A pleasant Tuesday to you, myeloma world.

We hope your week has started well. We been away for longer than ex­pec­ted, work­ing through some of the more technical details of the articles we discuss in today's Myeloma Morning.

Most of today's report focuses on two research articles that were published last week. Both articles were published in the journal Blood, and both are valuable contributions to what we know about multiple myeloma. As a result, we devote quite a bit of space to summarizing each of the articles.

Those long summaries mean that today's report is long. Very long. As in the longest Myeloma Morning we've ever published.

So most of our readers will want to work their way through the article in two or three sittings, rather than trying to digest it all at once.

The first research article we discuss today is about the impact of minimal residual disease status in older, newly diagnosed multiple myeloma patients who are not eligible for a stem cell trans­plant. It is based on data from a clinical trial that was carried out in Spain.

The second article reports on the role of two proteins – BCMA and APRIL – in the ability of multiple myeloma cells to survive, resist treat­ment, and proliferate. This study is based on laboratory research. It is primarily relevant to the devel­op­ment of new multiple myeloma ther­a­pies, and one possible new treat­ment – known as “01A” – is discussed in the article.

We should add that the BCMA / APRIL study is more than just another run-of-the-mill article about the biology of multiple myeloma.

BCMA has attracted a great deal of attention as a potential target for a new generation of myeloma ther­a­pies. A BCMA-targeted CAR T-cell ther­apy, for example, garnered a lot of press at last year's American Society of Hematology meeting (related ASH abstract ^[1]).

In addi­tion, the BCMA / APRIL study is from a highly respected team of multiple myeloma researchers, most of whom are asso­ci­ated with the Dana-Farber Cancer Institute in Boston.

Before we move on to the two summaries we just mentioned, we should note that today's report includes the usual list of myeloma-related research articles that have been published since the last Myeloma Morning. The list is at the end of the report, and, directly above that list, we have a “Quickly Noted” section. It has summaries of a few items in the new research list, as well as pointers to several Beacon forum discussions that readers may want to review.

Minimal Residual Disease In Transplant-Ineligible Patients

The article about minimal residual disease that we want to discuss with you today is from a group of Spanish multiple myeloma researchers. They report on the impact of minimal residual disease (MRD) status on treat­ment out­comes among a group of newly diagnosed myeloma patients who were ineligible for a stem cell trans­plant (abstract ^[2]).

The researchers found that the patients in their study who, based on MRD status, achieved the very deepest response to treat­ment had the best survival out­comes.

The investigators also found evi­dence that their MRD testing may provide addi­tional in­­for­ma­tion valuable for assessing a patient's prognosis. The testing measures how often many different types of cells – not just multiple myeloma cells – are found in a patient's bone marrow sample. Based on that in­­for­ma­tion, the researchers were able to identify three groups ("clusters") of patients with noticeably different marrow cell profiles and different over­all survival out­comes.

Background

It has long been known that multiple myeloma patients who have deeper responses to treat­ment tend to have a better survival prognosis. Traditionally, it has been sufficient to measure a patient's response using the traditional metrics of partial response (PR), very good partial response (VGPR), com­plete response (CR), and stringent com­plete response (sCR). These response metrics are based on how a patient's M-spike, free light chain levels, and plasma cell per­cent­age respond to treat­ment.

During the past 10 years, however, multiple myeloma treat­ment regi­mens have become increasingly effective. More and more patients are achieving com­plete and stringent com­plete responses. So myeloma researchers have been investigating more sensitive ways to measure how much “residual disease” is present in a patient's body after treat­ment.

Currently, the most common methods for measuring residual disease use samples from patients' bone marrow biopsies. Sensitive equipment is used to test each patient sample for the presence of multiple myeloma cells. If only a few, or no, multiple myeloma cells are found in the sample, the patient is said to be “minimal residual disease negative” (MRD negative, or MRD-). The terminology can be confusing because, in this case, being “negative” is a good thing. It means the patient is “negative” for minute signs of disease in their body.

