Good morning, myeloma world.

We have a slightly different edition of Myeloma Morning ^[1] cooked up for you today than is usually the case. Although we have one new myeloma research study that we will review – see the discussion further below about Cometriq – we will spend most of today's edition looking in more detail at an issue discussed in this Monday's edition of Myeloma Morning ^[2].

In that article, we discussed a recent study by physicians at the Mayo Clinic's Arizona campus. The Mayo Clinic study concerns a con­di­tion known as thrombotic microangioapathy (TMA), which developed in two myeloma patients the physicians had been treating with Kyprolis (car­filzomib) (abstract ^[3]).

Our summary of the study about Kyprolis and TMA raised concern among some of the Beacon's readers – in part because former Beacon columnist Pat Killingsworth passed away earlier this year due to com­pli­ca­tions arising from thrombotic thrombocytopenic purpura, which is one type of TMA. Pat was undergoing treat­ment with Kyprolis prior to his developing TTP.

We therefore decided to learn more about the potential connection between Kyprolis and TMA. We reached out to Dr. Jill Adamski, the lead author of the Mayo Clinic study, and spoke at length with her about the cases discussed in the article and broader issues related to them.

Because Dr. Adamski's research focuses mainly on TMA and other issues related to blood collection, pro­cess­ing, and transfusion, she suggested that we also discuss the study with her co-author and Mayo Clinic myeloma specialist, Dr. Rafael Fonseca, who provided addi­tional insights into possible implications of the study.

Here is what we learned.

First and foremost, we should make clear that we are speaking about a rare side effect. TMA is sufficiently rare as a Kyprolis side effect that it has not been reported in any of the numerous clinical trials that have tested Kyprolis as a myeloma ther­apy. Dr. Fonseca believes the possibility of TMA occuring as a side effect does not in any way outweigh the benefits of Kyprolis as a myeloma ther­apy.

In addi­tion, Kyprolis is not the only myeloma ther­apy known to cause TMA. Cases of TMA also have been reported in myeloma patients being treated with Velcade, and it can occur as a side effect of the high-dose mel­phalan ther­apy admin­istered during the au­tol­o­gous stem cell trans­plant process.

TMA occurs when the lining of the blood and lymph vessels in the body, including the vessels in the kidney, becomes damaged. The body's reaction to this damage is the formation of very tiny blood clots where the damage has occurred. If this happens in many locations throughout the body, the devel­op­ment of so many blood clots can cause platelet levels in the blood to drop to very low levels. This can interfere with clotting that should be occurring to avoid unwanted internal bleeding. In addi­tion, the process often can lead to kidney damage.

Dr. Adamski told us that there are three blood test results that can be watched for signs of TMA developing. They are a patient's platelet levels, their LDH (lactate dehydrogenase) level, and their creatinine level. If platelet levels are dropping, and LDH and creatinine levels are going up, and there are no changes in the status of a patient's multiple myeloma that might account for these changes, then the changing lab results could be signs that treat­ment is causing TMA.

As a concrete example, let's say that a myeloma patient is being treated with Kyprolis. Her M-spike is con­stant and her free light chain levels are heading toward normal levels. If, in this sort of situation, the patient's platelet levels start to drop while her LDH and creatinine levels are increasing, then this com­bi­na­tion of events could be a sign that TMA is developing.

If TMA develops and it is thought to be the result of a myeloma treat­ment such as Kyprolis, Dr. Adamski believes the most important step is to stop whatever treat­ment is most likely causing the TMA.

There also have been attempts to treat the TMA using “therapeutic plasma exchange”, a process that removes components of a patient's blood from their body. But, based on what has been published by other researchers, and based as well on experiences such as those Dr. Adamski and her colleagues discuss in their recent paper, Dr. Adamski is not convinced that plasma exchange helps in these cir­cum­stances. In fact, plasma exchange may make the situation worse.

There is a drug, Soliris (eculizumab), that may help counteract TMA. However, it has not been rigorously tested as a TMA treat­ment. Soliris is approved by the FDA to treat con­di­tions related to TMA – atypical hemolytic uremic syn­drome (aHUS), and paroxysmal nocturnal hemoglobinuria (PNH).

There is not enough in­­for­ma­tion at this time to know what factors affect a myeloma patient's risk of developing TMA during treat­ment. Dr. Adamski believes that certain patients may be genetically predisposed to develop­ing TMA during treat­ment, but she admits that this is just a personal hypothesis of hers. She also believes that TMA becomes more likely as a side effect as more and more damage is done to the lining of a patient's blood vessels and kidneys by, for example, treat­ments that cause such damage. At this time, the list of myeloma ther­a­pies believed to cause such damage includes mel­phalan, Velcade, and Kyprolis. Some might also include Ninlaro (ixazomib) in that list, since Ninlaro is in the same class of ther­a­pies as Velcade and Kyprolis – proteasome inhibitors – and there appears to be a connection between TMA and the way proteasome inhibitors work.

We will report more on TMA as we learn addi­tional in­­for­ma­tion that may be helpful to our readers.

Phase 1 Trial Results For Cometriq

The new research study that we'd like to summarize today is one by a group of U.S. myeloma specialists. The study in­ves­ti­gated the possible use of the drug Cometriq (cabozantinib) on its own as a treat­ment for multiple myeloma (abstract ^[4]).

Cometriq is an orally admin­istered drug approved by the U.S. Food and Drug Administration as a treat­ment for a form of thyroid cancer. It belongs to a class of drugs known as tyrosine kinase inhibitors.

The authors of the new study tested Cometriq in a total of 12 re­lapsed multiple myeloma patients, who were enrolled in two separate trials with the same design. To par­tic­i­pate in the trials, patients had to have been treated with an immuno­modu­la­tory agent – such as Revlimid (lena­lido­mide) or thalido­mide (Thalomid) – and with a proteasome inhibitor, such as Velcade or Kyprolis. The 12 patients in the two trials had a median of three pre­vi­ous lines of ther­apy.

The goal of the two trials was to establish a Cometriq dose appropriate for use in myeloma patients, and to get an initial sense of the drug's efficacy. Several different doses of Cometriq were tested during the trial.

Unfortunately, Cometriq did not show much efficacy as a myeloma ther­apy. There was 1 minimal response, and 8 patients had stable disease as their best response.

The researchers conclude that Cometriq on its own “does not have significant single agent activity in patients with re­lapsed and/or refractory multiple myeloma.” They do not rule out the possibility, however, that bio­markers may be found that indicate whether a myeloma patient may respond to treat­ment with Cometriq.

Beacon Forum Activity

There con­tinues to be quite a bit of activity in the Beacon forum these days. Here are some recent posts and discussions that readers may find interesting:

• Forum regular Multibilly provided an update on his informal “trial” of fenofibrate (Tricor) for his smoldering multiple myeloma. Multibilly's regular updates include graphs of his M-spike, free light chain results, and IgG level – so they are a useful look at how these lab results can vary in a smoldering myeloma patient (link to post ^[5])
• Debbie has posted an update about her ongoing autologous stem cell transplant. She took the plunge and shaved her head, and decided to share a picture of her new look with everyone in the forum (link to post ^[6])
• Paul shared an update about his ongoing treatment with Empliciti (elotuzumab) (link to post ^[7])
• Victoria is looking for people who, like her husband, have multiple myeloma and have had a kidney transplant (link to discussion ^[8]).