New Combinations Show Promise in Multiple Myeloma

Zosia Chustecka

December 22, 2009

December 22, 2009 (New Orleans, Louisiana) — Several key presentations at the recent American Society of Hematology (ASH) 51st Annual Meeting have featured new combinations of drugs in the treatment of multiple myeloma in patients older than 65 years.

The treatment of multiple myeloma has transformed in recent years, with the introduction of the immunomodulators thalidomide and lenalidomide and the proteasome inhibitor bortezomib joining older products such as melphalan and corticosteroids, but there is still much debate as to how these drugs are best used in combination with one another.

In a presentation chosen for the plenary session, Maria-Victoria Mateos, MD, PhD, from University Hospital in Salamanca, Spain, and colleagues reported on a novel approach to treatment, using a reduced bortezomib dosage for induction therapy, which they found maintained efficacy while reducing toxicity (Abstract 3). These data were also highlighted at a press conference during the meeting.

In other presentations, Antonio Palumbo, MD, from Turin University in Turin, Italy, reported on a new approach to initial treatment and superior results from using a 4-drug combination of bortezomib, melphalan, prednisone, and thalidomide (VMPT) vs those seen with the 3-drug regimen bortezomib, melphalan, and prednisone (VMP), which is the most recent standard for initial therapy (Abstract 128).

Dr. Palumbo also presented data that he says establishes a new standard for patients older than 65 years: initial treatment with melphalan, prednisone, and lenalidomide (MPR) followed by continuous lenalidomide maintenance, which gave better results than melphalan plus prednisone followed by placebo maintenance (Abstract 613).

Also, after Dr. Palumbo's presentation during a question-and-answer session, a practicing physician, who stated that he "treats only a few patients with multiple myeloma," asked how these new drug combinations compare with one another. His question could not be addressed because there have been no comparator trials as yet.

Spanish Trial of Reduced Bortezomib Dosage

The Spanish study presented by Dr. Mateos was conducted in 260 patients with a median age of 75 years.

"We were trying to optimise the treatment of elderly multiple myeloma patients," explained the lead researcher. "So we tried a less-intensive bortezomib, with weekly administration for induction followed by maintenance doses given every 3 months."

The trial also compared 2 different combinations for induction therapy: bortezomib with melphalan and prednisone (VMP) or bortezomib with thalidomide and prednisone (VTP), both given for 6 cycles. In the first cycle, bortezomib was given twice weekly but was reduced to once-weekly dosing for the remaining 5 cycles.

Both of these combinations of induction therapy were highly effective, with similar overall response rates (80% with VMP and 81% with VTP), but there was a clear difference in the toxicity profiles, Dr. Mateos reported. The VMP regimen was associated with a higher incidence of grade 3 neutropenia (seen in 37% of patients vs 21% of patients in the VTP group), which translated into more grade 3 infections (seen in 7% receiving VMP vs 1% receiving VTP).

However, Dr. Mateos commented that the risk for neutropenia and infections can be managed by the use of a granulocyte-macrophage colony-stimulating factor (GM-CSF) and prophylactic antibiotics. In contrast, the VTP regimen was associated with serious cardiovascular adverse events, seen in 8.5% of patients, and these included cardiac failure, atrial fibrillation, hypotension, myocardial infraction, and atrioventricular blockage. Also, there was a higher incidence of peripheral neuropathy in the VTP group: 9% vs 5% receiving VMP, although this was not statistically significant.

"We found that melphalan is probably the best partner for bortezomib in elderly untreated multiple myeloma patients because the efficacy is similar to VTP, but the toxicity profile is clearly different, with more neutropenia but less cardiotoxicity and peripheral neuropathy with VMP," she said.

For the maintenance therapy part of this trial, bortezomib was combined with either thalidomide or prednisone for up to 3 years. There were no significant differences between these 2 combinations, Dr. Mateos reported. Both markedly improved the quality of patient responses, increasing complete responses from 23% to 42%, and both had a good safety profile, she said.

"We asked the question, 'Could we achieve similar efficacy with a less intensive bortezomib regimen?', and the answer is clearly yes, we can," Dr. Mateos concluded.

She told the meeting that the group is now looking at replacing thalidomide with lenalidomide in both induction and maintenance therapy, with a view towards reducing toxicity further.

Four-Drug Combination

Dr. Palumbo reported that the bortezomib dosage was also reduced in the trial that he presented on the new 4-drug combination — VMPT being superior to VMP.

