In the study, patients who had relapsed and were no longer responsive to Velcade-based treatments received panobinostat in combination with Velcade and dexamethasone.

Although the results generally are being viewed as favorable, “It is hard to interpret them because you don’t really know how the patients would have done with just Velcade and dexamethasone alone,” explained Dr. Leif Bergsagel, a myeloma specialist from the Mayo Clinic in Arizona, in a discussion with The Beacon.  Dr. Bergsagel was not involved in the study.
 
“My interpretation right now is that the combination is helping a subset of patients, and we need to try and identify that subset in order to move the therapy forward,” added Dr. Bergsagel. 

Dr. Paul Richardson from the Dana-Farber Cancer Institute in Boston presented the study results at the American Society of Hematology (ASH) annual meeting in San Diego last month.

Panobinostat is an oral drug that is being developed by the pharma­ceutical company Novartis (NYSE: NVS) for a variety of different cancers. It belongs to a class of drugs called histone deacetylase (HDAC) inhibitors, which work by increasing the production of proteins that slow cell division and cause cell death.

Zolinza (vorinostat), another HDAC inhibitor being studied for the treatment of myeloma, was recently shown to have a small impact on progression-free survival when used in combination with Velcade in relapsed/refractory myeloma patients (see related Beacon news).

Previous laboratory studies have shown that panobinostat in combination with Velcade (bortezomib) may have significant anti-myeloma effects. Furthermore, a Phase 1 trial of this combination in relapsed and treatment-resistant (refractory) myeloma patients resulted in a high overall response rate (see related Beacon news).

The purpose of this Phase 2 trial was to determine the efficacy and safety of panobinostat with Velcade and dexamethasone (Decadron) in relapsed and Velcade-refractory myeloma patients.

All patients in the trial also were required to have been treated at some point with one of the immuno­modulatory anti-myeloma drugs, such as thalidomide (Thalomid), Revlimid (lenalidomide),  or poma­lidomide.

Fifty-five patients with a median age of 61 years participated in this study. The patients had received a median of four prior treatments, including 64 percent who had undergone stem cell transplantation.

The treatment regimen was composed of two phases. In the first phase, patients received eight 3-week treatment cycles, which included 20 mg of panobinostat on days 1, 3, 5, 8, 10, and 12 plus 1.3 mg/m² of Velcade on days 1, 4, 8, and 11 as well as 20 mg of dexamethasone on the day of and day after each Velcade dose.

Patients who responded or demonstrated stable disease proceeded to the second treatment phase, which consisted of four 6-week cycles including 20 mg of panobinostat three times per week on weeks 1, 2, 4, and 5 plus 1.3 mg/m² of Velcade on days 1, 8, 22, and 29 as well as 20 mg of dexamethasone on the day of and day after each Velcade dose.

Of the evaluated patients, 29 percent achieved at least a partial response, including 4 percent who achieved a near complete response.  No patients achieved a complete response.

Thus far, 16 patients have completed the first treatment phase and proceeded to the second phase. Ten patients are currently still in the second phase of treatment, including two patients who have completed 12 or more cycles.

Severe to life-threatening side effects included low platelet counts (53 percent of patients), fatigue (16 percent), anemia (16 percent) diarrhea (14 percent), pneumonia (14 percent), and low white blood cell counts (12 percent), most of which were manageable with a dose reduction. Peripheral neuropathy, a condition characterized by pain and tingling in the extremities due to nerve damage, occurred in 24 percent of patients, with 2 percent classified as having severe peripheral neuropathy.

The combination of panobinostat, Velcade, and dexamethasone is currently being tested in a Phase 3 clinical trial, which is comparing the combination to Velcade and dexamethasone without panobinostat. Dr. Bergsagel of the Mayo Clinic noted that these results will be critical for determining to what extent, and for which patients, the panobinostat combination is helpful.

Panobinostat is also being studied in combination with other common anti-myeloma drugs, including Revlimid, carfilzomib, and pomalidomide.

For more information, please see abstract 814 on the ASH annual meeting website and Dr. Richardson’s slide deck, which he has made available as a courtesy to The Beacon’s readers.

The afternoon myeloma sessions were focused, in fact, on potential new therapies.

The Beacon’s previous ASH 2011 update covered the afternoon presentations about carfilzomib and pomalidomide, two potential myeloma therapies that are in the late stages of development.

This update covers the afternoon’s presentations about four other potential new myeloma therapies — MLN9708, panobinostat, perifosine, and Zolinza.

There also were morning presentations on the third day of the ASH meeting that were about potential new myeloma therapies.  Those presentations were covered in an update published last week.

MLN9708

During the afternoon sessions, Dr. Shaji Kumar from the Mayo Clinic in Rochester, Minnesota, presented trial results for the investigational drug MLN9708.

Specifically, he presented results from a Phase 1 study of MLN9708 in patients with relapsed and refractory multiple myeloma (abstract).

MLN 9708 belongs to the same class of drugs as Velcade (bortezomib). However, unlike Velcade, MLN9708 can be taken orally.

The primary objective of the study presented by Dr. Kumar was to determine the maximum tolerated dose and safety of MLN9708 when it is administered once per week.

The study included 32 patients with a median age of 64.  The patients had received a median of six prior therapies.

During the trial, patients received a median of two treatment cycles. Three patients are currently continuing treatment; all others have discontinued treatment, mainly due to disease progression (69 percent).

Of the 18 patients who have been evaluated thus far for their response to the drug, one reached a very good partial response and one reached a partial response, for an overall response rate of 11 percent.

The majority of patients (72 percent) experienced treatment-related side effects.

However, only nine percent of the patients reported experiencing peripheral neuropathy, a condition characterized by pain and tingling in the extremities.  None of the reported cases were severe.

(For complete coverage of the MLN9708-related presentations at the ASH meeting, see the related Beacon news article.)

Panobinostat

Also during the afternoon sessions, Dr. Paul Richardson from the Dana-Faber Cancer Institute in Boston reported on Phase 2 trial results for the investigational drug panobinostat in combination with Velcade (abstract; presentation slide deck (pdf), made available by Dr. Richardson as a courtesy to The Beacon’s readers).

Panobinostat is an oral drug being developed by the pharmaceutical company Novartis as a potential treatment for a range of different cancers, including multiple myeloma.  It belongs to same class of drugs — known as “HDAC-inhibitors” — as Zolinza, another potential new myeloma drug discussed later in this article.

