Yesterday was the second full day of the 2010 American Society of Hematology annual meeting in Orlando. It was a particularly busy day in terms of material related to multiple myeloma, with numerous oral presentations during the day and an extensive poster session in the early evening.

One of the first presentations of the day was actually a press conference held to review the results of a Phase 3 study comparing the efficacy and safety of two different stem cell transplant regimens for multiple myeloma (abstract).

In one arm of this study, patients received two autologous stem cell transplants – that is, transplants using their own stem cells.

In the other arm of the study, patients received an autologous stem cell transplant followed by an allogeneic stem cell transplant with stem cells donated by a sibling. Allogeneic transplants by definition involve stem cells provided by a donor.

There is keen interest in the results of this study for at least two reasons.

First, previous research has shown that patients receiving tandem autologous transplants live longer than patients receiving only a single autologous transplant.

Second, allogeneic transplants are currently the only treatment that has the potential to completely remove all multiple myeloma cells from a patient’s body. However, allogeneic transplants are associated with more frequent and more serious – often deadly – side effects.

At the press conference and another presentation later in the day, Dr. Amrita Krishnan from the City of Hope Cancer Center in Duarte, California reported that the tandem autologous transplant regimen had similar efficacy as the autologous-allogeneic transplant regimen.

After three years, progression-free survival was 46 percent for patients receiving “auto-auto” transplants, compared to 43 percent for the patients receiving “auto-allo” transplants. Similarly, overall survival was 80 percent and 77 percent for the two groups, respectively.

Slightly more auto-auto patients relapsed (50 percent vs 46 percent for the auto-auto and auto-allo groups, respectively). However, treatment-related mortality was higher for the auto-allo group (4 percent and 11 percent for auto-auto and auto-allo, respectively).

The results of the trial generated substantial discussion, including questions as to whether the results indicate that allogeneic transplants should never be given to myeloma patients.

Dr. Krishnan, though, believes it is too early to conclude that allogeneic transplants are broadly inappropriate for myeloma patients. She believes they still need to be considered for high-risk patients. Even more importantly, the results highlight the need to find better ways to address the serious side effects of allogeneic transplants.

The oral presentations yesterday afternoon examined the results of different trials involving mainly autologous transplants combined with different induction, consolidation, and maintenance regimens.

The first talk was given by Dr. Philip McCarthy of the Roswell Park Cancer Institute in Buffalo, New York. He presented updated results from the CALGB Phase 3 study of Revlimid (lenalidomide) versus placebo maintenance therapy after an autologous stem cell transplant. Almost 570 patients were treated with melphalan, underwent a transplant, and then half received Revlimid maintenance therapy and the other half received a placebo (abstract).

In late 2009, a preliminary analysis of data from this study showed such a significant improvement in time-to-progression in the Revlimid maintenance arm that the study was unblinded and patients in the placebo arm were allowed to switch to receiving Revlimid.

Twelve-month results were presented at the American Society of Clinical Oncology meeting this summer (see related Beacon news), and 18 month results were presented at yesterday’s session.

The latest analysis shows that time-to-progression is significantly better in the Revlimid maintenance group (42.3 months) compared to the placebo group (21.8 months). Overall survival is similar for the two groups, but this may be due to the significant percentage of placebo patients who started Revlimid maintenance when the trial was unblinded in late 2009.

This study is one of several recent studies that support the use of Revlimid maintenance therapy after stem cell transplantation. One important caution from the study, however, is that 25 patients developed a second cancer -- that is, an additional cancer other than myeloma -- 15 while on maintenance therapy and 10 in the placebo group.

The results of another trial examining Revlimid, although not necessarily in the maintenance context, were presented by Dr. David Siegel of Hackensack University Medical Center in New Jersey (abstract).

In the trial discussed by Dr. Siegel, half the newly diagnosed myeloma patients received initial treatment with Revlimid/high-dose dexamethasone (Decadron) and the other half received Revlimid/low-dose dexamethasone. After four cycles, patients had the option of continuing Revlimid/dexamethasone treatment or, at any time, opting to undergo an autologous stem cell transplant.

The key finding of this study is that, across patients of all ages, those who received stem cell transplants early after their initial four cycles of Revlimid and dexamethasone had a higher projected three-year overall survival than patients who had later stem cell transplants.  The difference in overall survival is statistically significant, however, only for patients under the age of 65.

For patients under the age of 65, those who had an early transplant had a projected three-year overall survival rate of 94 percent, versus 78 percent for patients who had later stem cell transplants.

For patients over the age of 65, projected three-year overall survival rates were 83 percent and 69 percent for the early and late transplant groups, respectively.

Dr. Siegel and his co-authors note that one needs to be cautious about reading too much into these results, not least because patients were not randomly selected to receive either an early or late stem cell transplant. The results do suggest, however, that early transplantation may be beneficial for younger patients.  In addition, the results seem to call into question the commonly held belief that transplantation should be used more as a last resort in older patients.