When the study began, bortezomib was used twice-weekly, but this was amended to a once-weekly dosage, the same as in the Spanish study. Dr. Palumbo said this resulted in a "dramatic drop" in the incidence of peripheral neuropathy, without affecting the outcome (as measured by complete responses and progression-free survival). Grade 3/4 peripheral neuropathy was significantly lower with weekly bortezomib vs a twice-weekly dosage: the rates were 4% vs 18% (P = .0002) in the VMPT group and 2% vs 13% (P = .0003) in the VMP group.

This was a phase 3 study conducted in 511 patients with a median age of 71 years. The patients were randomized to receive either initial therapy with VMPT followed by bortezomib and low-dose thalidomide for maintenance, or VMP without maintenance.

The results showed that the 4-drug combination of VMPT produced superior response rates: a complete response was achieved in 34% of patients vs 21% of patients receiving VMP (P = .008).

The achievement of a complete response significantly prolonged progression-free survival duration in both groups of patients, but the result was greater in the VMPT group (P < .0001) vs the VMP group (P = .003), Dr. Palumbo reported. However, the 2-year overall survival duration was not significantly different (89.6% with VMPT and 89% with VMP).

Also, the 4-drug combination had a significantly higher rate of grade 3/4 neutropenia (37% with VMPT vs 28% with VMP; P = .02) and cardiac complications (10% vs 5%; P = .04). However, the rate of other adverse events was similar, with thrombocytopenia occurring in 21% vs 19%, peripheral neuropathy in 5% vs 8%, infections in 12% vs 9%, and gastrointestinal tract complications in 6% vs 8%, respectively.

"VMPT followed by maintenance with bortezomib and thalidomide was superior to VMP for response rates and progression-free survival," Dr. Palumbo concluded.

Continuous Lenalidomide Maintenance

In his other presentation, Dr. Palumbo suggested that the combination of melphalan, prednisone, and lenalidomide for initial treatment followed by continuous lenalidomide for maintenance (MPR-R) "can be considered a new standard" for patients older than 65 years newly diagnosed with multiple myeloma.

This approach (MPR-R) was shown to be superior to initial treatment with MPR followed by placebo maintenance (MPR) and was also superior to initial treatment with melphalan and prednisone followed by placebo maintenance (MP).

There was a highly statistically significant improvement in progression-free survival duration, Dr. Palumbo reported, with a 50% improvement from 15 months with MP to 22.5 months with MPR-R (P < .0001). As a result, the study was stopped early, he said.

Progression-free survival time was also significantly better with the MPR-R regimen vs MPR without maintenance, with a 47% reduction — the median progression-free survival duration was 13.2 months with MPR but was not reached with MPR-R (P = .002), he said. "The continuous maintenance therapy with lenalidomide was changing the outcome," he commented.

The overall response rate, the complete response rate, and the median time to first response were all significantly better for the MPR-R group vs the other 2 groups.

Adverse events including deep vein thrombosis, rash, fatigue, and infections were slightly higher in the MPR-R group vs the MP group, but there was a lower rate of discontinuation, Dr. Palumbo commented.

Since the ASH meeting, another large trial with lenalidomide in multiple myeloma has been reported. Data were released on December 18 by the National Institutes of Health from the Cancer and Leukemia Group B (CALGB-100104) study

This trial was stopped early after a highly significant improvement in time to progression was seen with lenalidomide vs placebo in patients who had received a stem cell transplant.

The trial involved 568 patients with multiple myeloma who had received an autologous transplantation after a high dose of melphalan. Of these, 460 patients with adequate organ function and no evidence of progressive disease were randomized to receive maintenance therapy with lenalidomide or placebo, starting at 100 to 110 days after the transplant procedure.

The median time to disease progression in the placebo group was 778 days; this has not yet been reached in the lenalidomide group because less than half of the patients had worsening of their myeloma. This represents a 58% reduction in the risk for disease progression and is highly statistically significant, notes the National Institutes of Health.

Dr. Mateos has received honoraria and has served on the speaker's bureau for Janssen-Cilag and Celgene. Dr. Palumbo has received honoraria from Janseen-Cilag and Celgene.

American Society of Hematology (ASH) 51st Annual Meeting: Abstracts 3 and 128. Presented December 6. Abstract 613. Presented December 7.

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