Hello, myeloma world. How has your Friday been so far?

We have an eclectic mix of five new myeloma-related research studies that we'd like to discuss with you today.

Three of the studies involve laboratory (preclinical) research, which is the sort of research we often leave to discuss later in these reports. But all three of the laboratory studies we cover today address interesting topics, so we will be looking at them first.

The first laboratory study concerns Darzalex ^[1] (daratumumab) and the possibility of combining it with an investigational anticancer drug.

The second study investigates a potential new virus-based therapy for multiple myeloma.

And the third study expands on existing research into how immuno­modu­la­tory drugs, which include Revlimid ^[2] (lenalidomide) and Pomalyst ^[3] (pomalidomide, Imnovid), work against multiple myeloma.

The other two studies – which we did not have space to mention in the title of today's report – are a review article about the treatment of very old myeloma patients, and an analysis of what diseases people have when they have monoclonal IgM in their blood (that is, when they have an IgM M-spike).

Making Darazalex A More Potent Myeloma Therapy

A team of researchers based mainly in the Netherlands has published a short article about the combination of the investigational drug YM155 (sepantronium bromide) and Darzalex. The article reports the results of laboratory research showing that YM155 may improve Darzalex’s effectiveness as a multiple myeloma therapy. Moreover, YM155 may improve – or at least sustain – the effectiveness of Darzalex in situations where the drug might otherwise be ineffective (full text - PDF ^[4]).

This new study reflects two strands of ongoing research related to Darzalex and, more broadly, multiple myeloma.

One strand is research into drugs that are not myeloma treatments, but which might improve the effectiveness of Darzalex. Some of the authors of the new YM155 study, for example, have previously reported results of laboratory research showing that combining the currently marketed acne and leukemia drug all-trans retinoic acid (Tretinoin, Vesanoid) with Darzalex may improve the drug’s anti-myeloma activity (abstract ^[5], related conference abstract ^[6]).

The other strand is research showing that bone marrow cells can reduce the ability of multiple myeloma drugs to treat the disease (see, for example, the full text of this article ^[7]).

In the current study, the authors first investigated whether the presence of bone marrow cells made Darzalex less effective at treating myeloma cells in laboratory test tubes. They found that myeloma cells together with bone marrow cells reacted much less to treatment with Darzalex than the myeloma cells by themselves.

The researchers then tested whether YM155 by itself is effective against myeloma cells by themselves and when the myeloma cells are with bone marrow cells. YM155 did have an effect on the myeloma cells by themselves, but did not have an effect on the cells when they were intermingled with bone marrow cells.

Next, the researchers tested the combination of YM155 and Darzalex against the same two types of myeloma cell samples – alone, and with bone marrow cells. The combination of YM155 and Darzalex had a more powerful effect on the myeloma cells by themselves than either YM155 or Darzalex had alone. Moreover, the combination had almost the same effect on the myeloma cells when they were together with bone marrow cells as it did on the myeloma cells when they were alone.

The authors duplicated the above findings when they carried out a similar experiment with mice. The animals were implanted with human myeloma cells and human bone marrow cells. The combination of YM155 and Darzalex had a much more powerful effect on the myeloma cells together with the bone marrow cells than either YM155 or Darzalex alone had on the myeloma cells in that mouse model.

YM155 belongs to a class of drugs known as survivin inhibitors, and the drug has been investigated for a number of years as a potential cancer therapy. Currently, however, YM155 does not appear to be under active development by the company that has been researching it, the Japanese pharmaceutical company Astellas.

Dr. Tuna Mutis, one of the authors of the YM155 and Darzalex study, informed The Beacon that he and his colleagues are investigating alternatives to YM155.

Anti-Myeloma Activity Of The Sendai Virus

One of the recent developments that has sparked a great deal of excitement in the multiple myeloma community is the possibility that a modified form of the measles virus could be a very effective treatment for multiple myeloma.

