Welcome to OncoFacts for February, 2010. For this issue of OncoFacts, we are going to focus on some of the most interesting data presented at the American Society of Hematology (ASH) Annual Meeting. We will discuss some of the data presented at the ASH Annual Meeting in the areas of multiple myeloma, myeloproliferative neoplasms, and myelodysplastic syndrome (MDS). Next month, we will look at data from the ASH Annual Meeting regarding chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), and lymphomas.

Highlights of the 2009 Meeting of the American
Society of Hematology

Multiple Myeloma

There were some very interesting presentations of data concerning multiple myeloma this year with important updates on front-line trials, new front-line regimens, data from ongoing maintenance trials, and novel front-line regimens for the elderly.

Abstract 353
Jean-Luc Harousseau updated the results of the IFM 2005-01 trial in which newly diagnosed stem cell transplant (SCT)–eligible patients with high-risk myeloma were randomized for induction therapy between vincristine-doxorubicin-dexamethasone (VAD) and bortezomib-dexamethasone (VD). Previous reports from this trial had shown significantly higher rates of complete response (CR) and very good partial response (VGPR) with the VD regimen compared to VAD.

This year, the IFM reported that progression-free survival (PFS) was significantly longer in all patients who were able to achieve at least a VGPR from either VAD or VD induction and was also longer in the group that achieved at least a VGPR after a single SCT compared to those who achieved less than a VGPR.

The actual numbers per treatment arm reported by Dr Harousseau were:

In this trial, achievement of at least VGPR after induction appeared to be a major prognostic factor for PFS, and the >VGPR rate was significantly higher with the VD induction regimen compared to VAD.

Abstract 529
Michel Attal also reported for the IFM on another trial linked to the 2005-01 trial. IFM 2005-02 accrued patients who had non-progressive disease after a first-line auto-SCT to receive consolidation with lenalidomide 25 mg daily for 21 days each month for 2 months followed by randomization to either low-dose (10 mg - 15 mg) lenalidomide maintenance or placebo. At the ASH meeting, the IFM reported the first interim analysis of this trial that included only the consolidation data. Six hundred fourteen patients were accrued to the trial. Five hundred forty-two received at least 1 dose of consolidation treatment. Four hundred thirty-five patients were able to complete 2 cycles of consolidation lenalidomide.

Pre-consolidation and post-consolidation data were available for 412 patients. Fifteen percent of patients improved their response with consolidation. Results from the maintenance phase of the trial are not available as yet. However, several weeks after ASH, the Data Safety and Monitoring Board (DSMB) for the Cancer and Leukemia Group B (CALGB) 100104/Intergroup trial released a statement that their study of patients who had received induction therapy and an auto-SCT followed by maintenance lenalidomide versus placebo had met its primary objective by achieving a 58% improvement in time to disease progression. This is still very early data, and there is no information regarding the other trial endpoints including response rate, PFS, OS, or safety. Other maintenance trials are ongoing.

Abstract 131
The German Myeloma Study Group presented the results of their DSMM XIa trial in previously untreated patients with multiple myeloma. They accrued 400 transplant-eligible patients, and 300 were evaluable for response. Over 60% of the patients had high-risk cytogenetics.

Three induction cycles of bortezomib-cyclophosphamide-dexamethasone (VCD) were administered consisting of bortezomib 1.3 mg/m² days 1, 4, 8 and 11, dexamethasone 40 mg days 1, 2, 4, 5, 8, 9, 11, and 12 plus cyclophosphamide 900 mg/m² on day 1 every 3 weeks. This regimen is somewhat similar to the cyclophosphamide-bortezomib-dexamethasone (CyBorD) regimen used front-line in high-risk patients by the Mayo Clinic group.

The overall response rate (ORR) was 84%, with 10% CR, and 74% partial responses (PR [many of which were VGPRs]). The ORR in the cytogenetically high-risk groups were del13q = 83.7% and t(4;14) = 90%. Only the del17p group had a significantly lower ORR at 69.2%. Myelosuppression accounted for most of the grade 3-4 adverse events. Peripheral neuropathy was mostly grade 1-2.

