How has your week started, myeloma world?

We hope it's going well so far.

We once again have a rather long list of new myeloma research we'd like to discuss with you. We sus­pect most of our readers will find at least one or two studies in the report to be of particular interest.

We begin today's report with a discussion of a somewhat rare eye-related side effect of Velcade ^[1] (bor­tez­o­mib) and a possible way to control the side effect.

Next, we take a quick look at two articles about imaging for people with multiple myeloma, then turn to a study about weight and multiple myeloma in African Americans.

Finally, we wrap up today's report with a study about dialysis options and a separate study about a novel use of free light chain testing.

Velcade-Related Eye Inflammation, Styes, And Doxycycline

We start today's review of new multiple myeloma research articles with an study by three Belgian physicians. The authors discuss a somewhat rare – but very bothersome – side effect of Velcade: blepharitis, or inflammation of the eyelids. The article describes the side effect, focusing on two specific cases of it, and documents how treat­ment with the antibiotic doxycycline may help control the side effect (abstract ^[2]).

Based on the number of case reports that have appeared in the literature since it was first reported two years ago, it appears that blepharitis and other related side effects are not uncommon among people being treated with Velcade.

Indeed, a number of Beacon readers have described the side effect in the Beacon's discussion forum; see, for example, this discussion ^[3] started two years ago, which in­cludes comments by two Beacon Medical Advisors, and a separate discussion ^[4] started late last year.

The authors of the new Belgian study note that, when blepharitis occurs in patients being treated with Velcade, it usually starts about two or three months after the patient begins Velcade ther­apy. The inflammation seems more likely to affect the upper eyelids than the lower eyelids, and it generally in­cludes the devel­op­ment of styes.

In some cases, the inflammation and styes can be controlled with treat­ments – in­­clud­ing antibiotics – applied to the eyes. However, this does not always work, and up until now it has not been uncommon for patients to have to stop their Velcade ther­apy because the blepharitis be­comes so severe.

Thus, the authors sought a way to make it possible for patients suffering from severe blepharitis to con­tinue Velcade treat­ment. The authors believe the antibiotic doxycycline may be one possible solu­tion to the problem.

Two of the authors' patients devel­oped severe blepharitis while on Velcade ther­apy, and the blepharitis responded only marginally to treat­ments applied directly to the eyes, such as antibiotic eye drops. The doctors then tried having the patients take one 100 mg capsule of doxycycline each day.

In both patient, the doxycycline was able to control the blepharitis after about two months. The blepharitis was not com­pletely elim­i­nated, but it was reduced so that it was mainly just redness. The patients did have to con­tinue on the doxycycline, how­ever, for an extended amount of time – up to 10 months in one case.

The study authors note that it is not yet clear why some patients treated with Velcade develop blepharitis. They add that

“It has been hypothesized that the pro­te­a­some blocking action of [Velcade] en­hances the release of pro-inflammatory cytokines, which incite sys­temic inflammation, as reflected in skin rashes, and ocular inflammation, in the form of blepharitis.”

If this hypothesis is correct, cases of blepharitis could start appearing in multiple myeloma patients being treated with Kyprolis ^[5] (car­filz­o­mib) or Ninlaro ^[6] (ixazomib), given that those drugs also are pro­te­a­some inhibitors like Velcade.

Imaging For People With MGUS & Multiple Myeloma

We have two articles about imaging (x-rays, MRIs, PET/CT scans, and the like) in today's list of new myeloma-related research. Both articles are review articles rather than summaries of new research results.

The first imaging-related article is by Dr. Elisabet Manasanch of the M.D. Anderson Cancer Center in Houston and Dr. Ola Landgren of Memorial Sloan-Kettering Cancer Center in New York City. The article is positioned as a commentary on another article in the same journal ^[7]. It is, how­ever, more of an editorial.

In particular, the article by Drs. Manasanch and Landgren – which is titled “Myeloma imaging: time to move on!” – argues for greater reliance on modern, whole-body imaging methods instead of con­ven­tional x-rays in the diag­nosis and man­agement of multiple myeloma.

The authors recog­nize that im­por­tant guidelines, such as those from the National Comprehensive Cancer Network (NCCN), call for whole body MRI or PET/CT only in certain cir­cum­stances. The NCCN guidelines, for example, state that, when deciding whether a newly diag­nosed patient has smol­der­ing or symp­tomatic multiple myeloma, MRI and PET/CT should only be used when x-rays do not conclusively decide the diag­nosis.