Laboratory studies have suggested that the combination of panobinostat and Velcade may have an anti-myeloma effect stronger than the anti-myeloma effect of either drug on its own.

In addition, 65 percent of the relapsed / refractory patients in a Phase 1 trial of the combination achieved at least a partial response to treatment.

The Phase 2 trial summarized by Dr. Richardson included 55 myeloma patients with a median age of 61 years.  All patients were refractory to Velcade and had a median of four prior treatment regimens.  Almost 70 percent of the patients had received a stem cell transplant.

Overall, 29 percent of the patients in the trial achieved at least a partial response to treatment, with 4 percent reaching a near complete response and 25 percent achieving a partial response.

The most common side effects included low platelet counts (thrombocytopenia), fatigue, diarrhea, anemia, and nausea.  More than half the trial participants experienced low platelet counts to an extent considered severe or life-threatening.

Dr. Richardson explained, however, that most side effects could be managed by dose reductions or interruptions.

Peripheral neuropathy was observed in 24 percent of patients, but all cases were classified as mild.

Dr. Richardson concluded that the combination of panobinostat and Velcade looks like a promising treatment for patients with Velcade-refractory myeloma.

Perifosine

Dr. Paul Richardson also presented the final results of a Phase 1/2 trial of perifosine plus Velcade and dexamethasone (Decadron) in multiple myeloma patients who previously relapsed from, and/or were refractory to, Velcade (abstract; presentation slide deck (pdf), made available by Dr. Richardson as a courtesy to The Beacon’s readers).

Perifosine is an orally administered drug that is being developed by Keryx Biopharmaceuticals and Aeterna Zentaris.  It belongs to a new class of anti-cancer drugs known as “Akt-inhibitors.”  Akt is a protein believed to play an important role in the development and spread of cancer cells.

The Phase 1 stage of the study discussed by Dr. Richardson enrolled 18 patients. For the Phase 2 part of the trial, an additional 66 patients were recruited for a total of 84 patients. The median patient age was 63 years, and patients had received a median of five prior therapies.

Of the 73 patients evaluable in regard to their response to treatment, 22 percent achieved a partial response or better to treatment.  Another 19 percent achieved a minor response, and 41 percent of the patients had stable disease for at least three months,

Median progression-free survival was 6.4 months.  Median overall survival for all evaluable study patients was 25 months.

Severe side effects included low platelet counts, low white blood cell counts, anemia, pneumonia and muscle or bone pain.  These generally occurred, however, in less than 20 percent of the patients in the trial.

Peripheral neuropathy of any grade was experienced by 29 percent of the patients in the trial.

Dr. Richardson concluded that perifosine in combination with Velcade and dexamethasone has demonstrated durable activity in both heavily pre-treated Velcade-refractory and Velcade-relapsed patients, with manageable side effects.

He also noted that an international Phase 3 trial is currently underway to confirm the efficacy of this combination therapy.

Zolinza

The last presentation to be covered in this update is one that was given by Dr. Meletios Dimopoulos from the University of Athens in Greece

He presented the results of a large Phase 3 trial comparing Zolinza (vorinostat) in combination with Velcade to Velcade plus placebo in relapsed / refractory myeloma patients (abstract).

Zolinza is an oral drug already approved by the U.S. Food and Drug Administration as a treatment for a type of lymphoma.  It is marketed by the pharmaceutical company Merck.  The drug also is approved for a similar use in Canada and Australia, but not in Europe.

Like two other drugs that have been investigated as potential myeloma treatments — panobinostat and Istodax (romidepsin) — Zolinza belongs to a class of drugs known as HDAC-inhibitors.   These drugs have been shown to reduce the spread of cancer cells through their impact on the rate of cell division, the repair of DNA mistakes, and the timing of cell death.

The Zolinza Phase 3 study included 637 patients from 174 treatment centers across 33 countries.  Patients in the study had received a median of two prior therapies. Median patient age was 62 years.

Among the patients who received Velcade in combination with Zolinza, 56 percent had a partial response or better.  In contrast, 41 percent of the patients who received Velcade plus placebo achieved a partial response or better.

In addition, progression-free survival was longer (7.6 months) in patients who received Velcade and Zolinza than in patients treated with Velcade plus placebo (6.8 months).

Although the 25-day difference in these time spans is statistically significant, it was not clear to many of the physicians attending the presentation that it is clinically significant.

In addition, the difference in overall survival between the two groups of patients in the study is not statistically significant.  Dr. Dimopoulos noted, however, that there is a trend toward a survival advantage for the Velcade-Zolinza combination.

Side effects were more frequently observed in the patients receiving the Zolinza-Velcade combination.  About half the patients receiving the combination had to reduce their dose, or discontinue treatment, as a result of side effects.  Only a quarter of the patients receiving Velcade plus placebo had to reduce their dose or discontinue treatment.

Given the recent new drug application for carfilzomib and the upcoming annual meeting of the American Society of Hematology — which undoubtedly will host discussions of many potential new myeloma treatments — it seems an appropriate time to go back to the experts’ review from earlier this year and highlight some of its key points.

The experts begin their review by noting that, despite significant advances in the treatment of multiple myeloma during the last decade, it continues to be challenging to find effective therapies for patients at high risk for early relapse and for patients resistant to multiple drugs or drug combinations.  This makes the search for new treatments particularly important.

The Next Generation of Novel Agents

Regimens containing the novel agents Velcade (bortezomib), thalidomide (Thalomid), and Revlimid (lenalidomide) have played a key role in improving progression-free and overall survival in multiple myeloma patients.  According to the authors of the review article, new drugs that work similarly as these novel agents, but have improved efficacy or safety, have been showing particular promise in clinical trials over the past several years.

Carfilzomib: The Next Generation Velcade

Velcade works by inhibiting proteasome, which is responsible for the break down of proteins in both healthy and cancerous cells. Treatment with Velcade results in the accumulation of proteins within the cell, and it is believed that this excess protein leads to cell death, suppressing tumor growth.

Carfilzomib, which belongs to the same class of drugs as Velcade, has shown high efficacy in clinical trials and may have fewer side effects than Velcade (see related Beacon news). Particularly notable are its lower rates of peripheral neuropathy (nerve damage in the extremities).

There also are other proteasome inhibitors under development for the treatment of myeloma, including salinosporamide A (NPI-0052), and MLN9708/2238, a chemical cousin of Velcade that can be taken orally.