A number of studies have shown that achieving MRD-negative status is asso­ci­ated with longer pro­gres­sion-free and over­all survival. These studies, however, have mainly been in patients who have received stem cell trans­plants.

With patients who have not have stem cell trans­plants, the data have not been as clear. A pre­vi­ous Spanish study, using data from a different clinical trial, found that achieving MRD-negative status led to longer survival in patients ineligible for a stem cell trans­plant. A study done mainly in the United Kingdom, on the other hand, did not identify a statistically significant connection between MRD status and survival.

So the authors of the current study decided to in­ves­ti­gate the impact of MRD status using data from a more recent clinical trial they carried out with newly diagnosed multiple myeloma patients who were trans­plant ineligible.

Design Of The Spanish Clinical Trial

The data for the current study comes from the PETHEMA/GEM2010MAS65 clinical trial. This trial tested two different ap­proaches to the treat­ment of newly diagnosed multiple myeloma patients who would not be going on to have a stem cell trans­plant.

All patients received treat­ment with two treat­ment regi­mens: Velcade (bor­tez­o­mib), mel­phalan, and pred­ni­sone (VMP); and Revlimid and dexa­meth­a­sone (Rd).

Patients in one arm of the trial received nine cycles of VMP treat­ment followed by nine cycles of Rd.

Patients in the other arm of the trial also received nine cycles of each treat­ment regi­men. However, the cycles alternated. First a cycle of VMP, then a cycle of Rd, then another cycle of VMP, and so on.

Patients who achieved at least a very good partial response after 9 cycles of treat­ment were tested to determine their MRD status. The same also was done at the end of each patient's treat­ment for patients who achieved at least a very good partial response.

Note that it is possible for a patient to be MRD negative but not have achieved a com­plete response. M-spike levels take time to drop even when a patient has responded very well to treat­ment. In addi­tion, myeloma can be a “patchy” disease, such that a bone marrow sample from one spot may be clear of disease even when disease is present in other parts of the body.

So a patient might have no myeloma cells in their bone marrow sample, thus registering as MRD negative, but still have an M-spike indicating, for example, that they have achieved only a very good partial response.

For those particularly interested in MRD mea­sure­ment issues, we'll note that the Spanish investigators used second generation, eight-color multiparameter flow cytometry to carry out the MRD testing.

Patient Groups

Based on each patient's MRD test results, the researchers defined three groups of patients.

1. Those who were MRD negative (less than one myeloma cell per 100,000 plasma cells tested)
2. Those who were somewhat MRD positive (between 1 and 9 myeloma cells per 100,000 cells tested)
3. Those who were MRD positive (10 or more myeloma cells per 100,000 cells tested)

A total of 162 patients had MRD testing done after 18 cycles of treat­ment. Of those 162 patients, 54 (33 per­cent) were in the first group (MRD negative), and 20 (12 per­cent) and 88 (54 per­cent) were in the second and third groups, re­spec­tive­ly.

Patients also were divided into high-risk and standard-risk disease groups based on the results of FISH testing for chromosomal ab­nor­mal­i­ties.

A patient was classified as having high-risk disease if he or she had one or more of the fol­low­ing ab­nor­mal­i­ties: t(4;14), t(14;16), or del(17p13). Patients without any of those ab­nor­mal­i­ties were classified as standard risk.

Median follow-up from time of trial enrollment was 36 months for the patients tested for MRD status.

Impact Of MRD Status On Treatment Outcomes

As in pre­vi­ous studies involving patients who underwent stem cell trans­plants, the patients in this study who reached MRD-negative status had better treat­ment out­comes. There was not much difference, on the other hand, in the treat­ment out­comes of patients in the two MRD-positive groups of patients.

For example, median time to pro­gres­sion from time of the second MRD assess­ment was not reached in the patients who were MRD negative, and was 15 months in both MRD-positive groups.

