The American Society of He­ma­tol­ogy meeting swung into full gear yesterday. The day was full of invited talks and a poster session.

The morn­ing kicked off with an education session in which attendees could learn about sev­er­al myeloma-related topics.

The first pre­sen­ta­tion was by Dr. Ola Landgren from the National Cancer In­sti­tute and National In­sti­tutes of Health in Bethesda, Maryland. Dr. Landgren spoke about mono­clonal gam­mop­athy of undetermined sig­nif­i­cance (MGUS) and smol­der­ing myeloma, precursor dis­eases of mul­ti­ple myeloma.

A study pub­lished by Dr. Landgren last year showed that all mul­ti­ple myeloma patients have MGUS initially, even though many are not diag­nosed until the MGUS has already progressed to myeloma (see re­lated Beacon news). Evidence sug­gests that MGUS can progress to smol­der­ing myeloma, which can then progress to mul­ti­ple myeloma.

Dr. Landgren ex­plained that the average rate of pro­gres­sion from MGUS to myeloma or a re­late cancer is 1 per­cent per year. However, some patients are at higher risk than others. Among patients at a low risk of pro­gress­ing, about 5 per­cent will progress in 20 years. However, among patients at the highest risk of pro­gres­sion, 58 per­cent will progress in that same amount of time. Since the vast majority of MGUS patients never progress, Dr. Landgren said that it is not nec­es­sary to screen the general pub­lic for MGUS. Instead, patients with MGUS should be stratified based on their risk of pro­gres­sion and then monitored ac­cord­ingly.

Smoldering myeloma, on the other hand, has a much higher rate of pro­gres­sion. For the first 5 years after diag­nosis, a smol­der­ing patient has a 10 per­cent chance each year of pro­gress­ing. After that, the risk be­comes less likely at 3 per­cent per year for the next 5 years and then 1 per­cent per year after that.

Currently, stud­ies have not shown a ben­e­fit to treating smol­der­ing myeloma patients to prevent pro­gres­sion or extend sur­vival. Therefore, Dr. Landgren rec­om­mended that smol­der­ing patients only be treated in a clin­i­cal trial setting. Outside of clin­i­cal trials, smol­der­ing patients should only be observed for signs of pro­gres­sion. It is not yet known whether early treat­ment may cause a more aggressive dis­ease at relapse.

Later in the education session, Dr. Sagar Lonial from Emory Uni­ver­sity’s Winship Cancer In­sti­tute spoke about ther­apy for re­lapsed myeloma patients.

At relapse, Dr. Lonial said the physician first needs to decide whether to treat the patient. If a patient has high cal­cium levels, kidney com­pli­ca­tions, low red blood cell counts, or bone in­volvement, then the patient re­quires treat­ment. However, he said that patients with only a biochemical relapse, such as the presence of mono­clonal pro­tein (M-protein), do not nec­es­sar­i­ly need to be treated. In the latter case, the physician should look at the aggressiveness of the pre­vi­ous relapse, risk of organ damage, and amount of the M-protein.

For patients at their first relapse who have slowly pro­gress­ing myeloma, Dr. Lonial sug­gested single agent ther­apy with Velcade (bor­tez­o­mib), Revlimid (lena­lido­mide), or thalidomide (Thalomid). He rec­om­mends Revlimid ther­apy for patients initially treated with Velcade and who have periph­eral neu­rop­athy. He rec­om­mends Velcade ther­apy for patients initially treated with Revlimid or thalido­mide, patients who pre­vi­ously had a good or long re­sponse to Velcade, or patients with kidney prob­lems.

Dr. Lonial rec­om­mends a stem cell trans­plant for these types of patients if they did not initially have a trans­plant or if they had a long remission after the first trans­plant (18 to 24 months). He pointed out that the duration of the sec­ond trans­plant is usually shorter than the first. Patients who have low blood cell counts that prevent them from tolerating treat­ment with novel agents may not have many other op­tions besides a trans­plant.