Pomalidomide: The Next Generation Revlimid

Pomalidomide is closely related to thalidomide and Revlimid.  Although the exact ways in which this class of drugs works remain unclear, all three are immunomodulatory agents (drugs that affect the immune system), and they apparently encourage a patient’s immune system to attack and destroy myeloma cells. Clinical trials have shown that pomalidomide is effective in patients who are resistant to treatment with thalidomide, Velcade, and Revlimid (see related Beacon news).

Dr. Vincent Rajkumar, a professor of medicine at the Mayo Clinic, noted in a recent column for The Myeloma Beacon that, of the many drugs currently in development for multiple myeloma, only pomalidomide and carfilzomib have shown significant single-agent activity in multiple clinical trials (see related Beacon news).

In addition to the improvements being made in the currently available multiple myeloma drug classes, ongoing research is being done to identify new classes of drugs.

The authors of the review article believe that several drugs, while not showing potential as single agents themselves, may prove to be effective if given in combination with other currently approved drugs, such as Velcade (see related Beacon news).   These include the histone deacetylase inhibitors, Zolinza (vorinostat), panobinostat and Istodax (romidepsin), which have shown activity when combined with Velcade.

The anti CS-1 antibody, elotuzumab has also been included in this list. This drug targets proteins that are displayed on the surface of myeloma cells but not on healthy cells.  Clinical trials are currently underway to examine the activity of elotuzumab in patients with refractory or relapsed myeloma. It is anticipated that the drug will work best when combined with Revlimid and dexamethasone (Decadron), rather than as a single agent.

Other potential drugs that may work best in combination with existing therapies include heat shock protein inhibitors (see related Beacon news), phosphoinositide 3-kinase pathway inhibitors (for example perifosine), and mTOR inhibitors, such as Torisel (temsirolimus).  At this time, however, none of the drugs in these classes have been approved by the U.S. Food and Drug Administration (FDA) specifically to treat multiple myeloma.

The authors conclude their review of current research on new myeloma treatments by touching on an alphabet soup of drugs in early-stage clinical trials – drugs such as ACE-011, BHQ880, BI-505, defibrotide, GDC-0449, imetelstat (GRN163L), MLN4924, MLN8237, NVP-BEZ235, and siltuximab (CNT 328).  In addition, the authors describe several potential early stage treatments that may stimulate the body’s immune system to attack myeloma cells.

Improving Clinical Trial Results

According to the authors of the review, a large number of drugs that are being developed for multiple myeloma have shown promise in preclinical trials.  These preclinical trials are not carried out in humans, but instead in other models of the disease, such as cells grown in the laboratory setting or small animals (for example mice).  The review authors point out, however, that despite initial promise, fewer than 10 percent of cancer drugs that begin testing in humans ever receive approval from the FDA for patient use.

The authors therefore stress that more preclinical testing is needed and that the models used during this testing should more closely mimic the disease as it is observed in humans. They emphasize, for example, that the environment surrounding the tumor is of equal importance to the tumor itself, and suggest that more models take this so-called “microenvirnoment” into more careful consideration.

They also recommend that patients be carefully selected when clinical trials of a drug begin.  Because some drugs may perform better in specific patient populations, these populations should be established before the start of clinical trials, and patients should be screened to ensure they are in this population before they are enrolled.

Personalized Treatment For Multiple Myeloma

The experts conclude their review by noting that, through work carried out over several decades, cancer biologists have discovered that cancer treatment cannot be a “one-size-fits-all” solution.  At the same time, determining the best method for treating an individual patient for their cancer at the correct time during their disease has proven to be the most challenging aspect of research.  Many researchers believe, however, that this kind of “personalized therapy” offers the most hope for cancer patients.

In this regard, the authors note that the International Staging System, the availability of genetic testing, and the development of risk classification systems by institutions such as the Mayo Clinic and the University of Arkansa have all contributed to greater individualization of multiple myeloma treatment.

The ultimate goal, according to the review authors, will be to identify subsets of patients that will respond most effectively to certain drugs or drug combinations and, thereby, improve the progression-free and overall survival of myeloma patients.  Further investigation is therefore needed into the classification of patients and the development of clinically relevant tests to identify patient classes.

While such studies may not be easy to implement, the authors believe that such issues are likely the next major frontier of myeloma research in the coming years.

For more information, please see the review in the Journal of Clinical Oncology (abstract).

MD Anderson Cancer Center Announces Start Of Phase 1 Trial With Carfilzomib Plus Panobinostat In Myeloma – The MD Anderson Cancer Center announced last week that it will be starting a Phase 1 trial in early August to determine the highest tolerable dose levels of carfilzomib in combination with panobinostat in relapsed and refractory multiple myeloma patients. The safety of the combination treatment will also be assessed. Carfilzomib, which belongs to the same class of drugs as Velcade (bortezomib), is a new drug from Onyx Pharmaceuticals that is currently being investigated as a potential treatment for multiple myeloma. Panobinostat is an oral experimental cancer drug that is being developed by Novartis. For more information, please see the clinical trial description.

Music Against Myeloma – On Wednesday, July 13, several bands will play at Greenhouse in Manhattan to raise awareness and funds for multiple myeloma. The event starts at 8 p.m. and will feature live bands, drink specials, cupcakes, and more.  All proceeds will go to the International Myeloma Foundation. For more information and tickets, please see the Music Against Myeloma website.

For a more detailed listing of myeloma-related events, please check the Myeloma Beacon Events Calendar.

The morning started with a session recapping highlights of the meeting from Sunday.  Dr. Ivan Borello from the Johns Hopkins University School of Medicine was invited to give a 15-minute presentation recapping the myeloma highlights (see Part 1 and Part 2 of The Beacon’s Day Three update for more information).

The rest of the myeloma-related information was presented during poster sessions in the morning and afternoon.  The highlights included results from a number of clinical trials studying potential new drugs for the treatment of myeloma, information about a couple of clinical trials that are still recruiting participants, and an analysis of secondary cancers in patients treated with Revlimid (lenalidomide).

One of the posters was on pomalidomide (CC-4047), a drug chemically related to Revlimid and thalidomide (Thalomid) that is being developed by Celgene for the treatment of multiple myeloma and related blood disorders.  Pomalidomide and carfilzomib are the two new myeloma drugs that are furthest along in clinical trials and most likely to be approved for use in the United States soon.  Preliminary results from the Phase 2 study presented during the poster session showed that pomalidomide plus dexamethasone (Decadron) is effective in relapsed myeloma patients, including those previously treated with Revlimid (abstract). Among the 61 participants, 35 percent responded, most within the first or second cycle of therapy. After about four months, almost all participants (97 percent) were still alive and two-thirds had not yet progressed.  Side effects mainly included low blood cell counts and a few cases of fatigue, blood clots, high blood sugar levels, and pneumonia.