Abstract 127
Shaji Kumar from the Mayo Clinic Rochester presented the results of the multi-center EVOLUTION Study. Two-drug and 3-drug regimens including agents such as bortezomib, lenalidomide, cyclophosphamide, and dexamethasone have been shown to be effective and well tolerated. The EVOLUTION Study was designed to determine if it would be possible to combine all 4 of these agents into an effective and safe 4-drug regimen.

Newly diagnosed patients were randomized to receive up to eight 21-day cycles of lenalidomide-bortezomib-dexamethasone (RVD), bortezomib-dexamethasone-cyclophosphamide (VDC) or the 4-drug regimen bortezomib-dexamethasone-cyclophosphamide-lenalidomide (VDCR). Approximately 35 to 40 patients were randomized to each arm of this phase II study. Initially, in the VDC regimen, cyclophosphamide was given on days 1 and 8, but because of lower response rates in the early stages of the study, the authors added a third dose of cyclophosphamide on day 15 with significantly improved results.

The overall response rate was in the 90% to 93% range and >VGPR rates were 55% to 60% for all regimens. The authors concluded that the 3-drug regimens were equally effective as the 4-drug regimen and suggested that the VDC regimen followed by maintenance lenalidomide should be evaluated.

Abstract 3
The ASH Plenary session included a report from the Spanish Myeloma Group evaluating 2 novel regimens for patients with myeloma who were older than 65 years. Two hundred sixty patients with newly diagnosed multiple myeloma were randomized to receive either bortezomib-melphalan-prednisone (VMP) or bortezomib-thalidomide-prednisone (VTP) followed by maintenance therapy with either bortezomib-thalidomide (VT) or bortezomib-prednisone (VP). The question being asked was “Which agent is a better partner for bortezomib – melphalan or thalidomide?”

The response rates for both VMP and (VTP induction were approximately 80%. There was a trend toward higher PFS and 3-year OS with VMP, but the differences were not statistically significant.

Maintenance therapy was able to increase CR rates from 25% to 42% (46% for VT and 38% for VP, not statistically different) and ORR from 80% to approximately 98%, but there were no statistically significant differences between VT and VP maintenance, although there was a trend in favor of VT.

The real difference between these 2 regimens was in the adverse event profiles. There were higher rates of hematologic toxicity with the VMP regimen and higher rates of peripheral neuropathy and cardiac toxicity with the VTP regimen.

Abstract 614
Smoldering multiple myeloma is defined by the presence of an M-protein in the serum of at least 3 gm/dL and/or bone marrow clonal plasma cells of at least 10% without any disease related symptoms or any hypercalcemia, renal impairment, anemia, and bone lesions (CRAB). The probability of progression from smoldering multiple myeloma to active myeloma is 10% per year for the first 5 years, then 3% per year for the next 5 years, then 1% per year thereafter.

The Spanish Myeloma Group decided to perform a phase III study comparing the lenalidomide–low-dose (LD) dexamethasone (Dex) regimen with therapeutic abstention in patients with smoldering multiple myeloma who were considered high risk (those with an M-protein >3 gm/dL and BM clonal plasma cells of >10%). Previous studies using thalidomide had demonstrated responses but significant toxicity. Ninety-four patients randomized to either therapeutic abstention or to treatment with lenalidomide 25 mg daily for 21 days out of each 4 week cycle for up to 9 cycles. The treated patients then went on to receive maintenance low-dose lenalidomide at 10 mg per day for 21 days every 2 months.

Lenalidomide was reasonably well tolerated, although 11% of patients did experience a serious adverse event. Overall survival at 2 years was 100% for the Len-LD Dex group and 96% for the therapeutic abstention group. Eighty-one percent of the Len-LD Dex group responded to therapy with >VGPR rate of 30%. Time-to-progression (TTP) to active myeloma was not reached in the treatment group with only 2 patients who progressed after withdrawing from treatment. The TTP in the therapeutic abstention groups was 19.3 months, with 16 patients who progressed.