For patients with aggressive, rapidly pro­gress­ing myeloma that has already re­lapsed mul­ti­ple times, Dr. Lonial said the op­tions are chemo­ther­apy, chemo­ther­apy plus Revlimid or Velcade, or a stem cell trans­plant in com­bi­na­tion with Revlimid and dexamethasone (Decadron). He ex­plained that in this group, the ef­fi­cacy of a trans­plant is likely to be short lived, but it is a quick way to con­trol the dis­ease, which can be quickly followed up with addi­tional ther­apy.

Dr. Lonial was par­tic­u­larly ex­cited about the emerging ther­a­pies: pomalidomide, carfilzomib, panobinostat and Zolinza (vorinostat) in com­bi­na­tion with novel agents, perifosine, and elotuzumab.

In the afternoon, there was a session about mul­ti­ple myeloma stem cells, which are thought to be the treat­ment-resistant cancer cells that re-grow new myeloma cells and cause relapse. There is grow­ing evi­dence of these cancer stem cells, but much about them is still unknown.

Dr. William Matsui from the Johns Hopkins Uni­ver­sity School of Medicine in Baltimore spoke about the origin of the myeloma stem cell. He be­lieves that there are myeloma stem cells, but that they are rare. Studies in­di­cate that 1 in 10,000 or 1 in 100,000 cancer cells are cancer stem cells.

The source of these myeloma stem cells is still unknown. B cells are im­mune cells that can be activated to pro­duce anti­bodies, at which point they are known as plasma cells. Dr. Mastsui pre­sented stud­ies showing that B cells are more likely the source of myeloma stem cells than plasma cells.

Dr. Matsui described that B cell-based strategies for targeting myeloma stem cells have been pursued, but the self-renewal of cancer stem cells needs to be pursued. He sug­gested that the reg­u­lar myeloma cells should be reduced using high-dose ther­apy, and then the cancer stem cells can be targeted. He also sug­gested that among the cur­rent myeloma ther­a­pies, myeloma stem cells are most sensitive to Revlimid, then dexa­meth­a­sone, and then Velcade.

The day concluded with a large poster session. Within the hall where the session was held, there were rows and rows of posters hung from boards. The room was divided into sections based on dis­ease and area of re­search. There were two sections for myeloma: one on the biology of myeloma and the other on myeloma ther­apy. Many posters were accompanied by a presenter or printouts of the posters for attendees to take with them.

The most im­por­tant posters of the session were in the “Therapy, excluding Transplantation” part of the session, and they reported on clin­i­cal trials of emerging myeloma ther­a­pies.

There were four posters about car­filz­o­mib, which is a new agent that works similarly to Velcade.

A Phase 2 study of car­filz­o­mib in patients who have not been pre­vi­ously treated with Velcade showed about 50 per­cent of patients responded to treat­ment. There was a minimal amount of periph­eral neu­rop­athy—pain and tingling in the extremities that is a common side effect of Velcade (abstract).

A Phase 2b study showed that chromosomal ab­nor­mal­i­ties do not affect patient re­sponse to car­filz­o­mib (abstract). In fact, the re­sponse rate for patients with one or more un­fa­vor­able ab­nor­mal­i­ties was greater (28 per­cent) than the re­sponse rate for patients with fa­vor­able or no ab­nor­mal­i­ties (24 per­cent).

Long-term re­­sults of four Phase 1 and 2 trials showed that car­filz­o­mib is well-tolerated during extended treat­ment. After at least 11 months of ther­apy with single-agent car­filz­o­mib, 60 per­cent of patients are still being treated, and 30 per­cent have been treated for more than 1.5 years (abstract).

A safety analysis of three Phase 1 and 2 clin­i­cal trials showed that car­filz­o­mib was well-tolerated with very low rates of severe side effects (abstract). The most common severe side effect was pneu­monia (3.5 per­cent). Very few patients ex­peri­enced periph­eral neu­rop­athy (4 per­cent with 0.4 per­cent having severe neu­rop­athy).