There were also two posters on elotuzumab, a new drug that is being developed by Bristol-Myers Squibb for the treatment of multiple myeloma.  One of the posters included results from a Phase 1 study of elotuzumab, Revlimid, and low-dose dexamethasone in 29 relapsed / refractory myeloma patients (abstract). Three doses of elotuzumab were tested. The overall response rate was 82 percent for all patients and 95 percent for Revlimid-naïve patients. At the highest dose tested, most patients had still not progressed after 16 months of follow-up. The combination was generally well tolerated with serious side effects mainly limited to low blood cell counts due to Revlimid and infusion site reactions during the first cycle due to elotuzumab. Other common side effects included fatigue, diarrhea, nausea, and constipation. The middle dose of elotuzumab appeared to have a slightly better response rate than the highest dose, so a Phase 2 study that was presented yesterday during the oral session is currently further evaluating the middle and highest doses.

Another study presented during the session helped provide a better understanding of how elotuzumab works (abstract).  Elotuzumab recognizes certain proteins called CS1 that are on the surface of myeloma cells, but not on normal cells. Scientists believe this recognition then triggers immune cells known as natural killer cells to kill the myeloma cells.  The study suggests that elotuzumab also directly activates natural killer cells by recognizing the same CS1 proteins on the surface of the natural killer cells.  Once elotuzumab activates these natural killer cells, they then appear to kill the myeloma cells.

There were also two posters on panobinostat, an oral drug being developed by Novartis for the treatment of a number of solid tumors and blood cancers, including multiple myeloma.  One of the posters included results from a Phase 1b study of panobinostat plus Velcade (bortezomib), and in some cases dexamethasone, in 62 relapsed / refractory myeloma patients (abstract). The optimal dosing determined during this trial was 20 mg panobinostat three times a week for two weeks followed by a week off. The overall response rate was 55 percent, and 40 percent of Velcade-refractory patients achieved a partial response. Serious side effects were mostly low blood cell counts, but some patients also experienced severe weakness. Other common side effects included gastrointestinal issues, nausea, fatigue, fever, dizziness, respiratory issues, and peripheral neuropathy (pain and tingling in the extremities).

The other panobinostat poster highlighted a large Phase 3 clinical trial that is still in progress (abstract).  The trial is further studying whether the addition of panobinostat improves the efficacy of Velcade plus dexamethasone. The investigators are still looking to enroll another 270 relapsed / refractory myeloma patients who have received one to three prior therapies.  For more information, see the clinical trial description.

There was also another poster highlighting an ongoing Phase 3 clinical trial.  This one is studying whether the addition of carfilzomib, a new agent being developed by Onyx Pharmaceuticals, improves the efficacy of Revlimid and dexamethasone in relapsed myeloma (abstract). This combination is of particular interest because Velcade-Revlimid-dexamethasone is extremely effective; however, some patients have difficulty tolerating the peripheral neuropathy that can accompany Velcade therapy. Carfilzomib, which works similarly to Velcade, appears to be more tolerable. The study investigators are still looking to enroll another 550 relapsed / refractory myeloma patients who have received one to three prior therapies.  For more information, see the clinical trial description.

There was also a poster on the topic of Revlimid and secondary cancers, a topic that was discussed in detail during the previous day of the meeting (see related Beacon news).  The study presented during the poster session was an analysis of 11 Celgene-sponsored studies in which relapsed / refractory myeloma patients were treated with Revlimid or Revlimid plus dexamethasone (abstract).

Among the 3,839 patients included in the analysis, 57 cases of secondary cancers were reported.  Taking into account how long the patients were treated or followed, 2.08 percent of them developed a secondary cancer each year.  The rate of patients developing secondary cancers was similar regardless of length of time on therapy; however, there appeared to be a slight trend toward higher risk with longer therapy.  The risk was also slightly, but not significantly, higher for patients who had undergone a prior stem cell transplant.

After a median follow-up of almost five years, 4 percent of participants had developed a second blood-related cancer, 10 percent developed a solid tumor, and 24 percent died, showing that myeloma patients are at greater risk of dying from myeloma or other causes than developing a second cancer. At three years, the overall survival was similar between patients who developed a secondary cancer and those who did not.

The study investigators concluded that the benefit-risk profile for Revlimid therapy remains strongly positive but that there are a number of limitations to the ways in which secondary cancers are tracked that may have affected their analysis.

Further details about Monday’s sessions are available in The Myeloma Beacon’s extensive Day 4 coverage in the Beacon multiple myeloma forums.  Additional coverage of key research results from the meeting will continue throughout the rest of the week in individual, topic-specific news articles.  For all Beacon articles related to this year’s ASCO meeting, see The Beacon’s full ASCO 2011 coverage.

More than 30,000 clinical specialists from all over the world are expected to attend the five-day meeting to discuss the current research in cancer treatment and care. This year’s meeting will primarily focus on the theme of “Patients, Pathways, Progress.”

The meeting will include many presentations and seminars focused specifically on multiple myeloma. The ASCO website currently lists over 40 myeloma-based abstracts.

The Myeloma Beacon will be covering the meeting, so readers can expect many articles during and after the meeting about the key myeloma findings.

At the meeting, Dr. Kenneth Anderson from the Dana-Farber Cancer Center will receive the David A. Karnofsky Memorial Award, which recognizes “innovative clinical research and developments that have changed the way oncologists think about the general practice of oncology.”  He is being honored for his achievements in myeloma research, including his studies on novel therapies that have helped transform myeloma therapy.

Treatments Under Development

Several of this year’s ASCO presentations will unveil results from Phase 1 and Phase 2 clinical trials of drugs under development for the treatment of multiple myeloma. In particular, there will be many presentations on carfilzomib, pomalidomide, elotuzumab, panobinostat, and several newer drugs that are in the early stages of clinical testing.

During a poster session on June 4, results will be presented from four Phase 2 clinical trials of carfilzomib for relapsed / refractory (resistant) myeloma.  These studies include a clinical trial of single-agent carfilzomib, a study of carfilzomib in combination with Revlimid (lenalidomide) and dexamethasone (Decadron), a study of carfilzomib in patients who have never been treated with Velcade (bortezomib), and a study of carfilzomib in combination with current myeloma treatments.  There will also be a poster on June 5 about an ongoing Phase 3 study comparing carfilzomib, Revlimid, and dexamethasone therapy to Revlimid and dexamethasone without carfilzomib.

