Good morning, myeloma world.

It truly was a dark and stormy night when we sat down early yesterday to start writing the next edition of Myeloma Morning. A spring windstorm was howling about outside and, before we knew it, the wily gusts had conspired to knock out electricity at Myeloma Morning Headquarters.

Fortunately, the watts and volts are back in working order, and we're glad to be writing for you again.

All the news we cover in today's Myeloma Morning concerns recently published research studies.

One study by German researchers was published a few days ago in the journal Blood, an important venue for the publication of myeloma-related research. The German study reports findings related to B cells and multiple myeloma that could be useful for the development of new immunotherapies directed against the disease.

A second study investigates whether Velcade (bortezomib) may have pro-myeloma effects in addition to its well-known anti-myeloma activity.

A third study explores whether a new class of drugs, known as PRL-3 inhibitors, could be effective in the treatment of multiple myeloma.

Finally, the last research study we will look at today concerns gene expression profiling (GEP). We men­tioned this study in a previous edition of Myeloma Morning, but said we would look at it in more detail at a later date. Readers who are not familiar with gene expression profiling may want to be sure to read this part of today's report, since it includes useful background information about what GEP is and how it is used.

Learning From B-Cell Responses To Multiple Myeloma

The first study we will look at today is by a group of German researchers. Their study focuses on B cells, the category of white blood cells that includes plasma cells. Myeloma cells, as many of our readers are aware, are unhealthy plasma cells that reproduce in an uncontrolled way.

The authors of the German study focus, in particular, on the role healthy B cells play in combating multiple myeloma. They investigate this issue in several ways. For example, they examine the activity of B cells in a small sample of 18 myeloma patients. Eleven of the patients had received an allogeneic (donor) stem cell transplant. All but one of the remaining seven patients had undergone an autologous (own) stem cell transplant. The patients who had received an allogeneic stem cell transplants had considerably more anti-myeloma B cell activity than the patients who had received autologous transplants.

The German researchers also describe a relatively inexpensive and fast methodology for investigating how B cells target and attempt to counteract multiple myeloma cells.

Because the German study is quite technical, we sought insights into it and its implications from Dr. Michaela Reagan, a myeloma researcher at the University of Maine and the Maine Medical Center Research Insitute. Dr. Reagan and several of her colleagues recently published a survey article about the biology and treatment of multiple myeloma (abstract) that we mentioned in a previous edition of Myeloma Morning.

Dr. Reagan noted that one reason the German study is significant is its focus on how healthy B cells defend the body against multiple myeloma. Much of the research about how the body defends itself against multiple myeloma focuses on another group of white cells, known as T cells, rather than B cells.

In addition, Dr. Reagan called attention to the “platform” – or methodology – the authors of the new study have developed for investigating B cell activity against multiple myeloma. This platform could be leveraged by other researchers to identify new immunotherapy-based approaches for treating multiple myeloma.

This is something Dr. Mascha Binder, one of the authors of the German study, echoed in comments about the paper she shared with The Beacon. “Our screening platform,” she said, “can be used to discover myeloma-specific cell surface target structures, thereby promoting the development of novel therapeutic monoclonal antibodies or CAR T-cell approaches.”

Does Velcade Have A Pro-Myeloma Effect?

A group of Israeli researchers have published a study reporting that Velcade may have pro-myeloma effects in addition to its well-known – and significant – anti-myeloma effects (abstract).

The authors report the results of several experiments that shed light on the potential pro-myeloma effect of Velcade. In one experiment, for example, the researchers injected myeloma cells into two groups of healthy mice. One group of mice had previously been given Velcade. The other group had been given a placebo. The mice who had been given Velcade died from the injected myeloma cells sooner than the other mice.

The results of this study do not alter, of course, the known anti-myeloma effects of Velcade – a drug widely regarded as having played an important role in improving the survival of myeloma patients in the past 10 to 15 years. The Israeli findings may lead, however, to additional research that could improve the efficacy of Velcade and other myeloma therapies.

PRL-3 As A Target For Multiple Myeloma Treatment?

The third new research article that we'll look at today is from researchers in Norway. They investigate whether reducing (inhibiting) the activity of an enzyme known as PRL-3 could be a new way to treat multiple myeloma (full text).

PRL-3 inhibition is being investigated as a way to treat a number of different cancers. The Norwegian study involved a number of laboratory experiments using myeloma cell lines to see if PRL-3 inhibition might work as a new way to treat multiple myeloma. The experiments included tests of a specific PRL-3 inhibitor that is so new it is known only by its chemical name (1-4-bromo-2-benzylidene rhodanine).

The authors of the new study find that inhibiting PRL-3 in fact does reduce the survival of myeloma cells in various laboratory tests. They therefore believe the method should be explored further, particularly in testing that would establish whether PRL-3 is a safe approach to cancer therapy.

Translating GEP Risk Signatures

Most myeloma patients and caregivers have heard about chromosomal abnormalities. They are the “translocations,” “deletions,” and “additions” of chromosomes in myeloma cells that can affect whether a patient's disease is considered “high risk”, “standard risk,” or perhaps “intermediate risk”. High-risk disease is likely to be more difficult to treat, with shorter times to relapse.

Chromosomal abnormalities are the most common way myeloma specialists assess the risk status of a patient's disease. Indeed, a recent edition of Myeloma Morning discussed the new International Myeloma Working Group consensus statement about which chromosomal abnormalities are markers of high-risk disease.