Although the excitement surrounding a measles-related treatment for myeloma has subsided somewhat, there is still a great deal of research being carried out investigating the possibility that virus-based therapies may be useful for the treatment of cancer – including multiple myeloma.

The next study that we look at in today's report describes research of this kind. The study is by a group of Japanese researchers who report results of laboratory research they've carried out. The research indicates that a modified form of the Sendai virus may have potential as a treatment for multiple myeloma (full text ^[8]).

The Sendai virus is the cause of a respiratory infection frequently seen in mice, rats, and other rodents. The virus also is attracting attention, however, as a potential treatment for several different kinds of cancer (see related review article ^[9]).

In the new Japanese study, the researchers worked with a form of the Sendai virus that had been exposed to radiation, thus making it unable to reproduce. They found that it significantly slowed the growth of multiple myeloma tumors in both test tube experiments and laboratory mice.

The authors established that the negative effect the virus has on myeloma cells may be due to the virus affecting calcium levels within the cells. The researchers also found that the modified form of the virus did not affect other blood cells.

Based on their research, the authors of the study conclude that a modified form of the Sendai virus could be “a promising tool for multiple myeloma therapy.”

Argonaute 2 (AGO2) And Multiple Myeloma

One of the key classes of drugs used to treat multiple myeloma is the group of “immuno­modu­la­tory agents”, sometimes abbreviated “IMiDs.” This class of therapies includes thalidomide, Revlimid, and Pomalyst.

An important step in understanding how these drugs work as treatments for multiple myeloma occurred about five years ago. Researchers initially determined that thalidomide causes birth defects through its effect on a cell protein known as cereblon.

The research linking thalidomide and cereblon quickly led to the realization that thalidomide and the other immuno­modu­la­tory drugs act against multiple myeloma cells also through their effect on cereblon in those cells.

Not long thereafter, researchers determined that patients whose myeloma cells produce little or no cereblon typically do not respond to treatment with immuno­modu­la­tory drugs.

Eventually, researchers found out more about the role of cereblon in the impact immunodulatory drugs have on multiple myeloma. They determined, in particular, that the drugs bind to cereblon, a step which reduces levels of two other important proteins, known as ikaros and aiolos. The reduced levels of these other two proteins are a key reason drugs like Revlimid have an anti-myeloma effect.

Now, some of the same U.S. and Chinese researchers who investigated the role of cereblon in patient responses to immuno­modu­la­tory agents have published a new, related, study.

In the new study, they report that immunomdulatory agents not only affect ikaros and aiolos levels through the way they bind to cereblon. The cereblon binding of the drugs also affects a third protein, known as argonaute 2 (AGO2), and this also aids the anti-myeloma effect of the drugs (full text ^[10]).

More specifically, the researchers found through a number of different laboratory tests that the immuno­modu­la­tory agents lower levels of AGO2 in myeloma cells through their impact on cereblon. The low level of AGO2 in the myeloma cells contributes to their death.

Just as importantly, the researchers determined that if they lowered the level of AGO2 in multiple myeloma cells using an approach that did not involve treatment with a drug like Revlimid, the multiple myeloma cells still died. This was true for multiple myeloma cells that were sensitive to treatment with immuno­modu­la­tory agents and to cells that were not sensitive to treatment with immuno­modu­la­tory agents.

Thus, the new study not only sheds new light on how immuno­modu­la­tory drugs act against multiple myeloma. It also suggests targeting AGO2 production in multiple myeloma cells could be an effective new approach to treating the disease.

Multiple Myeloma In People Over 80 Years Of Age

A group of British physicians have published an extended discussion of important issues related to the diagnosis and treatment of multiple myeloma patients over the age of 80 (full text ^[11]).

The discussion can be seen as a reflection of a growing interest among myeloma specialists in finding better ways to care for older, less fit myeloma patients.

The authors of the British study identify six challenges that come into play with multiple myeloma in patients over the age of 80. These include diagnosis, assessing fitness for treatment, supportive care, choice of initial treatment, choice of treatment at relapse, and end of life care.