On June 5, there will be three oral presentations about potential new anti-myeloma drugs.

First, Dr. Noopur Raje will present results from a Phase 1 study evaluating the optimal dosage for LY2127399 (a human antibody that has shown anti-myeloma activity) when given in combination with Velcade to previously treated myeloma patients.  Results indicate that more than 50 percent of patients may respond to this therapy.

Next, Dr. Jesus Berdeja will present results from a Phase 1 study of lorvotuzumab mertansine in combination with Revlimid and dexamethasone in a specific subset of relapsed / refractory myeloma patients whose myeloma cells contain the CD56 protein.  Preliminary results indicate that about 50 percent of the study participants may respond to this combination therapy.  Updated results will be presented at the meeting.

Then Dr. Paul Richardson will present a Phase 2 study that found the combination of elotuzumab, Revlimid, and dexamethasone to be active and well tolerated in relapsed myeloma patients.  Preliminary results indicate that 80 percent to 90 percent of myeloma patients may respond to this therapy. Results from the Phase 1 study will be presented in a poster session on June 6.  There will also be a poster presentation about elotuzumab’s effect on natural killer cells, which are immune cells that kill cancer cells.

During a poster session on June 6, researchers will present the results of a Phase 2 study evaluating the combination of pomalidomide plus dexamethasone in myeloma patients previously treated with Revlimid.  Preliminary results show that about 35 percent of patients previously treated with Revlimid respond to pomalidomide.

There will also be poster presentations about a Phase 1b study of panobinostat and Velcade and an ongoing Phase 3 study of panobinostat, Velcade, and dexamethasone, both in relapsed / refractory patients.

Additionally, results from a Phase 1 study of GDC-0941 will be presented during a poster session.  GDC-0941 is an oral phosphoinositide-3 kinase inhibitor.  The study tested the drug in patients with myeloma or an advanced solid tumor.

Revlimid And Secondary Cancers

A section of the oral session on June 5 will focus on the risk of developing secondary cancers after treatment with Revlimid. The U.S. Food and Drug Administration recently announced that it is currently investigating whether long-term use of Revlimid  increases a patient’s risk of developing a second cancer (see related Beacon news).

During the session, Dr. Antonio Palumbo will present the latest secondary cancer data from his study in which newly diagnosed, elderly myeloma patients were treated with melphalan (Alkeran) and prednisone with or without co-administration of Revlimid, followed by Revlimid maintenance.

Dr. Adrianna Rossi will then present data on the rate of secondary cancers six years after newly diagnosed myeloma patients were treated with Revlimid.

Then Dr. Meletios Dimopoulos will present secondary cancer data from two studies in which relapsed and/or refractory patients received Revlimid plus dexamethasone or a placebo plus dexamethasone.

Afterward, Dr. Ola Landgren will lead a discussion on the topic.

Bisphosphonates

This year’s ASCO oral session on myeloma will include presentations about bisphosphonates and their ability to treat myeloma bone disease as well as their potential beneficial impact on survival. Although bisphosphonates are currently the gold-standard treatment for myeloma bone disease, recent results from clinical studies have suggested that even myeloma patients without bone disease may benefit from treatment with bisphosphonates.

Dr. Kevin Boyd will present results from a study that evaluated the ability of Zometa (zoledronic acid) to reduce skeletal-related events and improve progression-free survival in myeloma patients both with and without bone disease. In another presentation about the same study, Dr. Faith Davies will discuss the impact of Zometa and Bonefos (clodronate) on survival times for newly diagnosed myeloma patients.

After these two talks, Dr. David Roodman will lead a discussion on the topic.

For more information on ASCO’s 47th Annual Meeting, including presentation abstracts, the final schedule, and information on attending, please see the American Society of Clinical Oncology meeting website.

Some of the highlights from the first part of Day 3 of the conference are summarized in this article.  Highlights from the second part of the day are summarized in a separate article (see related Beacon news).

Treating Older, Newly Diagnosed Myeloma Patients

The first session of the morning was about treating newly diagnosed multiple myeloma patients over the age of 65 years, specifically those who are ineligible for a stem cell transplant.  It complemented the session on Wednesday on treating new patients under the age of 65 years.

First, Dr. Vincent Rajkumar from the Mayo Clinic in Minnesota presented the potential treatment options for older newly diagnosed patients, reviewed clinical trial data relevant to those treatments, identified key issues around treating older patients, and spoke about his own personal treatment preferences.

Dr. Rajkumar explained that he chooses a patient’s initial treatment based on whether the patient is standard-, intermediate-, or high-risk.

First of all, he mentioned that he prefers not to use melphalan (Alkeran), despite its long history of use in myeloma.  He believes it can reduce the efficacy of future treatments.

Therefore, in the case of standard-risk patients, he recommends treatment with Revlimid (lenalidomide) and low-dose dexamethasone (Decadron) for 18 months.  At that point, he discusses with each patient the option of Revlimid maintenance therapy.

He believes intermediate-risk patients should be treated with a combination therapy that includes Velcade (bortezomib).  His preference is Velcade, cyclophosphamide (Cytoxan), and dexamethasone – a combination known as VCd or CyBorD – for one year, followed by Velcade maintenance for two years.

For high-risk patients, Dr. Rajkumar typically uses Revlimid, Velcade, and dexamethasone – known as RVd – until the patient (hopefully) achieves a complete response.  Then they are put on Velcade maintenance therapy until their disease progresses.

When treating patients with Velcade, Dr. Rajkumar almost always uses subcutaneous Velcade, rather than infused, administered once a week.  He feels this method and frequency of administration has shown good efficacy while also reducing the risk of peripheral neuropathy (pain and tingling in the extremities), which is a common side effect when Velcade is infused or given more frequently.

Throughout the rest of the session, researchers from a variety of countries discussed what myeloma specialists in their countries see as key issues related to the treatment of older, newly diagnosed patients, and the trials that are planned – or which have started recently – to shed light on the key open questions related to treating this patient group.

From the presentations, it was readily apparent that there is an extremely broad range of potential treatment options being investigated for older, newly diagnosed patients.  The speakers mentioned melphalan and prednisone in combination with one or more novel agents, cyclophosphamide and dexamethasone in combination with one or more novel agents, as well as Revlimid plus dexamethasone possibly with the addition of Velcade.

