a risk factor for pro­gres­sion from smol­der­ing multiple myeloma to active multiple myeloma (abstract).

The Spanish researchers find that smol­der­ing multiple myeloma patients who had Bence Jones protein in their urine at diag­nosis were more likely to progress to symp­tomatic multiple myeloma than smol­der­ing myeloma patients who did not have Bence Jones protein in their urine at diag­nosis.

Moreover, the impact of having Bence Jones protein in the urine at diag­nosis was independent of other factors known to affect a patient's risk of pro­gres­sion.

Background And Basic Information About The Study

Bence Jones proteins are immuno­glob­u­lin light chains found in the urine. They are a common symp­tom of multiple myeloma, and result when a patient's kidneys inadequately filter the light chains being produced by the patient's plasma cells. The unfiltered light chains end up in the patient's urine as Bence Jones protein.

The authors of the Spanish study conducted their investigation because they hypothesized that the presence of Bence Jones protein might reflect a high multiple myeloma tumor burden. Measures of tumor burden – such as patient's bone marrow plasma cell per­cent­age – traditionally have been good predictors of the risk of pro­gres­sion from smol­der­ing to symp­tomatic myeloma.

The researchers collected data for all people diag­nosed with smol­der­ing multiple myeloma in the Spanish region of Castilla-León between 1986 and 2013. They eventually compiled data on 152 smol­der­ing myeloma patients. The median age at diag­nosis of the patients was 70.

All patients had been tested for Bence Jones protein at diag­nosis. The protein was found in 27 per­cent of the cases, and the median level among those with the protein was 100 mg/24hr; 17 per­cent of the patients had a reading of 500 mg/24hr or more.

Bence Jones Protein And Risk Of Progression

Across all 152 patients in the sample, 48 per­cent progressed to symp­tomatic myeloma during the follow-up time. The median time to pro­gres­sion was 68 months.

Among the patients who had Bence Jones protein in their urine at diag­nosis, 59 per­cent progressed to symp­tomatic myeloma.

Importantly, the median time to pro­gres­sion was shorter in patients who had Bence Jones protein at diag­nosis (22 months) than in patients without Bence Jones protein at diag­nosis (88 months).

The researchers divided the patients further into three risk subgroups based on the amount of Bence Jones proteins in the urine: those with 500 mg or more /24hr; those with more than 0, but less than 500 mg/24 hr; and those without Bence Jones proteins in the urine.

They found that patients with the highest level of Bence Jones protein in the urine (500 mg or more /24 hr) had the shortest median time to pro­gres­sion (13 months), compared to patients with lower amounts of Bence Jones protein (37 months), and those without any Bence Jones protein in the urine (88 months).

Finally, the investigators tested whether the presence of Bence Jones protein had an independent effect on the risk of pro­gres­sion. This test was designed to answer the question: “If I know that a smol­der­ing myeloma patient is at a low risk of pro­gres­sion because, for example, they have a low M-spike and low bone marrow plasma cell per­cent­age, does it really matter whether or not they have Bence Jones protein in their urine?”

The answer is “Yes, it does matter.” When the Spanish researchers added a variable reflecting the presence of Bence Jones protein to standard models that predict a patient's risk of pro­gres­sion, the Bence Jones variable was statistically and clin­i­cally sig­nif­i­cant using data for the patients in their study.

(And when we say “standard models”, we mean models that in­clude the well-known Mayo Clinic and Spanish models for predicting the risk of pro­gres­sion from smol­der­ing to symp­tomatic multiple myeloma.)

Based on their findings, the Spanish researchers conclude that “the presence of Bence Jones proteinuria at diag­nosis of smol­der­ing multiple myeloma patients is asso­ci­ated with a sig­nif­i­cantly higher probability of pro­gres­sion to symp­tomatic multiple myeloma. Detection of Bence Jones proteinuria may help identify high-risk patients.”

The researchers also note that the presence of especially high (greater than 500 mg/24hr) levels of Bence Jones protein could be con­sidered a sign of ultra-high risk smol­der­ing myeloma, and may identify smol­der­ing patients who should be actively treated at diag­nosis.

Measuring The Bone Marrow Plasma Cell Percentage

We turn next to a study carried out by researchers in Japan (abstract). It concerns different methods that can be used to measure a person's “bone marrow plasma cell per­cent­age”, often just described as the “plasma cell per­cent­age.” This metric is the per­cent of cells in a bone marrow sample that are plasma cells.

The plasma cell per­cent­age is an important number in multiple myeloma. It is used to assess a patient's tumor burden at diag­nosis and during treat­ment. It also is frequently used to determine whether someone has smol­der­ing multiple myeloma or MGUS (monoclonal gam­mop­athy of undetermined sig­nif­i­cance).

It turns out, however, that there are different ways to measure a person's plasma cell per­cent­age, and they do not often agree. This is what motivated the authors of the Japanese study. They wanted to add to existing research com­par­ing the different ways to calculate the plasma cell per­cent­age. They also wanted to assess the reliability of an alter­na­tive way of measuring the per­cent­age.

There are two different bone marrow samples that can be used to calculate the plasma cell per­cent­age: the aspirate sample, and the core marrow sample. Two of the common methods to calculate the per­cent­age are based on aspirate samples, and a third is based on the core marrow sample.

The three common methods of plasma cell per­cent­age mea­sure­ment are:

1. Aspirate – May-Giemsa stain
2. Aspirate – flow cytometry analysis (CD38/CD45/CD138)
3. Core sample – CD138 immunohistochemistry

An alter­na­tive that the Japanese researchers in­ves­ti­gate also is based on the aspirate, but the aspirate sample is allowed to clot before the mea­sure­ment is carried using CD138 immunohistochemistry.

