Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

48th Annual Meeting and Exposition of the American Society of Hematology

Orlando, Florida / December 9-12, 2006

Results from a planned interim analysis of a randomized, phase III study suggest that the combination of pegylated liposomal doxorubicin (PLD) with the proteasome inhibitor bortezomib produces more efficacious time-to-progression (TTP) rates than bortezomib alone in patients with relapsed multiple myeloma (MM). As observed by Dr. Robert Orlowski, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, the effect of combining a proteasome inhibitor plus an anthracycline has been shown to be synergistic both in vitro and in vivo. “Bortezomib is also able to block some anthracycline-mediated resistance pathways while anthracyclines block some bortezomib-mediated resistance pathways.”

Researchers sought to determine if the combination bortezomib/PLD would improve clinical outcomes in relapsed/refractory MM compared with bortezomib alone. For the trial, 646 relapsed/refractory MM patients who had received at least one prior line of therapy were randomized to either the proteasome inhibitor 1.3 mg/m² on days 1, 4, 8 and 11 of every 21-day cycle, or the same dose and schedule of bortezomib plus PLD 30 mg/m² on day 4 of each cycle. Treatment was scheduled to continue for a total of eight cycles unless a complete response (CR) was attained or disease progressed.

The overall response rate (ORR), including both a CR and partial responses (PRs), was 48% in the combination arm vs. 43% in the single-agent arm, while duration of response was increased by about three months to 10.2 months vs. seven months for the combination vs. single-agent arms, respectively. The median TTP—the primary end point of the trial—was also significantly longer in the combination arm at 9.3 months vs. 6.5 months (P=0.000004) for the single-agent group, with a trend towards improved overall survival (OS) in the combination arm.

“The combination appeared to increase response and TTP in most of the subgroups analyzed,” Dr. Orlowski remarked, including those who had moderate to high elevations of beta 2 microglobulin and those who had not responded to prior therapy or prior stem cell transplantation. Previous anthracycline use did not reduce the benefit of the combination and the same was true for prior thalidomide use, he noted.

There was some increase in adverse events (AEs) with the combination strategy, including gastrointestinal events, neutropenia and other cytopenias but in general, “the magnitude of the increased toxicity was modest,” Dr. Orlowski stated. “In this interim analysis, PLD in combination with bortezomib reduces the risk of progression by 45%, despite only a small increase in the response rate. Our working hypothesis is that the quality of response may be better in the combination arm.”

Promising Salvage Protocol

Another promising salvage protocol for relapsed/refractory MM is combination lenalidomide/doxorubicin/dexamethasone (RAD). As reported by lead investigator Dr. Stefan Knop, University Hospital, Würzburg, Germany, a total of 58 heavily pretreated patients (median of three prior treatments) were included in the phase I-II study. After several patients developed febrile neutropenia, the protocol was amended to include growth-colony stimulating factor given in conjunction with lenalidomide 15 mg on days 1 to 21, doxorubicin 9 mg/m² on days 1 to 4, and dexamethasone 40 mg on days 1 to 4 and again on days 17 to 21.

Toxicity was mainly hematologic and was predominantly grades 1 and 2. Out of 37 evaluable patients, 28 patients achieved a PR, two achieved a negative CR and one had a minor response, for an ORR of 84%. Duration of response is not yet known, Dr. Knop indicated, but concluded, “RAD is a new and effective salvage protocol in relapsed/refractory MM, with predictable and manageable toxicity and with good activity in high-risk patients.”

For patients who become resistant to or who cannot tolerate dexamethasone, final results from another phase II study in which bortezomib was combined with liposomal doxorubicin and thalidomide suggest that this particular triplet may allow relapsed/refractory patients to regain control of their disease. Eighteen evaluable patients received bortezomib at standard doses but given only on days 1 and 4, followed by one week of rest, then again on days 15 and 18, plus liposomal doxorubicin 20 mg/m² on days 1 and 15 every four weeks, with daily thalidomide 200 mg for four to six cycles.