Many of the trials discussed during the session are carefully analyzing each participant’s chromosomal abnormalities and, in some cases, bone imaging results.  However, very few of the trials differentiate treatment based on a patient’s risk classification like Dr. Rajkumar recommends.

Several creative trial designs were also discussed.

For instance, Dr. Antonio Palumbo from the University of Turin, Italy, suggested using standard doses for “standard” patients and then a set of lower doses for patients who may be older or have other co-existing medical conditions.

Dr. María-Victoria Mateos of the University Hospital of Salamanca, Spain, also presented a creative trial design that uses two combination regimens: Velcade, melphalan, and prednisone (VMP) and Revlimid plus low-dose dexamethasone (Rd).  One set of patients in her group’s study will receive the two regimens in sequence: first several cycles of VMP, then several cycles of Rd.  The other set of patients will receive alternating rounds of the two regimens: first a cycle of VMP, then a cycle of Rd, then VMP again, and so on.  Dr. Mateos and her colleagues believe the alternating approach may yield better results,  but they will have to wait to see what the results say.

Treatments Under Development

The next key session of the day was an exciting set of presentations about new drugs and approaches to treating myeloma.  The focus of these presentations was on drugs that are still being researched and which, in most cases, are not yet government approved or generally available to treat myeloma.

Dr. Kenneth Anderson of the Dana Farber Cancer Institute in Boston gave the session’s introductory presentation.  It surveyed the field of myeloma drugs that are still under development.  Much of the presentation was similar to one he gave on Day 2 of the Workshop (see related Beacon news).  However, in this presentation, he also discussed some promising drugs that are in very early development, including BHQ880, PCI-32765, PD 0032891, everolimus, and WT161.

A bit later in the session, Dr. Anderson also delivered an additional presentation that focused on potential new myeloma drugs that are proteasome inhibitors, a class of drugs that includes Velcade.

One of the new proteasome inhibitors, carfilzomib, is already well known among myeloma researchers and patients.  But there are many other potential myeloma drugs in this class, and they all appear to be quite promising.  Three that are already in clinical trials, or will be soon, are CEP-18770, NPI-0052, and P5091.  Three others that have shown promise in the laboratory and may soon start clinical trial testing include MLN9708, ONX 0912 (PR-047), and PR-924.

Another key presentation during this session also focused on carfilzomib.  The presentation was given by Dr. Andrzej Jakubowiak of the University of Michigan.  He first summarized for the audience the design and results of earlier clinical trials involving the drug (see related Beacon articles).  Then he described at length updated results from a trial involving carfilzomib combined with Revlimid and dexamethasone (CRd) in both transplant eligible and ineligible newly diagnosed myeloma patients.  The CRd regimen is being used both as initial (induction) therapy as well as consolidation and maintenance therapy.

The response rates observed with this new combination therapy seem very promising.  A full 97 percent of patients achieved at least a partial response, and 60 percent of patients achieved either a near complete response or better.  After nine months, no patients have progressed, and all patients are still alive.  Moreover, the side effect profile of the CRd regimen looks favorable, with only 11 percent of patients reporting peripheral neuropathy, and no cases of peripheral neuropathy have been serious.

Another new myeloma drug that has received significant attention, pomalidomide, was the subject of the session’s next presentation, which was given by Dr. Martha Lacy of the Mayo Clinic.

Pomalidomide is a chemical relative of both Revlimid and thalidomide.  Like those other two drugs, it is taken orally as a capsule.

During her presentation, Dr. Lacy reported data that already had been presented in published papers or at previous conferences.  Those data primarily come from clinical trials where pomalidomide has been used in relapsed / refractory myeloma patients who have had many different previous therapies.  Even in patients that have received six or more different previous therapies, more than 25 percent of the patients taking pomalidomide have achieved at least a partial response.

The one potential challenge pomalidomide may face is its side effect profile.  In many of the trials Dr. Lacy reviewed, about a third of the patients taking pomalidomide experienced serious reductions in their white blood cell counts (also known as neutropenia).

After Dr. Lacy finished her presentation, Dr. Enrique Ocio of the University Hospital of Salamanca, Spain, presented information about a potential new class of myeloma drugs, histone deacetylase (HDAC) inhibitors.  Two drugs in this class – panobinostat and Zolinza (vorinostat) – are receiving the most attention in clinical trials.

After initially showing only limited efficacy as stand-alone treatments for myeloma, panobinostat and Zolinza are now typically being tested in combination with other myeloma treatments.  The initial focus has been on testing these drugs in combination with Velcade, partly because there is a theoretical rationale for such a combination.  The results, mainly from trials in relapsed / refractory myeloma patients, have been promising in terms of efficacy, but there have been some issues with the drugs causing low platelet counts (thrombocytopenia) in a number of trial participants.

Panobinostat and Zolinza also are now being tested in combination with Revlimid and dexamethasone, and initial results of these trials are promising, both in terms of efficacy and side effects.

The final presentation during the session on potential new myeloma drugs was given by Dr. Sundar Jagannath of the Mt. Sinai School of Medicine in New York City.  He spoke about promising drugs that are monocolonal antibodies.

Antibodies are proteins used by the immune system to identify and destroy foreign objects like bacteria, viruses, and cancer cells.  Monoclonal antibodies are produced from a single type of cell, making them completely uniform and able to hone in on a specific target, such as myeloma cells.

Dr. Jagannath explained that there are a number of monoclonal antibodies under development as potential myeloma treatments.  However, as has been the case with the HDAC inhibitors, clinical trials have found that monoclonal antibodies are typically not effective on their own.  Instead, they have the greatest impact when combined with another myeloma drug, such as Revlimid or Velcade.

Two monoclonal antibodies that are in late stage development are elotuzumab and siltuximab (CNTO-328).  Elotuzumab has shown good efficacy in early trials when combined with Velcade in relapsed / refractory myeloma patients, but even better efficacy when combined with Revlimid and dexamethasone.  A Phase 3 trial testing elotuzumab combined with Revlimid and dexamethasone in newly diagnosed patients is therefore planned.

Siltuximab also showed solid efficacy when combined with Velcade in early clinical trials, and one Phase 3 trial of the drug in combination with Velcade and dexamethasone in relapsed / refractory patients is already ongoing.  Another Phase 3 trial combining the drug with Velcade, melphalan, and prednisone in newly diagnosed patients is planned.

