It's good to see you again, myeloma world.

We got tied up the past couple days with, among other things, coverage of the Empliciti approval in Europe ^[1]. But we're glad to be back and we have two new research studies that we'd like to discuss with you.

First, we take a look at an Israeli study that does a deep dive into the t(11;14) chro­mosomal abnormality in newly diagnosed multiple myeloma patients. The focus of this particular deep dive is the impact other chro­mosomal abnormalities have on the prognosis of newly diagnosed patients with t(11;14).

Second, we review a study from Japan that investigates the relationship between a myeloma patient's weight at diagnosis and their overall survival. The study is more subtle than previous research on this topic, how­ever, because it breaks down the components of a patient's weight into muscle and two different forms of fat.

Even though the Japanese study is based on results for a sample of less than 60 newly diagnosed patients, it nicely highlights important, clinically relevant issues that already have been hinted at by previous studies on this topic.

We wrap up today's report with a “Quickly Noted” section with very brief summaries of two other studies. One is about an alternative three-drug conditioning regimen for autologous stem cell transplants, and the other looks at the use of rice bran (yes, rice bran) in addition to curcumin in patients with smoldering myeloma and monoclonal gammopathy of undetermined significance (MGUS).

T(11;14) And Higher-Risk Chromosomal Abnormalities

Researchers from Israel have published results of a study into the overall survival of multiple myeloma patients with the t(11;14) chromosomal abnormalities. In particular, the researchers examine the impact specific higher-risk chromosomal abnormalities have on the prognosis of patients with t(11;14) at diagnosis (abstract ^[2]).

According to the Israeli researchers, t(11;14) is the most common chromosomal translocation among newly diagnosed multiple myeloma patients. It is estimated that about 15 percent of newly diagnosed patients have the t(11;14) abnormality.

The t(11;14) translocation is not considered, however, a chromosomal abnormality that noticeably worsens a patient's prognosis. Patients with t(11;14) are usually considered to be in the “standard risk” category unless they have other, “high risk” chromosomal abnormalities.

Of course, this raises the important question: How much of a negative impact on a t(11;14) patient's prog­nosis does a “high risk” chromosomal abnormality cause?

That is precisely the question the authors of the Israeli study set out to address.

The researchers retrospectively analyzed bone marrow samples and clinical data from 212 newly diagnosed multiple myeloma patients with t(11;14) who were tested at their center in Israel between 2001 and 2013.

For each of these patients, the researchers established whether the patients also had one or more of the following seven chromosomal abnormalities that have been described as markers of higher risk disease: del(17p), del(13q), del(1p), gain(1q), multiple gains of 1q, del(16q), and del(14q). (Note that the Israeli researchers use del(IGH) to designate del(14q).)

Of the 205 bone marrow samples in which the researchers had data on all seven of the additional chromosomal abnormalities, 40 percent of the samples had none of the additional abnormalities, 48 percent had one or two of the additional abnormalities, and 12 percent had three to six of the additional abnormalities.

The most frequent additional abnormalities from the group of seven were del(13q) (37 percent) and del(14q) (33 percent), which according to the Israeli researchers is in line with their previous research. The least frequent additional high risk chromosomal abnormalities were del(1p) (3.4 percent) and multiple gains of 1q (2.9 percent).

Across all patients in the study, the median overall survival from time of diagnosis was 63 months.

The authors found evidence that having an increasing number of any of the seven higher-risk chromosomal abnormalities was associated with lower overall survival. Patients who had two of the seven higher-risk abnormalities tended to have lower overall survival, for example, than patients who had only one – or none – of the higher risk abnormalities.

The association between the number of additional abnormalities and survival, however, was not strongly statistically significant.

When the researchers looked individually at each of the seven higher-risk abnormalities, they found that two less common abnormalities – multiple gains of 1q, and del(1p) – had a very negative impact on overall survival. Median overall survival in the patients with either of those abnormalities was less than half what it was in the other patients.

The impact of the two rare abnormalities – multiple gains of 1q and del(1p) – was also very statistically significant. Nevertheless, it should be noted that each of these two abnormalities was found in just 6 or 7 patients among the more than 200 in the overall sample. Caution therefore seems in order when it comes to generalizing based on such a limited number of observations.