A presentation by Dr. Pieter Sonneveld of Erasmus Medical Center in Rotterdam, Netherlands, reported results of a European Phase 3 study examining Velcade (bortezomib) induction therapy prior to high-dose melphalan and stem cell transplantation followed by a Velcade maintenance regimen (abstract).

Half of the patients in this trial received vincristine (Oncovin)-doxorubicin (Adriamycin)-dexamethasone induction, melphalan (Alkeran) treatment, and autologous or allogeneic transplantation, followed by maintenance with thalidomide (Thalomid) for two years. The other half received the same treatment except with Velcade-doxorubicin-dexamethasone induction and Velcade maintenance. Over 600 newly diagnosed patients participated in the trial – about 300 in each of the two arms.

Responses, progression free survival, overall survival were all better in the Velcade group. At 36 months, overall survival was 78 percent in the Velcade arm and 71 percent in the thalidomide arm. Additionally, more patients remained on Velcade treatment due to thalidomide toxicity issues in the thalidomide arm.

A related presentation was given by Dr. Michele Cavo of the Bologna University School of Medicine in Italy. In the European Phase 3 study discussed by Dr. Cavo, newly diagnosed myeloma patients received Velcade-thalidomide-dexamethasone (VTD) or thalidomide-dexamethasone (TD) induction followed by melphalan and tandem transplants, then consolidation with the same regimen as the induction therapy, followed by maintenance with dexamethasone (abstract).

There were increased complete and near-complete responses with VTD versus TD (31 percent versus 11 percent complete response or near complete response, respectively, and 62 percent and 45 percent, respectively, after consolidation). Three-year progression-free-survival was 68 percent for the VTD group and 56 percent for the TD group. Additionally, Velcade overcame the poor prognosis of patients with the chromosomal abnormality t(4;14).

There was a tendency to greater overall survival in the VTD arm, but the difference between the two groups was not statistically significant. Projected overall survival at 44 months is 84 percent in the VTD arm and 74 percent in the TD arm.

Rates of severe side effects were similar across the two arms. Unlike several of the other studies discussed yesterday, patients in the thalidomide arm of this study did not experience significant toxicity issues or discontinuation of therapy due to thalidomide use.

While on the subject of thalidomide, it is worth mentioning a study presented yesterday by Dr. Keith Stewart of the Mayo Clinic in Scottsdale, Arizona. Dr. Stewart reported on the results of a Phase 3 trial that examined maintenance therapy with thalidomide and prednisone (abstract).

In this study, recently diagnosed myeloma patients who had received an autologous stem cell transplant were randomly assigned to receive either thalidomide and prednisone maintenance therapy or no maintenance therapy at all (just observation).

Previous studies have shown that thalidomide maintenance extends progression free survival, but results for overall survival have varied.

In the results presented by Dr. Stewart, progression-free survival was 28 months for the thalidomide maintenance group versus 17 months for the observation only arm.

Four-year overall survival was 68 percent for the thalidomide maintenance patients and 60 percent for the observation-only arm. Median five-year overall survival has not yet been reached for the maintenance group; however, the trend is in favor of maintenance, although the difference is not statistically significant.

Side effects were higher, as expected, in the thalidomide maintenance group, with peripheral neuropathy and blood clotting being particular concerns.

During yesterday’s evening poster session, many of the research results on display concern potential new myeloma treatments that are still under development. There were posters, for example concerning carfilzomib, elotuzumab, panobinostat, perifosine, pomalidomide, and Zolinza (vorinostat). These potential treatments are already well known, and the The Beacon will be covering news related to them either in upcoming meeting updates or in stand-alone, focused news articles (see, for example, the Beacon’s recent article about carfilzomib news from this meeting).

There were, however, posters about two potential myeloma treatments that have not yet received much attention.

One poster discussed BT-062, a new drug being developed by the German company Biotest AG. The authors of the poster reported results from a Phase 1 trial that are sufficiently promising that Biotest plans to initiate a Phase 1/2 study of the drug in relapsed / refractory myeloma patients (abstract).

Another poster reported on results of a small-scale Italian Phase 2 trial examining the potential use of an older drug, fotemustine, in combination with Velcade and dexamethasone. Fotemustine, also known by the brand name Muphoran, is approved in Europe as a treatment for melanoma. It is not currently available for sale in the United States (abstract).

The results of the Italian trial, report the poster’s authors, indicate that the combination of fotemustine, Velcade, and dexamethasone “is safe and gives encouraging results in relapsed/refractory myeloma patients,” with 80 percent of trial participants achieving at least a very good partial response.

The Myeloma Beacon is publishing regular ”as it happens” updates from the third full day of ASH in this thread in the Beacon’s myeloma forums. Similar “as it happens” updates also will be provided for tomorrow, Day Four. As always, the news from each day also will be summarized in daily updates like this one.