Monoclonal antibodies that are in early-stage clinical trials for myeloma include BHQ880, BT062, daratumumab (HuMax-CD38), and IMMU-110 (hLL1-DOX).

For more detailed summaries of the day’s sessions, see The Myeloma Beacon’s extensive Day 3 coverage in the Beacon forums.  For links to abstracts of some of the presentations given during the day, see the IMW programme.  News from the final day of the workshop will also be summarized in a daily update like this one.

This is not new. It has been the story with myeloma for ages. The myeloma cells are smart and are seemingly able to easily overcome any adversity that comes their way in the form of pesky new drugs. For those of us dealing with this disease on a daily basis, we need some good news.

What are the most promising drugs today that can outsmart the myeloma cells? Will they work in patients who have failed other therapies? Will they have a reasonable safety profile?  Will a future filled with many active treatments and options happen soon enough?

If I were a patient with myeloma and none of the current treatments were working for me, I would need to have at least some idea which drugs are the most promising, so that I could hunt for the best clinical trial. However, an Internet search turns up so many possibilities that it is hard for even trained hematologists to determine the best options among the array of clinical trials.

In this column, I will highlight drugs that are unquestionably active in myeloma. These are new treatments that are not commercially available, but in my opinion clearly work in myeloma, even in patients who have failed other treatments. I will also discuss other promising drugs where the data suggest that there is at least a reasonable probability that they actually work in patients.

Note that by highlighting these drugs, my intention is not to suggest that the other agents being studied are unimportant. In fact, deciding the best treatment option or a clinical trial for a given patient is a complex process that requires a great deal of thought and depends on many variables.

My goal is to simply inform, and to illustrate the rationale for my hope and enthusiasm.

In the first category are compounds that have shown clearcut activity in myeloma in terms of reducing monoclonal (M)-protein levels by 50 percent or more when used on their own (single-agent activity). Of countless drugs that have been looked at and not yet approved for commercial use, only pomalidomide and carfilzomib have shown significant single-agent activity in multiple clinical trials. They seem to work in situations where other myeloma treatments have stopped working. They are both in advanced stages of development (i.e., Phase 3 trials are underway).

Pomalidomide: Pomalidomide (also called CC-4047) is a new immunomodulatory analogue of thalidomide (Thalomid) and Revlimid (lenalidomide). It was first studied by Schey and colleagues from the United Kingdom who treated 24 relapsed or refractory patients and found a response rate of 54 percent. Next, Lacy and colleagues at the Mayo Clinic tested the combination of pomalidomide with low dose dexamethasone (Decadron) and showed efficacy in relapsed disease, in patients who had failed Revlimid and in patients who had failed both Revlimid and Velcade (bortezomib). These results have since been confirmed by the Multiple Myeloma Research Consortium (MMRC) and by investigators from the Intergroupe Francophone du Myeloma (IFM). Side effects seem reasonable and similar to Revlimid. Clinical trials are ongoing around the world. I hope that pomalidomide is approved soon.

Carfilzomib: Carfilzomib is a new proteasome inhibitor. It has a different chemical structure than Velcade, the prototype proteasome inhibitor. In a series of clinical trials conducted by the MMRC, carfilzomib produced responses in approximately 50 percent of patients with relapsed myeloma, including 15 percent who were refractory to Velcade. Carfilzomib is given intravenously. It appears to be well tolerated and has a lower risk of neuropathy (pain or tingling in the extremities) compared with Velcade. As with pomalidomide, confirmatory studies are ongoing around the world, and I am hopeful that the drug will be approved soon.

In the second category are agents that have not shown clear single-agent activity in myeloma, but are promising nevertheless based on responses seen when they were combined with other drugs.

The histone deacetylase inhibitors, Zolinza (vorinostat) and panobinostat, have both shown activity when combined with Velcade. With these drugs, we have reports of patients with myeloma that was progressing while receiving Velcade therapy that responded promptly upon the addition or either Zolinza or panobinostat. Clinical trials with these agents also suggest that the response rate when used in combination with Velcade is more than what we would ordinarily expect to see with Velcade alone. Large trials are ongoing with these treatments, and we eagerly await the results of these trials to determine the role and fate of these two drugs.

Another treatment in this category is the anti CS-1 antibody, elotuzumab. The response rate with elotuzumab plus Revlimid and dexamethasone (Rd) appears to be much higher than what would be expected with Rd alone.

Other potential drugs that could join this category are heat shock protein inhibitors (e.g., KW-2478) and phosphoinositide 3-kinase pathway inhibitors (e.g., perifosine).

There is one other drug that does not fit well into either category listed above, but nevertheless is just as promising: MLN9708, an oral proteasome inhibitor. My enthusiasm for this agent stems from the fact that it is available on clinical trials and that it belongs to a drug class that has already produced two active agents, namely Velcade and carfilzomib.

I raised some questions in the beginning. I think I answered the first three. The fourth (also stated in the title) was not meant to be rhetorical. I know for a fact that the many myeloma investigators working on these trials understand the urgency of the situation. The companies that make these compounds recognize the need for speed and have been incredibly supportive. The myeloma field has shown the oncology world a path to drug development with 4 new drug approvals in the last 10 years. I am quite hopeful that for most myeloma patients, the future will indeed happen soon enough.

Dr. S. Vincent Rajkumar is a professor of medicine at the Mayo Clinic in Rochester, Minnesota. His research focuses on clinical, epidemiological, and laboratory research for myeloma and related disorders.

This article is the second part of a two-part series based on The Myeloma Beacon’s interview with Dr. Anderson.  It will cover Dr. Anderson’s thoughts on where myeloma treatment is headed in the coming years.  For more information on Dr. Anderson’s current approach to treating multiple myeloma, please see part one of this series.

Emerging Therapies

According to Dr. Anderson, there are several promising agents being developed to treat multiple myeloma.

The first promising agent that he discussed was carfilzomib, a proteasome inhibitor like Velcade (bortezomib).  “Carfilzomib appears to be active in relapsed myeloma and very well tolerated with very little in the way of neuropathy [pain or tingling in the extremities],” Dr. Anderson explained.

He was also impressed with pomalidomide’s potential.  Pomalidomide is an immunomodulatory drug like thalidomide (Thalomid) and Revlimid (lenalidomide).  “Pomalidomide, like thalidomide and Revlimid, targets the tumor in the microenvironment, but excitingly pomalidomide is active even when thalidomide and Revlimid are not.  Pomalidomide is also active when Velcade is not.”

