Results from a number of multiple myeloma studies were presented yesterday during the second day of the American Society of Hematology (ASH) 2011 annual meeting in San Diego.

Predicting Response To Immunomodulatory Drugs

During an oral presentation and a poster presentation yesterday, researchers discussed the role of the protein cereblon in the treatment of myeloma.  Results from one study (abstract ^[1]) in myeloma cell lines suggested that cereblon plays a key role in whether multiple myeloma patients respond to the immunomodulatory drugs Revlimid ^[2] (lenalidomide) and pomalidomide ^[3].  Another study (abstract ^[4]) showed that myeloma patients with higher levels of cereblon in their bone marrow are likely to respond better to treatment with Revlimid and dexamethasone ^[5] (Decadron).

These studies suggest that, in the future, tests may be developed to allow physicians to easily check a myeloma patient's cereblon levels.  This, in turn, will help determine whether or not the patient should be treated with an immunomodulatory drug such as Revlimid or pomalidomide.

Velcade And Secondary Cancers

Secondary cancer has been an important topic this year within the myeloma community, with most of the attention focused on the possibility that Revlimid may increase a myeloma patient's risk of developing a second cancer (see related Beacon ^[6] news).

A poster presentation yesterday reviewed data from several trials to determine whether there is a link between Velcade ^[7] (bortezomib) and developing a second cancer (abstract ^[8]).

In the APEX trial comparing treatment with Velcade to treatment with dexamethasone in relapsed/refractory myeloma patients, Velcade-treated patients had a rate of secondary cancers of 0.88 cases for every 100 patient-years. In contrast, patients treated only with dexamethasone had no cases of secondary cancer.

Similarly, in the VISTA trial in newly diagnosed myeloma patients, which compared Velcade, melphalan ^[9] (Alkeran), plus prednisone ^[10] (VMP) as initial therapy versus just melphalan plus prednisone (MP), there were 1.66 cases of secondary cancer for every 100 patient-years of treatment in the VMP arm of the trial versus 1.30 in the MP only arm of the trial.

The two studies indicate that Velcade-treated patients have slightly higher rates of secondary cancer than myeloma patients not treated with Velcade.

However, the researchers who conducted this study noted that the rate of secondary cancers observed in the Velcade-treated patients is similar or lower than the rate of cancer in the general U.S.population similar in age to myeloma patients.

Additionally, a safety review of Revlimid conducted by the European Medicines Agency concluded "that there were 3.98 cases of new cancer for every 100 patient-years in patients receiving Revlimid compared with 1.38 cases in those not receiving Revlimid."  Therefore, any secondary cancer risk associated with Velcade would appear to be substantially lower than the risk documented thus far for Revlimid.

Potential New Myeloma Therapies

During yesterday’s poster session, there were presentations about several potential new myeloma therapies and new combination therapies.

One presentation discussed the long-term efficacy and safety of pomalidomide in combination with dexamethasone for the treatment of relapsed/refractory multiple myeloma patients (abstract ^[11]).

The overall response to treatment was 65 percent, including 7 percent stringent complete response, 7 percent complete response, 25 percent very good partial response, and 27 percent partial response.

Half of the patients responded within a rapid 1.7 months, and half responded for more than 21.3 months.

Ninety-one percent of the patients in the study were still alive one year after entering the trial, and 76 percent were alive after two years. Median overall survival has not yet been reached after a median follow-up of about 34 months.

The researchers also noted that standard-risk patients appear to perform better on the combination treatment than higher-risk patients, and the researchers concluded that the treatment is "highly effective" and "well-tolerated."

Another poster presented results from a Phase 2 trial of ARRY-520 ^[12] (filanesib ^[13]) (abstract ^[14]).  The trial included 32 myeloma patients previously treated with Velcade and at least one immunomodulatory drug (thalidomide or Revlimid).  During the trial, these patients were infused with ARRY-520 on days 1 and 2 of a 14-day cycle.

Overall, 12.5 percent of the study participants achieved a partial response, and another 6 percent achieved a minimal response.  The median time to response was about four months.

The researchers who conducted the study concluded that ARRY-520 "shows promising evidence of single-agent clinical activity and an acceptable safety profile in heavily pretreated patients."

However, more than 25 percent of the patients treated with the drug experienced serious side effects, such as low white blood cell counts and low platelet counts, despite receiving G-CSF ^[15] (Neupogen ^[16] or Neulasta ^[17]) to help sustain white blood cell counts.