But chromosomal abnormalities are not the only game in town when it comes to assessing whether a patient has high-risk or standard-risk disease. Another approach, known as gene expression profiling (GEP), is preferred by some myeloma specialists and institutions – the most prominent example being the University of Arkansas of Medical Sciences (UAMS).

What is gene expression profiling?

A GEP test of a person's myeloma cells measures the activity of specific genes in those cells. A single GEP test typically will assess the activity of many genes all at once. A common UAMS-developed GEP test, for example, assesses the activity of 70 genes.

A person's GEP test result is their GEP “profile”, which consists of the list of genes tested during the GEP, and whether each gene was active or not.

Over time, myeloma specialists have determined that certain GEP profiles are associated with higher-risk disease, and others with lower-risk disease. This has led to the development of “GEP risk signatures”, which translate a patient's long list of GEP test results into a single number, or a classification, that describe how “high risk” a patient's disease is likely to be.

A GEP risk signature might take a patient's GEP profile and say that, on a scale of 0 to 100, where 0 is very low risk and 100 is very high risk, the patient's risk score is 38, or low risk.

Different research groups have developed different GEP risk signatures. There are about ten such signatures. They differ in terms of both the number of genes they include and the specific genes they include.

The need for GEP signature translation

There is a problem developing, however, with GEP risk signatures. Most of the widely used GEP signatures for multiple myeloma are based on results from testing equipment that have been is becoming dated. Newer GEP testing equipment uses more detailed probes to measure the activity of individual genes. The new equipment is being used more and more in laboratories around the world.

In some ways, this “problem” is a good problem. The new GEP equipment will give researchers more information about the genetics of multiple myeloma cells. This could improve treatment outcomes and possibly aid in the development of new myeloma therapies.

The downside of the new equipment is that the GEP results it produces cannot just be plugged into existing GEP risk signatures. Completely different probes are used with the new equipment to measure genetic activity, and these measurements are different than what was provided by the probes used with the older equipment.

A new study by Danish researchers attempts to address the “problem” being created by new GEP equipment by finding out whether a “translation” can be done of results from the new equipment (abstract).

The researchers gathered detailed information on the probes used by the new GEP equipment and the probes used as the basis for nine GEP risk signatures created using old GEP equipment.

Next, they created translation rules, saying – for example – that if probe “X” from the new equipment detected activity, it was the same as if probe “A” from the old equipment detected activity. These rules were developed based on manufacturer information about what each probe was designed to detect. Of course, translations were not always possible, but many were.

The researchers then used new GEP equipment to collect GEP test results from over 120 multiple myeloma patients. The patients were a mix of newly diagnosed patients planning to undergo a stem cell transplant, and patients who already had undergone a transplant. The GEP testing was done with the explicit purpose of seeing how accurate translation of the GEP results would be.

(The study focused on stem cell transplant patients because this group of patients has been the traditional focus of researchers who have developed GEP risk signatures.)

The GEP test results for each patient in the Danish study were translated into up to nine different GEP risk signatures. The study authors then checked to see how well the translated GEP signatures were able to predict progression-free survival and overall survival in the myeloma patients.

The authors found that creating translated risk signatures was useful. On the one hand, the translated signatures were not as strongly predictive of patient outcomes as probably would have been the case if the signatures had been generated using the original GEP probes associated with the signatures. On the other hand, a number of the individual translated signatures – as well as combinations of the translated signatures – were still very good at predicting survival outcomes,

“Translated GEP risk signatures maintain significant prognostic power” in myeloma patients who undergo stem cell transplantation, the authors conclude.

(We are grateful for the assistance of Dr. Emil Hermansen, lead author of the Danish study, in the devel­op­ment of our summary of that study. Dr. Hermansen generously provided insight into the motivation for the study and how it was carried out. Our summary of the study and its results, however, is our own; it has not been reviewed or approved by Dr. Hermansen.)

New Myeloma-Related Research Articles

1. Beyar-Katz, O. et al., “Bortezomib-induced proinflammatory macrophages as a potential factor limiting anti-tumour efficacy” in The Journal of Pathology, April 1, 2016 (abstract)
2. Fook-Alves, V. L. et al., “TP53 regulated inhibitor of apoptosis 1 (TRIAP1) stable silencing increases late apoptosis by upregulation of caspase 9 and APAF1 in RPMI8226 multiple myeloma cell line” in Biochimica et Biophysica Acta, March 24, 2016 (abstract)
3. Miletić, V. et al., “Neuropathic tremor associated with anti-MAG IgM-monoclonal gammopathy and prostate adenocarcinoma: Which one is the culprit?” in Parkonsonism & Related Disorders, March 16, 2016 (abstract)
4. Paulino Pereira, N. R. et al., “Are allogeneic blood transfusions associated with decreased survival after surgical treatment for spinal metastases?” in The Spine Journal, March 23, 2016 (abstract)
5. Schieferdecker, A. et al., “A transplant immunome deep sequencing and screening platform defines a unique targetable epitope fingerprint of multiple myeloma” in Blood, March 31, 2016 (abstract)
6. Slørdahl, T. S. et al., “The phosphatase of regenerating liver-3 (PRL-3) is important for IL-6-mediated survival of myeloma cells” in Oncotarget, March 31, 2016 (full text)
7. Takeda, T. et al., “Mangiferin enhances the sensitivity of human multiple myeloma cells to anticancer drugs through suppression of the nuclear factor κB pathway” in The Journal of Oncology, April 1, 2016 (abstract)