Monday was the third full day of “ASH 2010,” this year’s annual meeting of the American Society of Hematology.  This day was the busiest of the entire meeting in terms of multiple myeloma-related material.  Presentations summarizing the latest myeloma research stretched from 7 a.m. until 8 p.m.

The morning presentations from Monday will be covered in this update, and presentations from the afternoon and evening will be covered in another update later today.

The day featured a large number of presentations and posters about Velcade ^[1] (bortezomib), examining its use in different patient populations and in different combinations with other drugs.  There also were some important results presented about Revlimid ^[2] (lenalidomide) – including results that have sparked a controversy about the safety of that drug.

Among new drugs still under development as potential myeloma treatments, Pomalidomide ^[3] and carfilzomib ^[4] were discussed in a number of presentations, and there was a report about the new experimental treatment PD0332991.

In addition, several presentations during the day covered trial results involving thalidomide ^[5] (Thalomid), and there was an update about ongoing research into Zometa ^[6] (zoledronic acid) and its use in multiple myeloma.

The first presentation of the day was given by Dr. Laura Rosiñol of the Hospital Clinic in Barcelona. She summarized the results of a Spanish Phase 3 study comparing three induction regimens prior to stem cell transplantation in newly diagnosed myeloma patients 65 years of age or younger (abstract ^[7]).

The three induction regimens tested were: thalidomide and dexamethasone (TD); Velcade, thalidomide, and dexamethasone (VTD); and a multi-step combination involving vincristine ^[8] (Oncovin), BCNU (Carmustine), cyclophosphamide ^[9] (Cytoxan), melphalan ^[10] (Alkeran), prednisone ^[11], dexamethasone ^[12] (Decadron), and Velcade that goes by the acronym “VBMCP/VBAD/B.”  (This description ^[13] of the Spanish trial has details of the VBMCP/VBAD/B regimen.)

Patients in the trial who received the VTD induction regimen had a statistically significant better complete response rate (35 percent) and progression-free survival (median not yet reached at 27 month follow-up) compared to the patients in the two other arms of the trial.   At the same time, the four-year overall survival rate was about 76 percent for all three induction regimens.

Among high-risk myeloma patients, complete response rates were significantly higher in the VTD arm than in the other two arms.  In fact, high-risk patients who received the VTD induction regimen had the same complete response rate as standard-risk patients.  Across all arms of the study, however, patients with the chromosomal abnormality t(11;14) consistently had a lower complete response rate (12 percent) than patients without the abnormality.

Side effects were similar across the three induction regimens, with the notable exception that 12 percent of VTD patients experienced peripheral neuropathy (nerve damage to the extremities that can cause pain and tingling sensations) compared to 1 percent in the other two groups of patients.

The next presentation Monday morning was by Dr. David Vesole of the John Theurer Cancer Center in Hackensack, New Jersey.  He reported on results from a new analysis by age group of data from a trial comparing the use of Revlimid and high dose dexamethasone (RD) versus Revlimid and low-dose dexamethasone (Rd) in newly diagnosed multiple myeloma patients (abstract ^[14]).

The initial analysis of this study was published in 2009 (see related Beacon ^[15] news).  It showed that survival was better in patients in the Rd arm of the trial.  Patients in the Rd arm took 40 mg of dexamethasone on days 1, 8, 15, and 22 of a 28-day cycle.  Patients in the RD arm took 40 mg of dexamethasone on days 1-4, 9-12, and 17-20 of a 28-day cycle.

Dr. Vesole reported that analysis of the trial data by age group did not alter the original findings of the study.  Patients in the low-dose arm had higher survival rates whether they were under the age of 65 or over.  In addition, older patients in the RD arm of the trial showed more rapid disease progression than younger patients in the same arm.  Although younger patients showed an initially higher response to RD compared to Rd, this did not translate into better progression-free survival or overall survival.  Dr. Vesole and his colleagues therefore continue to believe that low-dose dexamethasone should be the standard of care for all newly diagnosed patients receiving Revlimid, regardless of age.

Next on the morning’s agenda was Dr. María-Victoria Mateos of the University Hospital of Salamanca, who reported on the results of a Spanish trial designed to determine the impact of cytogenetic abnormalities in elderly newly diagnosed myeloma patients receiving different Velcade-based induction and maintenance regimens (abstract ^[16]).