However, Drs. Manasanch and Landgren believe there is too much value in imaging methods more modern than x-rays for them not to be used more frequently. The newer imaging methods, the authors argue, provide more in­for­ma­tion about the status of a patient's disease, and about a patient's prognosis. For these reasons, the authors write, “in our clin­i­cal practice, PET-CT has replaced the role of skeletal x-ray.”

The second of the two imaging articles was published back in March, but it just came to our attention. It's a general look at when to use dif­fer­en­t kinds of imaging in patients with multiple myeloma and other plasma cell disorders. The authors of the review are primarily imaging specialists asso­ci­ated with the M.D. Anderson Cancer Center in Houston, and the article has a number of examples of dif­fer­en­t types of imaging used in dif­fer­en­t situations related to the treat­ment and man­agement of multiple myeloma and related disorders.

Body Weight And Multiple Myeloma In African Americans

A new study by U.S. researchers in­ves­ti­gates the link be­tween body weight and multiple myeloma in African Americans. The study con­firms results seen in other studies with data for people of predominantly European descent; namely, that being overweight is a risk factor for devel­op­ing multiple myeloma (abstract ^[8]).

The new study is based on data for almost 240,000 African Americans who took part in seven dif­fer­en­t long-term health studies. None of these studies was focused specifically on multiple myeloma.

For each of the 240,000 people in the over­all sample, the researchers had in­for­ma­tion on the person's height and weight when they entered the study they took part in. Further­more, if someone died during the course of the study they par­tic­i­pated in, their under­lying cause of death was recorded.

Using the height and weight data, the study authors could calculate each person's initial “body mass index” (BMI). This number is a measure of how underweight, or overweight, a person is. Having a BMI less than 18.5 is con­sidered being underweight. A BMI over 25 is con­sidered being overweight.

Using the death-related in­for­ma­tion, the researchers could de­ter­mine if a person either stayed alive during the entire course of the study they par­tic­i­pated in, died from multiple myeloma, or died from some under­lying cause other than multiple myeloma.

When they analyzed their data, the researchers found that people who had a high initial BMI were more likely to have ended up in the “died from multiple myeloma” category than people with a low initial BMI. Moreover, the risk of ending up in the “died from multiple myeloma” category rose as a person's initial BMI rose.

For example, a man who had a very high initial BMI (that is, a BMI over 35) was 80 per­cent more likely to end up in the “died from multiple myeloma” category than a man who had a “normal” initial BMI (between 18.5 and 25).

Having an elevated BMI also was asso­ci­ated with a higher risk of dying from multiple myeloma among the women in the authors' sample. However, the impact of initial BMI on risk was not as high among the women as it was among the men.

The link be­tween BMI and multiple myeloma that the authors find among the African Americans in their study mirrors what has been found in general, not race-specific, studies of BMI and the risk of multiple myeloma (see, for example, this study ^[9]).

The results of the study also may explain some – but only some – of the dif­fer­ence in how often multiple myeloma occurs among African Americans and white Americans. People of African descent are two to three times more likely to develop multiple myeloma than people who are white. African Americans also are more likely than white Americans to be overweight.

However, there also is strong evi­dence that genetic factors play a role in how often African Americans and white Americans develop multiple myeloma. See, for example, this Beacon news article ^[10] on the frequency of certain chromosomal ab­nor­mal­i­ties in newly diag­nosed African American and white American multiple myeloma patients.

We should add that, although high body weight tends to in­­crease a healthy person's risk of devel­op­ing multiple myeloma, this does not mean that people diag­nosed with multiple myeloma should strive to keep their weight very low. There are, in fact, studies that show that being somewhat overweight may im­prove a myeloma patient's survival in at least certain cir­cum­stances (related Beacon news article ^[11]).

High Cut-Off Dialysis In Multiple Myeloma Patients Requiring Dialysis

A group of German researchers has published a new study investigating the use of high cut-off dialysis in multiple myeloma patients suffering severe kidney im­pair­ment (full text ^[12]).

High cut-off dialysis is a form of dialysis specifically designed to remove excess free light chains from a patient's blood.

Previous studies have suggested that high cut-off dialysis may be better than either standard dialysis or plasma exchange in helping myeloma patients who are suffering from reduced kidney function due to very high free light chain levels (see, for example, this Beacon news article ^[13]).

Similarly, the latest recom­men­da­tions of the Inter­na­tional Myeloma Work­ing Group (IMWG) in regard to myeloma patients with reduced kidney function suggest that high cut-off dialysis be con­sidered as an option for such patients (abstract ^[14]).