The discussion related to supportive care is useful for giving a sense of the range of different issues that come up in addition to the basic challenge of treating multiple myeloma. These issues can include pain management, anemia, kidney issues, and infections.

The discussion of initial treatment options and the issues that need to be considered in choosing that treatment also is quite detailed. The authors generally recommend Revlimid and lower dose dexamethasone as initial therapy for patients over 80, but describe the logic behind their recommendation and alternative choices for specific patient subgroups.

IgM Monoclonal Gammopathy

A new study by physicians in China looks at people who have monoclonal immunoglobulin IgM detected in the body. It describes what proportion of these people were eventually diagnosed with different diseases related to having monoclonal IgM (an IgM M-spike, or IgM paraprotein) (abstract ^[12]).

Most people with multiple myeloma have myeloma cells that produce monoclonal IgG or IgA, or their cells produce monoclonal free light chains. Cases of myeloma involving monoclonal IgD, IgE, or IgM are much rarer.

In cases where people have monoclonal IgG or IgA, usually it is determined that the disease accounting for the monoclonal immunoglobulin is either multiple myeloma or the myeloma precursor disease known as monoclonal gammopathy of undetermined significance (MGUS).

In the case of monoclonal IgM, however, this is only partly the case. Cases of IgM MGUS are common, but IgM multiple myeloma is a rare diagnosis, and most of cases of an IgM M-spike may end up with a diagnosis other than MGUS or multiple myeloma.

What the authors of the new Chinese study have done is look at all people who, from January 2008 to December 2014, were seen at their hospital in Beijing and were found to have a monoclonal protein in their blood. They then narrowed the focus to the 377 people who were found to have IgM protein in their blood (“IgM monoclonal gammopathy”), and determined the characteristics of these people, including their eventual diagnosis.

They found that the median age of the people with IgM monoclonal gammopathy was 62, and the median IgM M-spike was 0.83 g/dL.

The eventual diagnosis in the 377 cases were IgM MGUS (157 patients, 41.6%), Waldenstrom macro­globu­li­nemia (105 patients, 27.9%), B cell non-Hodgkin’s lymphoma (69 patients, 18.3%), primary cold agglutinin disease (pCAD, 16 patients, 4.2%), primary amyloidosis (14 patients, 3.7%), cryoglobulinaemia (six patients, 1.6%), IgM MGUS associated neuropathy (five patients, 1.3%), multiple myeloma (three patients, 0.8%), and POEMS syndrome (two patients, 0.5%).

New Myeloma-Related Research Articles

1. Cao, X. X. et al., “The clinical spectrum of IgM monoclonal gammopathy: a single center retrospective study of 377 patients” in Leukemia Research, May 4, 2016 (abstract ^[12])
2. De Haart, S. J. et al., “Sepantronium bromide (YM155) improves daratumumab-mediated cellular lysis of multiple myeloma cells by abrogation of bone marrow stromal cell-induced resistance” in Haematologica, May 5, 2016 (full text - PDF ^[4])
3. Jiang, Y. et al., “Cytoplasmic calcium increase via fusion with inactivated Sendai virus induces apoptosis in human multiple myeloma cells by downregulation of c-Myc oncogene” in Oncotarget, April 29, 2016 (full text ^[8])
4. Willan, J. et al., “Multiple myeloma in the very elderly patient: challenges and solutions” in Clinical Internvetions in Aging, April 15, 2016 (full text ^[11])
5. Xu, Q. et al., “Expression of the cereblon binding protein argonaute 2 plays an important role for multiple myeloma cell growth and survival” in BMC Cancer, May 3, 2016 (full text ^[10])
6. Yang, X. et al., “Cancerous inhibitor of PP2A silencing inhibits proliferation and promotes apoptosis in human multiple myeloma cells” in BioMed Research International, April 6, 2016 (full text ^[13])