Overall survival also was noticeably better in the MRD-negative patients, and very similar in the MRD-positive patients. Three-year survival from time of the second MRD assess­ment was 70 per­cent in the MRD-negative patients and 63 per­cent and 55 per­cent in the two MRD-positive groups, re­spec­tive­ly.

(We should add that the three-year survival statistic for the two MRD-positive groups is misleading, as the over­all survival curves for the two groups are largely the same over most of the period for which data are available.)

Among patients who reached MRD-negative status, there was no difference in time to pro­gres­sion between patients with high-risk and standard risk disease. In both cases, median time to pro­gres­sion has not been reached.

A patient's risk status did matter, however, if they were MRD-positive. Median time-to-progression in this group was 15 months for standard-risk patients and 12 months for high-risk patients.

Interestingly, age did not have an affect on time to pro­gres­sion among patients who were MRD-negative. Patients in that group who were over the age of 75 had the same time to pro­gres­sion as patients 65 to 75 years of age (median time to pro­gres­sion not reached for both age groups).

This was not the case among the patients who were MRD-positive. There, being in the older group was asso­ci­ated with shorter time to pro­gres­sion (a median of 11 months versus a median of 16 months).

Development Of Immune Profiles

The MRD equipment used during the study counted more than just multiple myeloma cells as it assessed a patient's MRD status. It also counted and reported the number of 13 other types of cells in each patient's bone marrow sample.

Using these results and each patient's treat­ment out­comes, the researchers in­ves­ti­gated whether certain marrow cell profiles were asso­ci­ated with better or worse treat­ment out­comes. A statistical analysis established that there seem to be three such profiles, which the study authors labeled Cluster A (16 patients), Cluster B (116 patients), and Cluster C (13 patients).

Patients in Cluster A had the best treat­ment out­comes, while B and C had progressively worse out­comes. Three-year survival in the three groups was 100 per­cent, 61 per­cent, and 25 per­cent, re­spec­tive­ly (A, B, and C).

For those interested in the biology of the different clusters, we will add that the patients in the clusters with worse out­comes tended to have progressively more erythroblasts and B-cell precursors, and progressively fewer mature naïve and memory B-cells, compared to the distribution of cells in Cluster A (the cluster with the best treat­ment out­comes).

Authors' Conclusions

To sum up the key findings of their study, the authors write that, just as has been found in patients who are trans­plant-eligible, “MRD monitoring is one of the most relevant prognostic factors in elderly multiple myeloma [patients], complementary to the cytogenetic risk and superior to conventional response criteria; thus, patients with standard-risk multiple myeloma and those in com­plete response but remaining MRD-positive ex­peri­ence poor out­comes, and warrant potential treat­ment individualization to im­prove their survival.”

The Role Of BCMA And APRIL In Multiple Myeloma

The second article we look at in detail today focuses on two proteins: BCMA (“B cell maturation antigen”) and APRIL (“a proliferation-inducing ligand”) (abstract ^[3]).

In particular, the article explores the roles played by BCMA and APRIL in the ability of multiple myeloma cells to grow, survive treat­ment, and spread throughout the body. The article summarizes laboratory work carried out by a team of researchers based primarily at the Dana-Farber Cancer Institute in Boston.

The Dana-Farber research indicates that BCMA encourages many processes that enable myeloma cell growth, survival, and proliferation. APRIL's role is to encourage BCMA to do what it does – it binds to and then activates BCMA.

The researchers also find that the mono­clonal anti­body 01A (short for “hAPRIL01A”) interferes with APRIL's ability to activate BCMA. The anti­body appears to be toxic to multiple myeloma cells, and its anti-myeloma effect is enhanced in the presence of Revlimid (lena­lido­mide) or Velcade (bor­tez­o­mib).