The more common del(14q) abnormality also seemed to have a negative effect on overall survival among the t(11;14) patients in the Israeli study. The abnormality was associated with a reduction in median overall survival of a bit more than two years, and the impact was statistically significant.

The del(17p) and del(13q) abnormalities had a less statistically robust impact on overall survival in the t(11;14) patients. However, the magnitudes of their impact on overall survival were similar to what was seen with del(14q) – a reduction of a bit more than two years.

Subcutaneous Fat And Overall Survival In Newly Diagnosed Multiple Myeloma

There have been a number of studies over the years investigating different ways that body weight and multiple myeloma interact with one another. Most of the studies seem to fall into one of two categories.

The first category of research looks at the impact of body weight on a person's risk of developing multiple myeloma. These studies typically find that people who are overweight are more likely to develop multiple myeloma than people who are not overweight. The Beacon reported on a study along these lines in the previous edition of Myeloma Morning ^[3]; that study focuses on African Americans, body mass index, and a person's risk of dying from multiple myeloma.

The second category of studies focuses on the impact of body weight once a person has multiple myeloma. These studies often find that being overweight – to at least some extent – may improve a multiple myeloma patient's overall survival (see, for example, the study discussed in this Beacon news article ^[4]).

A new study by researchers in Japan falls in the second category of studies. It is, however, more subtle than many previous studies. The Japanese researchers go beyond investigating the impact of a patient's weight on their survival. They also investigate whether the amount of muscle and different kinds of body fat a patient has influences their survival (abstract ^[5]).

Study Design And Results

In their study, the Japanese researchers retrospectively analyzed data from 56 consecutive patients who were diagnosed with multiple myeloma at their (single) treatment center between May 2009 and January 2015. The median patient age at diagnosis was 71 years; 21 percent of patients were overweight or obese at the time of diagnosis.

To be included in the analysis, the patients had to have had a CT or (18F-FDG) PET/CT examination before initial treatment, with image quality adequate for evaluating body composition.

Overall, 10 patients underwent CT and 46 underwent 18F-FDG PET/CT examination. The median period between imaging and date of diagnosis was 11 days and 17 days between imaging and the start of treatment.

Based on the imaging results, the researchers calculated three measures of each patient's body composition:

• SMI – skeletal muscle index – a measure of how much muscle tissue the patient has
• SAI – subcutaneous adipose tissue index – a measure of how much under-the-skin fat the patient has
• VAI – visceral adipose tissue index – a measure of how much fat around the abdominal organs the patient has.

The researchers then analyzed whether there was a connection between a patient's overall survival, the three body composition metrics, and whether or not a patient was overweight.

The authors found that only the measure of subcutaneous fat was associated with a patient's overall survival.

In particular, patients who had low amounts of subcutaneous fat had lower overall survival than patients who had higher amounts of subcutaneous fat.

For example, when the researchers split the patients into two groups based on their subcutaneous fat index (SAI), the patients with high levels of the subcutaneous fat index had a two-year overall survival of 91 percent, versus 58 percent for the patients with low levels of the subcutaneous fat index.

The amount of muscle or visceral fat a patient had was not associated with overall survival, nor was the patient's weight (as captured by whether or not they were obese).

These results held when the researchers did both simple and more sophisticated statistical analyses of the data. The results also held when the analyses were conducted separately for the men and women in the sample.

The study authors also found that none of the measures of body composition – neither SMI, SAI, nor VAI – had any statistically significant association with a patient's progression-free survival. There was, however, some tendency for patients with low levels of subcutaneous fat to have shorter progression-free survival – that is, to experience somewhat faster disease progression after diagnosis.

In addition, the researchers found that patients with low levels of subcutaneous fat tended to have bone lesions that showed more intense myeloma-related activity (“SUV_max”) on PET/CT scans.

Interpretation Of The Results

Because the Japanese study is based on a small, retrospective sample of patients from a single treatment center, one has to be very careful about drawing too many conclusions from it. That said, the study's findings fit well with the results of previous research, while adding some useful detail.

To understand the implications of the study's findings, it is useful to keep in mind a statement the authors make about the role subcutaneous fat (adipose tissue) plays in the body, and what it means when a patient has low levels of such fat at diagnosis:

“One of the main functions of subcutaneous adipose tissue is energy storage. Low subcutaneous adipose tissue thus reflects the severe energy exhaustion caused by cancer, leading to the poor clinical outcomes.”