The company developing the drug, Array BioPharma, plans to continue testing the drug in different combinations – with dexamethasone, with carfilzomib ^[18], and with Velcade and dexamethasone – in relapsed myeloma patients.

Another study presented during the poster session looked at the safety and efficacy of the so-called "T-BiRD" regimen in 26 newly diagnosed myeloma patients (abstract ^[19]).  Like the "BiRD" regimen, it is a combination of the antibiotic clarithromycin (Biaxin), Revlimid, and dexamethasone, with the addition of thalidomide.

The overall response rate to the treatment was 77 percent; specifically, 4 percent had a complete response, 31 percent had a very good partial response, and 42 percent had a partial response.  In addition, patients appeared to respond quickly to the regimen.

After about four years of follow-up, overall survival was 84.5 percent. Survival was similar in patients with standard- and higher-risk genetic characteristics. However, there appeared to be a trend toward greater overall survival in standard-risk patients.

Nearly 70 percent of the participants successfully collected enough stem cells and underwent a stem cell transplant in addition to the T-BiRD regimen.  However, 31 percent of the trial participants halted T-BiRD treatment due to side effects.

There was also a poster about a trial studying an investigational cancer vaccine known as Stimuvax (L-BLP25).  The trial involved 34 patients with previously untreated smoldering or active myeloma (abstract ^[20]).  Although none of the participants responded to the vaccine, the vaccine showed some signs of slowly reducing monoclonal (M)-protein levels over time in the trial participants.  Therefore, the researchers who conducted the study believe the vaccine still warrants further investigation.

Survival Studies

Yesterday evening, Dr. Nicholas Kröger from the University Medical Center in Hamburg, Germany, spoke about the effect “molecular remission” has on a myeloma patient’s survival (abstract ^[21]).  Molecular remission is a more stringent form of complete response, where a more sensitive test is used to determine whether there is still evidence of myeloma in a patient's bone marrow.

The study included 73 myeloma patients who were treated during the period from 2000 to 2008. Due to the time period when the study was conducted, patients were initially treated with older treatment regimens, rather than ones involving novel myeloma drugs.

After their initial therapy, patients received high-dose melphalan and an autologous transplant (using their own stem cells).  Two to three months later, the patients went through further treatment with melphalan, fludarabine, and  anti-thymocyte globulin followed by an allogeneic (donor) stem cell transplant.

Overall, 86 percent of participants responded.  Specifically, 60 percent of patients achieved a complete response, 8 percent a very good partial response, and 18 percent a partial response.

Molecular remission was observed in 30 patients, or 46 percent of the patient sample.  Of those 30 patients, 15 had a "sustained" molecular remission, meaning that repeated tests showed no evidence of myeloma. The other 15 had only intermittent molecular remission.

After a median follow-up of seven years, the five-year progression-free survival was 29 percent for the overall study population, 31 percent for those with intermittent molecular remission, and 85 percent for those with sustained molecular remission.

The five-year overall survival was 52 percent.  However, the survival rate was 87 percent for those who achieved intermittent molecular remission and 91 percent for those who sustained a molecular remission.

Dr. Kroeger said during the presentation that, in his opinion, the key is to get patients to a molecular remission if at all possible, but it is not important how or when this is achieved.  Once a patient achieves a molecular remission, he doubts there is a substantial benefit to be gained from further treatment.

The other key takeaway that Dr. Kroeger mentioned is that donor lymphocyte infusions markedly improve the efficacy of donor transplants.  However, he did not fully explore this point in the abstract or talk.

Another poster from yesterday compared survival rates of people diagnosed with multiple myeloma at young ages (45 years or less) to those diagnosed at older ages (abstract ^[22]).  The analysis included 100 younger patients.  Among those, 45 percent received initial therapy that included a novel agent, 85 percent underwent a transplant using their own stem cells, and 15 percent underwent a donor stem cell transplant.

The median overall survival of the younger patients was 7.8 years as compared to 4.4 years for the older patients.  Also for the patients who were 45 years or younger at the time of diagnosis, the overall survival rates at five and seven years were 69 percent and 59 percent, respectively.

For more detailed coverage of yesterday’s myeloma-related presentations and research at the ASH meeting, see the ASH 2011 Day Two ^[23] thread in The Myeloma Beacon discussion forum.

The Beacon is publishing regular “as it happens” updates from Day Three ^[24] of ASH in the Beacon’s myeloma forums ^[25].  Similar “as it happens” updates will be provided for Day Four ^[26].  As always, the news from each day also will be summarized in daily updates like this one.