We will get to the detailed findings of the study in a moment. First, however, we want to share what the lead author of the study, Dr. Yu-Tzu Tai of Dana-Farber, told us about the motivation behind the research summarized in the new research paper. She explained that

“In a pre­vi­ous study, my colleagues and I reported that BCMA is the most frequently produced cell membrane protein in multiple myeloma cells, and it is found universally in myeloma cells – not just in some myeloma cells.

“In addi­tion, there is research that looks at the antigens found on multiple myeloma cells. Antigens are molecules that trigger immune responses, and usually are the target of immunotherapies developed to treat cancer. When it comes to the antigens found on myeloma cells, BCMA is the most specific to multiple myeloma cells.

“No study has explained, however, why BCMA is produced at such high levels in multiple myeloma cells, and what its function is in multiple myeloma cells.

“Similarly, APRIL is a protein that binds to BCMA and activates it. People with multiple myeloma have elevated levels of APRIL in their blood. However, no study so far has explained how APRIL activates BCMA in multiple myeloma cells.

“So, we wanted to better understand APRIL's connection to BCMA, and BCMA's role in multiple myeloma. Having a richer, more detailed understanding of what these proteins do should im­prove our ability to develop new myeloma ther­a­pies that interfere in the APRIL and BCMA pathways in the disease.”

The key results of the Dana-Farber study address four topics. For those of our Myeloma Morning readers who interested in more detail about the findings, we've arranged descriptions of them by the four topics they address.

1. Overall impact of BCMA on multiple myeloma cell growth and proliferation

One important topic the investigators explored is whether changes in the amount of BCMA produced by multiple myeloma cells has an effect on the growth and proliferation of those cells. They found that it did.

In particular, when the researchers triggered higher levels of BCMA pro­duc­tion in select cells from multiple myeloma cell lines that usually have low levels of BCMA pro­duc­tion, the cells with greater BCMA pro­duc­tion grew and proliferated faster.

Similarly, when the researchers developed multiple myeloma cell lines with reduced levels of BCMA pro­duc­tion, the cells in those cell lines did not grow and proliferate as fast as their parent cells, which produced higher levels of BCMA.

The investigators also found that BCMA triggered the growth of human multiple myeloma cells with the p53 mutation that had been implanted in laboratory mice.

2. Pathways by which BCMA influences multiple myeloma cell growth and survival

The Dana-Farber team also set out to understand the different ways BCMA affects the ability of multiple myeloma cells to grow, resist treat­ment, and inter­act with their surrounding en­viron­ment. The study authors were able to link BCMA to:

• The activation of pathways -- such as pAKT, pMAPK, and NFkappaB -- that encourage the growth and survival of multiple myeloma cells
• The production of proteins – such as CD31 and VEGF – that encourage angiogenesis, or the growth of blood vessels to nourish the multiple myeloma cells
• The production of proteins – such as PD-L1, TGFbeta, and IL10 – that suppress the immune system's response to threats (such as multiple myeloma cells)
• The production of proteins that encourage the activity and effectiveness of osteoclasts, the cells that break down bone tissue.

3. APRIL's role in stimulating the activity of BCMA

The investigators found that there was a link between APRIL binding to BCMA and the stimulation of PD-L1, TGFbeta, and IL10 protein pro­duc­tion. The pro­duc­tion of those proteins helps protect multiple myeloma cells by suppressing the immune system response to the cells.

The researchers also found indications of a link between APRIL binding to BCMA and the activation of the NFkappaB pathway, which encourages cell growth and survival.

4. The impact of 01A on multiple myeloma cells

Finally, the study authors explored the effect of the 01A mono­clonal anti­body on multiple myeloma cells. They dem­onstrated that 01A is toxic to multiple myeloma cells, killing the cells in the presence of bone marrow cells that can often serve to protect myeloma cells.

01A also prevented the growth of human multiple myeloma cells implanted in mice, and Revlimid and Velcade apparently enhance 01A's anti-myeloma activity.

Next steps based on the study's findings?