Half of the patients in the Spanish trial received induction therapy with Velcade, melphalan, and prednisone (VMP), while the other half received a Velcade-thalidomide-prednisone (VTP) induction regimen.  Half of each of those groups then received maintenance therapy consisting of Velcade plus thalidomide (VT), while the other half received maintenance with Velcade plus prednisone (VP).

Response rates, although lower for high-risk patients (defined based on their chromosomal abnormalities), were statistically similar.  However, progression-free survival was worse in high-risk patients, and this difference was particularly pronounced after maintenance therapy. Additionally, the type of induction therapy did not affect the progression-free survival.  Overall survival was 38 months for the high-risk group and not yet reached for standard-risk patients.

Response rates and progression-free survival were similar regardless of whether patients had extra chromosomes (hyperdiploidy). However, overall survival was higher among patients with extra chromosomes.

Afterward, Dr. Michel Attal of the Hopital Purpan in Toulouse reported on the final analysis of data from the IFM Revlimid maintenance trial (abstract ^[17]).  The IFM study is the European counterpart to the CALGB Revlimid maintenance trial, which was discussed in the Beacon’s ASH 2010 Day Two update ^[18].  Interim results for both the CALGB and IFM trials were presented at this summer’s ASCO meeting (see related Beacon ^[19] news).

The IFM trial is designed to compare Revlimid maintenance therapy versus placebo after stem cell transplantation in myeloma patients younger than 65.  Patients in the study underwent a stem cell transplant using their own stem cells, received Revlimid consolidation therapy, and then half received Revlimid maintenance therapy while the other half received placebo.

Revlimid consolidation improved responses and progression-free survival compared to transplantation alone.  Maintenance therapy did not significantly increase the number of patients who achieved complete response.  However, four years after diagnosis, progression-free survival was 60 percent for the Revlimid maintenance group compared to 33 percent for the placebo group. This difference was seen even if patients achieved a complete response after induction therapy, showing the importance of maintenance therapy even if patients achieve a good response after initial treatment.

Overall survival was similar for both the Revlimid maintenance and placebo arm.  The five-year post-diagnosis survival rate is 83 percent across all the patients.  Dr. Attal said that longer follow-up is needed to assess the impact of maintenance therapy on survival. However, he said that the better progression-free survival with maintenance therapy is a huge improvement in quality of life, and he said, “I’m convinced some of these patients will be cured.”

During the question & answer segment of the session, one attendee said “Revlimid maintenance is likely to become a new standard.” Another attendee, though, was more sceptical, and wanted to see a difference in overall survival, because maintenance therapy causes side effects and is expensive.

Concern about the potential side effects of Revlimid maintenance therapy is one of the important developments of this year’s ASH meeting.  Results of the IFM and CALGB trials presented at the meeting show that more patients in maintenance arms of those trials developed second cancers in addition to their myeloma (“secondary malignancies”) than patients who were in the placebo arms of the trials.

In the CALGB trial, about 15 maintenance-arm patients developed secondary malignancies, compared to 10 patients in the placebo arm.  In the IFM trial, 17 maintenance-arm patients developed second cancers, compared to three in the placebo arm.

The Beacon contacted Celgene, the manufacturer of Revlimid, for comment on the issue, but Celgene has not yet provided a response.

It is unclear, however, whether these results actually demonstrate that Revlimid maintenance therapy causes additional secondary cancers.  Simply comparing absolute numbers is misleading, for a number of reasons.  In both trials, patients in the placebo arm were switched to the maintenance arm after initial data analyses documented a significant benefit to maintenance therapy.  Also, the longer progression-free survival of patients in the maintenance arm means that, on average, those patients have been tracked longer than the placebo arm patients, and, regardless of how a myeloma patient is treated, the risk of developing secondary cancer increases with time from diagnosis.

There is also the fact that, despite the many previous trials conducted with Revlimid and the extensive use of the drug in the community setting, no apparent connection between the drug and secondary cancer was seen until the CALGB and IFM presentations of the past few days.