The new German study compares dialysis out­comes for multiple myeloma patients at a single treat­ment center who underwent either high cut-off dialysis or standard dialysis. The patients were seen at the treat­ment center be­tween September 2005 and August 2015, and had to have elevated free light chain levels to be in­cluded in the analysis.

Patients in the study who received high cut-off dialysis had a much quicker reduction in their free light chain levels, and a more extensive re­cov­ery in their kidney function, than the patients who underwent standard dialysis.

These results should be interpreted with some caution, how­ever, as patients in this study were not ran­domly selected to be treated with one or the other dialysis techniques. The study is a retro­spec­tive­ study where physician and patient pref­er­ences played a sig­nif­i­cant role in which dialysis option a patient pursued.

It is there­fore possible, for example, that patients in this study who were more likely to respond to any form of dialysis ended up receiving high cut-off dialysis, thus biasing the study's results.

A clin­i­cal trial was started more than five years ago to explicitly compare high cut-off and standard dialysis in myeloma patients requiring dialysis (information about the trial ^[15]). The trial concluded at the end of 2014. However, no results of the trial have yet been published.

Free Light Chain Testing Of The Fluid Around The Lungs

A group of myeloma specialists based in New York City have published a short paper with results of a study into free light chain testing applied to the fluid from around patients' lungs (abstract ^[16]).

The researchers conducted such testing in cases where a multiple myeloma patient was experiencing fluid accumulation in their “pleural cavity”, which is the space around the lungs. The accumulation of such fluid can be due to several dif­fer­en­t problems, one of which can be the devel­op­ment of extramedullary myeloma (myeloma tumors outside the bones) in the lungs or lung cavity.

The study authors found that testing free light chain levels in the “pleural effusion” – the fluid from the pleural cavity – can help de­ter­mine if extramedullary myeloma is causing fluid accumulation in the pleural cavity. If the level of a patient's “involved” free light chain is higher in their lung fluid than in their blood, this is a sign that extramedullary myeloma is likely to be at least one of the causes of the fluid accumulation.

(A patient's “involved” free light chain is the free light chain that is above nor­mal levels when the patient's multiple myeloma is not well controlled. For example, a patient whose kappa free light chain level spikes when their disease relapses has the kappa free light chain as their “involved” free light chain.)

New Myeloma-Related Research Articles

1. Amini, B.et al., “State-of-the-art imaging and staging of plasma cell dyscrasias"” in Radiologic Clinics, March 21, 2016 (abstract ^[17])
2. Fan, X. et al., “Epigenetic identification of ZNF545 as a functional tumor suppressor in multiple myeloma via activation of p53 signaling pathway” in Biochemical and Biophysical Research Communications, May 1, 2016 (abstract ^[18])
3. Gerth, H. U. et al., “Impact of high-cut-off dialysis on renal recovery in dialysis-dependent multiple myeloma patients: results from a case-control study” in Plos One, May 6, 2016 (full text ^[12])
4. Manasanch, E. E. & Landgren, O., “Myeloma imaging: time to move on!” in Leukemia & Lymphoma, May 5, 2016 (abstract ^[19])
5. Marron, T. U. et al., “Validation and utility of the free light chains assay in pleural effusions of patients with multiple myeloma” in Clinical Lymphoma, Myeloma & Leukemia, May 5, 2016 (abstract ^[16])
6. Mizutani, S. et al., “Quadruple cancers of non-producing multiple myeloma, cholangiocellular carcinoma, and two different thyroid cancers” in Internal Medicine, May 1, 2016 (full-text PDF ^[20])
7. Natoni, A., Macauley, M. S. & O'Dwyer, M. E., “Targeting selectins and their ligands in cancer” in Frontiers in Oncology, April 18, 2016 (full text ^[21])
8. Smith, D., Mann, D. & Yong, K., “Cyclin D type does not influence cell cycle response to DNA damage caused by ionizing radiation in multiple myeloma tumours” in the British Journal of Haematology, May 4, 2016 (abstract ^[22])
9. Sonderman, J. S. et al., “Multiple myeloma mortality in relation to obesity among African Americans” in the Journal of the National Cancer Institute, May 4, 2016 (abstract ^[8])
10. Valizadeh, N. & Norozi, S., “Massive pulmonary thrombo-embolism in a case of multiple myeloma and concurrent anti-phospholipid syndrome” in the Indian Journal of Cancer, April 28, 2016 (full text ^[23])
11. Veys, M. C., Delforge, M. & Mombaerts, I. “Treatment with doxycycline for severe bortezomib-associated blepharitis” in Clinical Lymphoma, Myeloma & Leukemia, May 5, 2016 (abstract ^[2])