4. Aspirate (clot) - CD138 immunohistochemistry

We checked with Beacon Medical Advisor Dr. James Hoffman of the Sylvester Cancer Center in Miami, and he con­firmed that methods #1, #2, and #3 are commonly used in the United States, with method #1 being the most frequently relied upon method.

The Japanese researchers compared the results of all four methods – that is, the three common methods, and the one alter­na­tive – using 150 sets of bone marrow samples from 120 multiple myeloma and MGUS patients seen at a single treat­ment center in Japan from April 2011 to December 2015.

Based in part on the results of pre­vi­ous research, the authors con­sidered method #3, which calculates the plasma cell per­cent­age using the core marrow sample, to be the “gold standard” for plasma cell per­cent­age mea­sure­ment.

The authors therefore focused on how results for the other three methods compare to those from the core sample.

What they found is that the traditional aspirate methods (#1 and #2) yielded results that were con­sis­tently lower than the core sample methodology. The alter­na­tive clot-based aspirate ap­proach (#3), on the other hand, produced plasma cell per­cent­age mea­sure­ments that were con­sis­tently very close to those of the core sample ap­proach.

The difference in plasma cell per­cent­age esti­mates between the traditional aspirate methods (#1 and #2) and the core sample method (#3) were sub­stan­tial enough, the Japanese researchers note, that they could have altered whether many of the MGUS patients in their sample were classified as MGUS or smol­der­ing multiple myeloma.

The myeloma specialists we have consulted on this issue, however, question whether switching the diag­nosis in such cases would be warranted. In an oft-referenced posting in the Beacon's discussion forum, for example, Beacon Medical Advisor Dr. Peter Voorhees of the University of North Carolina – Chapel Hill lays out the issue and his ex­peri­ence related to it:

“If someone has 6% plasma cells by aspirate and 13% by CD138 on core biopsy, are they an MGUS patient or a smol­der­ing myeloma patient? In my ex­peri­ence, patients with these results tend to behave more like MGUS. As such, I am hesitant to call it smol­der­ing myeloma under those cir­cum­stances.”

In any case, the Japanese research is a helpful reminder to Beacon readers that different methods for measuring the bone marrow plasma cell per­cent­age can yield different results.

Tight Junction Protein 1 (TJP1) And Proteasome Inhibitor Sensitivity

We wrap up our report today with a look at an important new study by a team of U.S. and Chinese researchers. They conclude that a protein known as “tight junction protein 1”, or TJP1, is a marker of how well a multiple myeloma patient will respond to pro­te­a­some inhibitor treat­ments such as Velcade, Kyprolis, and Ninlaro (abstract).

The new study has been published in the highly regarded journal Cancer Cell, and it summarizes an extensive body of research. In their article, the authors explain how they developed the hypothesis that TJP1 might be linked to pro­te­a­some inhibitor sensitivity, how they tested the hypothesis in multiple myeloma cell lines in both test tube and animal model experiments, and how they explored the sig­nif­i­cance of TJP1 in the results of clin­i­cal trials.

Based on their findings, the authors conclude that multiple myeloma patients with tumor cells producing high levels of TJP1 are more likely to respond to treat­ment with a pro­te­a­some inhibitor than patients whose tumor cells are producing low levels of TJP1.

The researchers also identify ways that TJP1 inter­acts with other proteins in multiple myeloma cells, and these inter­actions may offer opportunities for overcoming resistance to pro­te­a­some inhibitors by combining them in novel ways with other drugs.

In particular, TJP1 seems to affect what the authors describe as the “EGFR/JAK1/STAT3 path­way” in multiple myeloma cells. This inter­action suggests that combining an EGFR inhibitor such as the Tarceva (erlotinib), or a JAK1 inhibitor such as Jakafi (ruxolitinib), with a pro­te­a­some inhibitor could im­prove the anti-myeloma activity of the pro­te­a­some inhibitor in patients who would other­wise be resistant to it. This ap­proach may have the highest likelihood of success, the authors note, in patients whose myeloma cells produce high levels of the protein EGFR.

In a summary of their research, the investigators write that their findings

“provide a framework for the use of TJP1 as a bio­­marker to target pro­te­a­some inhibitor-based ther­apy to those patients who are most likely to benefit. Moreover, they provide a roadmap for translation of ap­proaches targeting the EGFR/JAK1/STAT3 path­way to en­hance pro­te­a­some inhibitor sensitivity, and possibly overcome pro­te­a­some inhibitor resistance.”

New Myeloma-Related Research Articles

1. González-Calle, V. et al., “Bence Jones proteinuria in smoldering multiple myeloma as a predictor marker of progression to symptomatic multiple myeloma” in Leukemia, May 2, 2016 (abstract)
2. Kiely, F. et al., “Self-reported quality of life and symptom burden in ambulatory patients with multiple myeloma on disease-modifying treatment” in the American Journal of Hospice and Palliative Care, May 2, 2016 (abstract)
3. Matsue, K. et al., “Quantification of bone marrow plasma cell infiltration in multiple myeloma: usefulness of bone marrow aspirate clot with CD138 immunohistochemistry” in Hematological Oncology, May 3, 2016 (abstract)
4. Sangani, R. G. et al., “Echocardiography-defined pulmonary hypertension in multiple myeloma: risk factors and impact on outcomes” in the Southern Medical Journal, May 2016 (abstract)
5. Zhang, X. D. et al., “Tight Junction Protein 1 Modulates Proteasome Capacity and Proteasome Inhibitor Sensitivity in Multiple Myeloma via EGFR/JAK1/STAT3 Signaling” in Cancer Cell, April 28, 2016 (abstract)