Besides these two investigational drugs, Dr. Anderson saw the most potential in combinations of treatments.

Dr. Anderson mentioned combinations of Velcade and a histone deacetylase inhibitor, either Zolinza (vorinostat) or panobinostat, which have achieved responses in the majority of patients who have not responded to Velcade.

He also felt that Velcade in combination with the AKT inhibitor perifosine appears to be effective in patients who have previously been treated with or did not respond to Velcade.

In combination with Revlimid and dexamethasone (Decadron), Dr. Anderson was most excited about the addition of the antibody elotuzumab.  He said that this combination has achieved a very high response rate in myeloma patients.

Personalized Therapy

In the next several years, Dr. Anderson thinks that personalized therapy for multiple myeloma patients will become more and more common.

He explained that myeloma patients can be treated differently based on their genetic profile.  However, he said, “We first need to be better able to profile patients to determine who is likely to respond to which treatment; and secondly, personalized medicine in myeloma will require us to develop more targeted therapies.”

If advances are made in these two areas, Dr. Anderson said, “I would think over the next three to five years that personalized treatments will occur.”

Myeloma Stem Cells

In the coming years, myeloma specialists also hope to better understand myeloma stem cells, the cancerous cells that reproduce and may be responsible for relapse of the disease.

“So far, we have not been able to reproducibly identify that stem cell, but there is great emphasis on trying to understand its biology so we can effectively target it,” said Dr. Anderson.  “Ultimately, in order for cure to occur, the ability for myeloma to return and cause relapse will have to be overcome.”

Cure For Myeloma

Many myeloma specialists differ in opinion about the goal of treating multiple myeloma patients.

For some, the goal is to cure myeloma patients by achieving and maintaining a complete response or eliminating all traces of myeloma.  Others argue that the aggressive treatment needed to nearly wipe out the myeloma cells can severely impact a patient’s quality of life, and yet the patient is still likely to relapse.  Many of these physicians would prefer to get the disease to a safe level and then treat to control the disease while maintaining a high quality of life for the patient.

When asked his opinion in the debate, Dr. Anderson replied, “Absolutely, the goal should be to cure our patients.”

“I strongly think that in the era of novel therapies, used in combination and as maintenance, sustained complete responses will be achievable in the majority of patients,” said Dr. Anderson. “First achieving complete responses and then sustaining those complete responses is, in fact, the pathway towards cure, and I do think we’re closer to that goal than ever before.”

Dr. Anderson said that this approach does not have to significantly impact quality of life.  “Quality of life is obviously paramount and of the highest importance,” he said. “The good news is that novel therapies used appropriately really are also very well tolerated.”

“I don’t think it needs to be one or the other.  I think we can actually achieve high response rates, and fortunately, they are associated not only with living longer, but living longer with a quality life,” he added.

Advancing Research Through Clinical Trials

Dr. Anderson said that the quickest way for advances to be made in the treatment of myeloma is for patients to participate in clinical trials.  “I would most enthusiastically urge patients to endorse the concept of clinical trials and ask patients to participate whenever possible.”

He said patients should participate because “you will get top notch, cutting edge, novel treatments that will give you the best possible chance for doing well in myeloma.”

For those who are concerned about randomized clinical trials, in which half of the patients receive the standard of care instead of the study drug, Dr. Anderson said, “We don’t know which of the options are better.  Usually in a randomized trial, there is the opportunity later on to receive the treatment that you were not chosen to receive if it in fact is beneficial.  In other words, a patient often ends up receiving the new medicine either right away or later.”

Dr. Anderson concluded by saying, “I think it’s a very exciting time in myeloma, and it’s a unique privilege for all of us to help, together with our patients, improve the outcome in this disease.”

For more information about Dr. Anderson’s approach to treating multiple myeloma, please see part one of this series.

BT-062 Is Safe In Relapsed/Refractory Multiple Myeloma (ASH 2010) – The investigational drug BT-062, which is being developed by the German company Biotest AG, is safe in relapsed/refractory multiple myeloma patients, according to the Phase 1 trial results presented at the 2010 Meeting of the American Society of Hematology (ASH). Researchers tested seven different dose levels (10 mg/m² to 200 mg/m²). Researchers observed severe skin- and mucous membrane-related side effects at the highest dose level. They therefore determined the maximum tolerated dose to be 160 mg/m². A sufficient amount of anti-myeloma activity was observed for this drug to continue to Phase 1/2 testing, which puts more emphasis on the efficacy of the drug. For more information, please see abstract 3060 on the ASH Meeting website.

ARRY-520 Shows Single-Agent Activity in Relapsed/Refractory Myeloma (ASH 2010) – Phase 1 clinical trial results presented at ASH earlier this week showed that the experimental drug ARRY-520 from Array BioPharma has anti-myeloma effects as a single agent. Four of 30 relapsed/refractory myeloma patients enrolled in the study responded to treatment. ARRY-520 was administered intravenously at different doses (1 mg/m² to 2.25 mg/m²) on days 1 and 2 of a 14-day cycle with or without growth factors.  The maximum tolerated dose was 1.25 mg/m² ARRY-520, but the dose could be increased with the addition of growth factors. The most commonly reported side effect was low white blood cell counts. Inflammation of the digestive tract mucus membrane was observed at higher dose levels.  The maximum tolerated dose in combination with growth factors, which is still being investigated, will be used in the Phase 2 trials that Array BioPharma plans to initiate soon. For more information, please see abstract 1959 on the ASH Meeting website and the Array BioPharma press release.

Panobinostat Combination Shows Potential For Relapsed/Refractory Multiple Myeloma (ASH 2010) – According to Phase 1 trial results presented at ASH, the oral experimental cancer drug panobinostat (LBH589) from Novartis showed promising results in combination with melphalan (Alkeran), prednisone, and thalidomide (Thalomid). Of the 24 relapsed/refractory myeloma patients enrolled in the study, 50 percent responded to the treatment, with 17 percent achieving a very good partial response. However, the initial dose of 15 mg of panobinostat was associated with severe side effects (low white blood cell counts in 69 percent of patients and low platelet counts in 46 percent).  Therefore, researchers decided to lower the dose to 10 mg. The rate of low platelet counts decreased, but the rate of low white blood cell counts remained high. The researchers concluded that different dosing schedules need to be investigated to further decrease the rate of blood-related side effects. For more information, please see abstract 3019 on the ASH Meeting website.