As presented by Dr. Swaminathan Padmanabhan, Roswell Park Cancer Institute, Buffalo, New York, the ORR was 83.3%, with a CR rate of almost 22% and a CR plus PR rate of 56%. Response was seen regardless of prior therapies, which included doxorubicin, stem cell transplant and steroids. Median progression-free survival (PFS) and OS in the trial were 10.9 and 15.7 months, respectively. Patients were treated with weight-adjusted warfarin prophylaxis and no venothrombotic events were noted. “This is a very active regimen and it can overcome resistance patients may have had to previous therapies,” noted Dr. Padmanabhan. “The week’s rest allows the microtubules to recover so this translates into decreased neuropathy.”

Data are still limited regarding patients’ progress following treatment for MM. To that end, Dr. Maria Roussou, University of Athens, School of Medicine, Greece, and colleagues reassessed their original series of 43 patients who had been previously treated with a pulsed, oral regimen consisting of cyclophosphamide 150 mg/m² every 12 hours on days 1 to 5, thalidomide 400 mg/day on days 1 to 5 and on days 14 to 18, and dexamethasone 20 mg/m² (CTD) on days 1 to 5 and on days 14 to 18, every 28 days for three cycles.

Patients who responded received maintenance treatment with monthly courses of CTD, given for the first five days of each month. Out of this original group, 14 patients did not respond to CTD and 29 patients (67%) achieved a PR. The median PFS for all patients was 10 months. In an updated analysis of 40 out of the 43 patients who received further treatment, 10 died prior to further therapy, nine patients received conventional chemotherapy and the remaining 21 patients received a novel regimen. Among the nine patients who received further treatment with a conventional regimen, there was one PR and the median PFS was 2.7 months.

Median survival in this group was 8.3 months. In the 21 patients who received a novel regimen, six achieved a PR and the PFS was 5.3 months, with a median survival of 9.6 months. Interestingly, a PR to a novel regimen was documented in 31% of CTD-sensitive patients and in 20% of those who were resistant to CTD.

In the current update of their original pulsed CTD trial with a minimum follow-up now exceeding four years, 7% of the original cohort remain free of symptoms and without disease progression, suggesting that use of a novel agent following progression is more likely to delay progression than conventional chemotherapy.

Seeking Optimal Induction Strategies

Noting that the optimal induction regimen prior to stem cell transplantation has not yet been defined, Dr. Jean-Luc Harousseau, Hôtel-Dieu Hospital, Nantes, France, presented results from an interim analysis of the Intergroupe Francophone du Myélome (IFM) phase III study in which newly diagnosed MM patients were randomized to either bortezomib/dexamethasone or bortezomib monotherapy, both given in 28-day cycles. The CR plus near CR (nCR) rate was 20% in the combination arm vs. 9% for the single-agent arm, while the true CR rate was 9% with the combination vs. 4% with the single agent.

The CR plus very good PR (VGPR) was 43% with the combination vs. 26% for monotherapy and the percentage of patients who either failed therapy, had a minimum response or who had stable or progressive disease was 12% vs. 22%, respectively. As Dr. Harousseau indicated, there was essentially no difference in grade 3 or higher AEs between the two treatment arms. Results thus suggest that the use of a novel agent in induction regimens prior to transplantation may improve the CR rate.

Long-term results for patients who were treated with bortezomib alone and in combination with dexamethasone, both given as front-line therapy to newly diagnosed patients, were also presented by Dr. Sundar Jagannath, Aptium Oncology Research Network, Los Angeles, California. Data on all 49 study patients indicated that response to monotherapy was rapid (within two cycles) with almost half of patients achieving a response, including a 10% CR or nCR rate. Following the addition of dexamethasone, 88% of patients had responded by the end of six cycles, including 18% who achieved a CR and another 20% who achieved a VGPR. At the end of two years, 85% of patients were still alive at a median follow-up of 27 months.

Cell harvest and engraftment were successful in all patients proceeding to transplant and for those who did, the estimated two-year survival rate was 91%. The most common toxicities were fatigue, constipation, nausea and sensory neuropathy but they were all predictable and manageable, as Dr. Jagannath indicated. He concluded that either alone or in combination with dexamethasone, data presented here during the scientific sessions demonstrated that “bortezomib is an effective front-line therapy in MM.”