The connection between low levels of subcutaneous fat at diagnosis and reduced overall survival seems to be due to two potentially parallel explanations.

First, the low level of fat at diagnosis may reflect disease that is more advanced and perhaps more aggressive. The more advanced disease has drawn down the patient's energy reserves, and is reflected in the more intense myeloma activity in the patient's bones and a trend to faster disease progression in these patients.

Second, patients who do not have as much subcutaneous fat at diagnosis may be less likely to build the energy reserves necessary to ensure recovery from infections and other challenges that present themselves later as they fight their disease and deal with the side effects of treatment.

These explanations are in line with what could have been concluded based on previous research, which looked mainly at body weight and survival. Body weight and measures of subcutaneous fat tissue are correlated, the Japanese researchers note, but body weight does not always accurately reflect the volume of subcutaneous fat. In addition, visceral fat – that is, fat found around the abdominal organs – does not play the same sort of role in storing energy that subcutaneous fat plays.

Quickly Noted

A group of U.S. researchers have published results of a study investigating the use of melphalan, busulfan, and Velcade ^[6] (bortezomib) as the conditioning regimen during autologous stem cell transplants for myeloma patients. They compare results using their regimen to those for a matched sample of patients who had the traditional high-dose melphalan as a conditioning regimen. The researchers find that the three-drug conditioning regimen resulted in superior one-year progression-free survival and equivalent one-year overall survival (abstract ^[7]).

A group of Australian researchers have published results of a preliminary study examining the potential impact of adding rice bran to curcumin in patients with smoldering multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS), and a form of leukemia. They conclude that rice bran may be of benefit to these patients (full text ^[8]). The authors of the rice bran study also published a study four years ago that investigated whether curcumin may be of benefit to smoldering myeloma and MGUS patients (see related Beacon ^[9] news article).

New Myeloma-Related Research Articles

1. Dotterweich, J. et al., “The KISS1 receptor as an in vivo microenvironment imaging biomarker of multiple myeloma bone disease” in Plos One, May 9, 2016 (full text ^[10])
2. Ferretti, A., De Angelis, G. & Petrucci, M. T., “Severe clavicular disease in multiple myeloma” in the British Journal of Haematology, May 10, 2016 (abstract ^[11])
3. Golombick, T. et al., “Addition of rice bran arabinoxylan to curcumin therapy may be of benefit to patients with early-stage b-cell lymphoid malignancies (monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, or stage 0/1 chronic lymphocytic leukemia): a preliminary clinical study” in Integrative Cancer Therapies, May 6, 2016 (full text ^[8])
4. Leiba, M. et al., “Translocation t(11;14) in newly diagnosed multiple myeloma patients, is it always favorable?” in Genes, Chromosomes & Cancer, May 6, 2016 (abstract ^[2])
5. Levin, N. et al., “Marizomib irreversibly inhibits proteasome to overcome compensatory hyperactivation in multiple myeloma and solid tumour patients” in the British Journal of Haematology, May 9, 2016 (full text ^[12])
6. Rodriguez, T. E. et al., “Busulfan, melphalan, and bortezomib versus high dose melphalan as a conditioning regimen for autologous hematopoietic stem cell transplantation in multiple myeloma” in Biology of Blood and Marrow Transplantation, May 7, 2016 (abstract ^[7])
7. Rondeau, V. et al., “Prediction of patients with multiple myeloma eligible for second- or third-line treatment in France” in Annals of Hematology, May 10, 2016 (abstract ^[13])
8. Shen, X. et al., “Identification of a novel microRNA miR-4449 as a potential blood based marker in multiple myeloma” in Toxicology, May 6, 2016 (abstract ^[14])
9. Spur, E. M. et al., “Inhibition of chymotryptic-like standard proteasome activity exacerbates doxorubicin-induced cytotoxicity in primary cardiomyocytes” in Toxicology, May 4, 2016 (abstract ^[15])
10. Takeoka, Y. et al., “Prognostic impact of low subcutaneous adipose tissue on survival outcome in patients with multiple myeloma” in Clinical Lymphoma, Myeloma & Leukemia, May 4, 2016 (abstract ^[5])