Hello again, myeloma world.

As we continue catching up after the recent onslaught of new myeloma-related research, we're pleased to report that it's a sunny spring day outside. More importantly, our top story today reflects Mother Nature's pleasant disposition.

In particular, there is updated data about multiple myeloma survival in the United States, and it's good news.

It's just an annual update – a single new value for survival five-years from the time of diagnosis. And it's for patients diagnosed all the way back in 2008 – the most recent year for which extensive data are available.

But the new estimate is a sizable jump from the previous year, and it suggests increases in multiple myeloma survival are occurring once again. We have more on this story in the rest of our report below.

We also have a summary of a study on the use of Pomalyst (pomalidomide) and dexamethasone in relapsed myeloma patients with moderate kidney impairment, as well as information on a separate study investigating the risk of developing monoclonal gammopathy of undetermined significance (MGUS).

Finally, we discuss a new myeloma cell line that is a bit different from other myeloma cell lines, and we look at results of a study exploring the safety of JQ1, a molecule that once attracted a lot of attention in some myeloma circles.

Our daily list of new multiple myeloma research studies is at the end of today's article. It includes, we will admit now, an interesting article by Italian researchers, appearing in the journal Leukemia. We are not ignoring this article, but rather saving discussion of it for another edition of Myeloma Morning ^[1].

The Newest Five-Year Multiple Myeloma Survival Estimate

Every year around this time, the U.S. National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program updates its annual estimates of key cancer statistics. The SEER cancer statistics – which are available for anyone to view online ^[2] – are the most important compendium of U.S. cancer statistics.

For multiple myeloma, a closely watched metric in the SEER database is the measure of how many multiple myeloma patients survive 5 years after their diagnosis. This number started increasing significantly in the early 2000s, but then paused for patients diagnosed in 2005, 2006, and 2007 – the latest years for which statistics had been available.

Most myeloma specialists expected, however, that the pause would be short lived. There were just too many new myeloma therapies being approved for survival not to be positively affected.

Sure enough, the latest data released today shows the expected uptick in survival. The five-year relative survival of myeloma patients increased from 45.6 percent for those diagnosed in 2007 to 49.6 percent for those diagnosed in 2008 (see graph below).

Now, as we said, the published data today are for relative survival, which is a measure of survival adjusted for the level of survival that would have been expected for the specific patients given their age, gender, race, and other characteristics. We have a more complete explanation of the difference between relative and absolute survival below.

In terms of changes in absolute survival – the type of survival most people think about – the new estimates indicate it increased from about 39.9 percent in 2007 to 43.4 percent in 2008. In other words, across all multiple myeloma patients diagnosed in 2008 in the United States, a little more than 43 percent were still alive five years later.

If you're interested in what five-year relative survival may look like in more recent years – and into the future – you should check the graph in this forum posting ^[3] from 2014. The graph was prepared by Mayo Clinic myeloma specialist Dr. Leif Bergsagel for a presentation he did at the 2014 American Society of Hematology meeting.

Pomalyst In Myeloma Patients With Moderate Kidney Impairment

Next, we turn to a new analysis of data from the so-called MM-003 Phase 3 trial comparing Pomalyst plus low-dose dexamethasone to high-dose dexamethasone alone in relapsed and refractory myeloma patients. Researchers have investigated the efficacy and safety of Pomalyst-dexamethasone therapy in myeloma patients with moderate kidney impairment (full text ^[5]). Moderate kidney impairment was defined as having a creatinine clearance of at least 30, but less than 60 mL/min at the start of the trial.

The study authors found that patients with moderate kidney impairment who received Pomalyst plus low-dose dexamethasone had longer progression-free survival than those who received high-dose dexamethasone (4.0 months versus 1.9 months). Importantly, these numbers are almost identical to those for patients without kidney impairment (4.0 months versus 2.0 months).

Pomalyst plus low-dose dexamethasone also lead to improved overall survival in patients with moderate kidney impairment compared to high-dose dexamethasone (10.4 months versus 4.9 months). The share of patients who experienced improvement kidney function, which was defined as an increase in creatinine clearance from less than 60 to 60 or more mL/min, was similar in both treatment groups (42 percent and 47 percent, respectively). However, median progression-free and overall survival were once again higher in patients receiving Pomalyst plus low-dose dex (6.5 months and 12.6 months, respectively), compared to patients receiving high-dose dexamethasone (3.2 months and 10.1 months, respectively).

The researchers point out that the side effects, dose modifications, and discontinuation rates were similar for among patients with moderate kidney impairment and those without kidney impairment.

Risk Factors For Developing MGUS

Researchers from the University of Pennsylvania recently re-evaluated risk factors for the development of MGUS (abstract ^[6]).  Previous studies have shown that obesity and diabetes may be associated with an increased risk of developing MGUS. However, according to researchers, there may be a detection bias leading to this association because people with other health issues require more frequent testing than the general population. They therefore conducted a case control study comparing data from 2,363 MGUS patients to those of 9,193 matched healthy people.