As Dr. S. Vincent Rajkumar of the Mayo Clinic told The Myeloma Beacon, “I doubt that there is a true link between secondary malignancies and [Revlimid] therapy based on our frontline experience with this drug.”

The controversy about Revlimid and secondary malignancies is a very important one, and the Beacon will be covering it in more detail in the coming weeks.

Following the report summarizing the new IFM trial results, Dr. Gareth Morgan of the Institute of Cancer Research in London reported on additional results from his trial comparing the use of bisphosphonates Zometa and Bonefos (clodronate) in newly diagnosed myeloma patients (abstract ^[20]).

Earlier this year at the ASCO annual meeting, Dr. Morgan presented results showing that myeloma patients treated with Zometa had longer overall survival than patients treated with Bonefos (see related Beacon ^[21] news).

The design of Dr. Morgan’s trial is relatively intricate.  Patients can follow intensive or non-intensive pathways that differ in terms of the induction regimen used and whether or not patients undergo a stem cell transplant using their own stem cells.  After receiving induction therapy, patients are randomly selected to be treated with either Zometa or Bonefos, and all patients also have the option of receiving maintenance treatment with thalidomide.

In his presentation on Monday, Dr. Morgan reported that fewer patients treated with Zometa had bone complications compared to patients treated with Bonefos (clodronate), and this was true regardless of whether patients had any bone lesions at the start of the trial.

In addition, treatment with Zometa was always associated with better response rates and higher overall survival times, although differences with the results for Bonefos were not always statistically significant.

Based on these new results, some attendees at the session asked whether recommendations regarding the use of bisphosphonates for myeloma need to be updated to include administration of Zometa at diagnosis, regardless of bone health, and for longer than the currently recommended two years.

The final talk in Monday’s morning session was given by Dr. Philippe Moreau of the University Hospital in Nantes, France. He presented results of a Phase 3 trial comparing intravenous (IV) administration of Velcade with subcutaneous administration (abstract ^[22]).

Currently in Europe and the United States, the only approved way to administer Velcade is via IV injection.  A new formulation of Velcade is being developed, however, that can be given as a subcutaneous injection.  This may be more convenient for many patients, since subcutaneous injections typically can be administered at home by caregivers or patients themselves.

In the trial discussed by Dr. Moreau, relapsed myeloma patients who had not been previously treated with Velcade were randomly assigned to receive either IV or subcutaneous Velcade injections.  All patients initially received up to four cycles of Velcade alone.  Thereafter, patients who demonstrated no better than a partial response and had not progressed were given the option of adding oral dexamethasone to their treatment regimen.

Dr. Moreau reported that results of the trial reveal no statistically significant difference across the IV and subcutaneous arms of the trial in terms of: median number of cycles of treatment, time on study, percent of patients needing dexamethasone, response rate, time to response, time to progression, and overall survival.  The overall response rate was 42 percent for both arms after four cycles of treatment and 52 percent after eight cycles. The one-year survival was 76 percent for IV administration and 73 percent for subcutaneous administration. Time-to-progression, although similar, was slightly faster in the IV arm.

Perhaps the most significant finding of the trial was that side effects were significantly reduced with subcutaneous Velcade. Severe side effects occurred in 70 percent of IV patients and 57 percent of subcutaneous patients. Peripheral neuropathy occurred in 53 percent of IV patients and 38 percent of subcutaneous patients. Severe neuropathy occurred in 16 percent and 6 percent of patients, respectively.  Six percent of patients in the subcutaneous group had injection site reactions; one percent of the group had severe reactions.

Dr. Moreau concluded that subcutaneous Velcade had efficacy similar to IV Velcade, but with an improved safety profile – especially in regard to peripheral neuropathy. “In my opinion, these findings are really important for our patients,” said Dr. Moreau. A physician in the audience described the results as “fabulous data.” Another physician pointed out that weekly IV Velcade also causes less neuropathy, and said it would be useful to know how well weekly subcutaneous Velcade performs, since it would be particularly well-suited for the maintenance setting.

The Myeloma Beacon published “as it happens” updates from the third full day of ASH in this thread ^[23] in the Beacon’s myeloma forums ^[24].   Similar “as it happens” updates have been provided for Day Four ^[25], which will also be summarized in a daily update like this one.