We asked Dr. Tai what direction she and her colleagues plan to take based on the results of the BCMA/APRIL study. She told us that one area they want to explore is whether APRIL has an effect on the cells in the bone marrow en­viron­ment that are not multiple myeloma cells, but which can serve to protect and/or nourish multiple myeloma cells. They also want to explore whether 01A may block any APRIL-related effects on those surrounding cells.

She also believes the team will be investigating whether APRIL or BCMA influence the immune system's response to multiple myeloma in ways beyond those they were able to identify so far.

When asked if she believes that there should be addi­tional research into 01A as a potential multiple myeloma treat­ment, Dr. Tai said that “Based on our current findings, it would be reasonable to pursue further, especially in com­bi­na­tion ther­apy.”

Quickly Noted

A study by researchers in Japan looks at a common side effect of au­tol­o­gous stem cell trans­plan­ta­tion: "dysgeusia", or distortion in a patient's sense of taste (abstract ^[4]). The researchers found that the devel­op­ment of mouth sores during trans­plan­ta­tion was an important risk factor for taste distortion post trans­plan­ta­tion. Likewise, preventing mouth sores through the use of cryotherapy – ice cubes or other substances that keep the mouth cold – was linked to a lower risk of taste distortion developing.

A study by researchers in China explores a possible link between levels of homocysteine in the blood and a person's risk of developing multiple myeloma (full text ^[5]). Homocysteine is an amino acid that is not found in foods, but instead is formed by the body. Elevated levels of homocysteine in the blood can lead to heart-related problems. There also is evi­dence linking elevated homocysteine levels and an increased risk of cancer, including studies published in Chinese that suggest a link between homocysteine levels and multiple myeloma.

The new Chinese study explores the potential link between homocysteine and multiple myeloma by investigating whether a genetic predisposition to higher homocysteine levels in the blood is linked to a higher risk of developing multiple myeloma. The study authors find that there is evi­dence of such a link.

Finally, we have several discussions in the Beacon's forum that we thought might interest Myeloma Morning readers:

• Beacon Medical Advisor Dr. James Hoffman of the Sylvester Cancer Center in Miami provides feedback in a discussion about amyloid deposits in multiple myeloma patients and how permanent they are (link to Dr. Hoffman's posting ^[6])
• What tips do you have for how to care for a central line (central venous catheter) after it's installed as part of the stem cell transplant process? (link to discussion ^[7])
• Forum regular Ron Harvot shares an update and photo from his most recent bike race, where he and his racing partner cycled 166 miles (link to Ron's posting ^[8])
• There's a new posting in a thread started last November, when someone described how they experienced some nausea and shakiness after stopping treatment with Revlimid (link to discussion ^[9])

New Myeloma-Related Research Articles

1. Draak, T. H. et al., “Correlation of the patient's reported outcome inflammatory-RODS with an objective metric in immune-mediated neuropathies” in the European Journal of Neurology, April 29, 2016 (abstract ^[10])
2. Fajardo, S., Zook, F. & Dotson E. “Specialty pharmacy for hematologic malignancies” in the American Journal of Health System Pharmacy, April 29, 2016 (abstract ^[11])
3. Okada, N. et al., “Evaluation of the risk factors associated with high-dose chemotherapy-induced dysgeusia in patients undergoing autologous hematopoietic stem cell transplantation: possible usefulness of cryotherapy in dysgeusia prevention” in Supportive Care in Cancer, April 29, 2016 (abstract ^[4])
4. Wester, R. & Sonneveld, P., “Innovations in treatment and response evaluation in multiple myeloma” in Haematologica, May 2016 (full text ^[12])
5. Xuan, Y. T. et al., “A Mendelian randomization study of plasma homocysteine and multiple myeloma” in Scientific Reports, April 29, 2016 (full text ^[5])
6. Zhang, L. et al., “Potential role of exosome-associated microRNA panels and in vivo environment to predict drug resistance for patients with multiple myeloma” in Oncotarget, April 29, 2016 (full text ^[13])