They found that there was no association between obesity and diabetes and MGUS risk. When the researchers ran an additional analysis of antidiabetic therapies and MGUS risk, they found a decreased risk of MGUS developing among diabetes patients treated with metformin alone compared to people without diabetes. The decreased risk associated with metformin use was not, however, statistically significant.

Based on their findings, the researchers conclude that “while previously described risk factors for MGUS might be the result of detection bias.” They add that “Future studies should investigate the mechanisms by which metformin may protect against the development of MGUS.”

Myeloma-Derived Stromal Cell Line

A lot of laboratory research related to multiple myeloma involves the use of multiple myeloma cell lines, which are collections of multiple myeloma cells with a specific set of characteristics.

Ongoing research suggests, however, that the bone marrow environment that surrounds multiple myeloma cells may have a very important role in the disease's development and progression. Indeed, the cells in that environment may be “diseased” in ways very similar to the diseased plasma cells that are multiple myeloma cells.

Thus, in an effort to improve options for multiple myeloma laboratory research, a team of scientists at Washington University in St. Louis, Missouri has developed a new line of “myeloma-derived stromal cells”, known as MSP-1. The cells are based on ones taken from the bone environment of multiple myeloma patients. In a short paper in the journal Haematologica (full text PDF ^[7]), the researchers describe the new cell line.

Safety of JQ1

Long-time Beacon readers may recall the investigational drug JQ1. At one point several years ago, there was a great deal of excitement in some quarters about JQ1's potential as a myeloma therapy. A new study by researchers at Genentech investigates the safety of JQ1 in laboratory mice. The authors find that, at JQ1 doses that would be efficacious, the drug appears to suppress the immune system significantly and cause substantial weight loss (abstract ^[8]).

New Myeloma-Related Research Articles

1. Abe, M., Miki, H., and Nakamura S., “Multiple myeloma” in Rinsho Ketsueki, April, 2016 (abstract ^[9])
2. Boursi, B. et al., “Reappraisal of risk factors for monoclonal gammopathy of undetermined significance” in the American Journal of Hematology, April 13, 2016 (abstract ^[6])
3. De La Puente, P. et al., “Newly established myeloma-derived stromal cell line MSP-1 supports multiple myeloma proliferation, migration, and adhesion and induces drug resistance more than normal-derived stroma” in Haematologica, April 14, 2016 (full text PDF ^[7])
4. Lee, D. U. et al., “Nonselective inhibition of the epigenetic transcriptional regulator BET induces marked lymphoid and hematopoietic toxicity in mice” in Toxicology and Applied Pharmacology, April 11, 2016 (abstract ^[8])
5. Martello, M. et al., “Opposite activation of the Hedgehog pathway in CD138+ plasma cells and CD138-CD19+ B cells identifies two subgroups of patients with Multiple Myeloma and different prognosis” in Leukemia, April 14, 2016 (abstract ^[10])
6. Shao, J. et al., “Involvement of the arachidonic acid cytochrome P450 epoxygenase pathway in the proliferation and invasion of human multiple myeloma cells” in PeerJ, April 11, 2016 (full text ^[11])
7. Weisel, K. C. et al., “Analysis of renal impairment in MM-003, a phase 3 study of pomalidomide + low‐dose dexamethasone vs high‐dose dexamethasone in refractory or relapsed and refractory multiple myeloma” in Haematologica, April 14, 2016 (full text ^[5])

Relative Survival Versus Absolute Survival

(This is background information for those who need a refresher on relative versus absolute survival.)

The survival rates published today by SEER are what are known as relative survival rates. These are different than the survival rates typically seen in myeloma research articles, which are technically absolute survival rates.

It is common in myeloma research studies to find statements such as "The five-year survival rate was 60 percent." This (absolute) survival rate means that, five years after their myeloma diagnosis, 60 percent of the patients in the study were still alive.

The 60 percent absolute survival rate, however, does not put the survival experienced by the myeloma patients into perspective. More specifically, it does not say how many more myeloma patients died over the course of the five years compared to how many people in the general population – of the same age, gender, and ethnicity – would have died during the same period.

Relative survival rates, on the other hand, provide such perspective. They take into account that people without myeloma also die.

In particular, the relative survival rate is calculated by dividing the absolute survival rate for a group of cancer patients by the absolute survival rate for a similar group of people from the general population.

As an example, take the (fictitious) study mentioned above with the 60 percent absolute five-year survival rate. Assume that a large group of people similar in age, gender, and race to those in the study – but from the general population – would have experienced an 80 percent absolute survival rate over the same five-year period.

In that case, the relative survival rate of the myeloma patients in the study would be 75 percent (60/80=0.75, or 75 percent).

Absolute and relative survival rates will be very similar for younger myeloma patients, because younger people from the general population do not die that often. Relative survival rates for older myeloma patients, on the other hand, will be higher than their corresponding absolute survival rates.