There were three posters about Zolinza (vorinostat), a histone deacetylase in­hib­i­tor that is already approved for a cer­tain type of lym­phoma.

A Phase 1 study of Zolinza in com­bi­na­tion with Revlimid and dexa­meth­a­sone in re­lapsed and re­frac­tory patients showed that 52 per­cent of patients responded with a median time to pro­gres­sion of 5 months. The most common severe side effects were low blood cell counts, diarrhea, and fatigue (abstract).

Another Phase 1 study of Zolinza in com­bi­na­tion with Velcade and Doxil (doxorubicin lipo­somal) in re­lapsed and re­frac­tory patients showed an over­all re­sponse rate of 72 per­cent and a re­sponse rate of 44 per­cent in Velcade re­frac­tory patients. Low platelet counts were the most common side effect (abstract).

Two stud­ies are eval­u­ating the ef­fi­cacy of Zolinza in com­bi­na­tion with Velcade in re­lapsed and re­frac­tory myeloma patients. The Phase 3 clin­i­cal trial is still recruiting patients. Interim re­­sults of the Phase 2 study sug­gest that the com­bi­na­tion may have ac­­tiv­ity in patients who are re­frac­tory to Velcade and Revlimid/thalidomide (abstract).

There was one poster about poma­lido­mide, but rather than looking at how patients responded to poma­lido­mide, it looked at how patients who had already re­lapsed after poma­lido­mide responded to salvage ther­apy afterward. The num­ber of patients who went on to each type of treat­ment was small and the patients were not ran­domized to re­ceive their next treat­ment, but patients who re­ceived a stem cell trans­plant after poma­lido­mide had the highest re­sponse rate (75 per­cent). Re­sponses to Velcade (25 per­cent) and Revlimid (29 per­cent) were similar (abstract).

There was a Phase 1 trial investigating elotuzumab, a mono­clonal anti­body. It was being tested in com­bi­na­tion with Revlimid and low-dose dexa­meth­a­sone in re­lapsed and re­frac­tory patients. A partial re­sponse or better was seen in 82 per­cent of patients who had pre­vi­ously been treated with Revlimid and 96 per­cent of patients who had not yet been treated with Revlimid. Treatment took about 7 weeks before patients responded, and the median time to pro­gres­sion has not yet been reached. The most common severe side effects were low white blood cell and platelet counts (abstract).

There were also two posters about lorvotuzumab mertansine (IMGN901), a cancer-killing drug bound to an anti­body that directs the drug right to the cancer cell.

A Phase 1 study of lorvutuzumab mertansine in heavily pre-treated myeloma patients is on­go­ing with the goal to de­ter­mine the max­i­mum tol­er­ated dose and ac­­tiv­ity of the drug. Preliminary re­­sults show 18 per­cent of patients achieved at least a partial re­sponse. About half of the patients remained on treat­ment for at least 3 months, and 7 per­cent have been on ther­apy for more than a year. A few patients have ex­peri­enced severe fatigue, kidney failure, weakness, or muscle issues (abstract).

Another Phase 1 study of lorvutuzumab mertansine in com­bi­na­tion with Revlimid and dexa­meth­a­sone in re­lapsed and re­frac­tory patients is on­go­ing with the pur­pose to de­ter­mine the max­i­mum tol­er­ated dose of lrvutuzumab mertansine in this com­bi­na­tion. The study is still recruiting patients. Early re­­sults showed that at the lowest dose to be tested, two out of three patients achieved a partial re­sponse and remain on treat­ment (abstract).

The Myeloma Beacon will be pub­lishing reg­u­lar "as it hap­pens" up­dates from the sec­ond full day of ASH in this thread in the Beacon's myeloma forums.   Similar "as it hap­pens" up­dates also will be provided for Day Three and Day Four.  As always, the news from each day also will be summarized in daily up­dates like this one.