The authors concluded that these preliminary results showed that in patients with smoldering multiple myeloma at high risk of progression to active disease, delayed treatment is associated with early progression. However, other myeloma specialists suggest that these results need to be confirmed by larger studies before this becomes a generally recommended therapeutic approach in smoldering multiple myeloma.

Abstract 128
Antonio Palumbo updated the results of a GIMEMA trial randomizing elderly patients with myeloma between bortezomib-melphalan-prednisone (VMP) alone and the 4-drug regimen bortezomib-melphalan-prednisone-thalidomide (VMPT) followed by maintenance bortezomib-thalidomide (VT). At the American Society of Clinical Oncology (ASCO) 2009 Annual Meeting, Dr Palumbo reported an increase in the >VGPR rate with VMPT but no difference in PFS or OS. At ASH, he confirmed the higher CR, VGPR, and PR rates with VMPT compared to VMP and also presented the PFS and time to next treatment (TTNT) data from the trial.

Three-year PFS was 60% with the VMPT→VT regimen and 42% with VMP without maintenance. Time to next treatment at 3 years was also significantly better with VMPT→VT. Whether the PFS or TTNT would have been similar if VMP had been followed by VT maintenance was not tested in this trial.

Complete response was associated with a significantly longer PFS whether it was achieved with VMPT or VMP. The 2-year overall survival was the same for both arms at 89%.

Perhaps the most interesting aspect of this trial was that after accruing approximately 25% of the participants, GIMEMA changed the bortezomib schedule in both arms. Instead of bortezomib 1.3 mg/m² twice a week for 4 out of 6 weeks in the first 4 cycles and then only for 2 out of 6 weeks in the remaining cycles, bortezomib was given at 1.3 mg/m² weekly for 4 out of 5 weeks for all 9 cycles. This change had no significant impact on response rates or PFS, but significantly reduced the incidence of peripheral neuropathy. In addition, when the investigators examined the total amount of bortezomib administered in the twice-weekly and weekly schedules, there was no significant difference.

The 4-drug regimen, in conclusion, did produce higher response rates and longer PFS but at a cost of increased hematologic and cardiac toxicity. However, the greatest impact of this study is perhaps its demonstration that weekly bortezomib is equally as effective as twice weekly with a marked reduction in the incidence and severity of peripheral neuropathy.

Abstract 613
One of the most potentially practice-changing abstracts of the ASH meeting was also presented by Antonio Palumbo. This phase III study randomized elderly patients with myeloma to 1 of 3 regimens: melphalan-prednisone (MP) alone, MP plus lenalidomide (MPR) and MP-lenalidomide followed by maintenance low-dose (10 mg/day x 21 q28) lenalidomide (MPR-R). The independent Data Monitoring Committee reviewed the data from the first interim analysis and determined that the study had crossed the O’Brien-Fleming superiority boundary for the primary endpoint, demonstrating a highly significant improvement in PFS for MPR-R compared to MP.

Overall response rate, PFS, CR rate, VGPR rate, and time to next treatment were all statistically superior for MPR-R compared to MP alone. In addition, the PFS for MPR with lenalidomide maintenance (MPR-R) was significantly better than for MPR without maintenance. However, despite the fact that response rates were better for MPR than MP, there was no difference in PFS between MP and MPR without maintenance lenalidomide. So the question rises as to whether the difference in PFS actually reflects the comparison of maintenance lenalidomide versus no maintenance.

Grade 3-4 adverse events were all greater in the MPR-R than in the MP arm. The 1-year OS rates were not different at the time of this analysis. The authors concluded that MPR followed by lenalidomide maintenance (MPR-R) is a new option for front-line therapy of elderly patients with myeloma.

Abstract 302
One of the novel agents we have been hearing about for the past year or so is carfilzomib. This is a second generation proteasome inhibitor that binds irreversibly to selective targets within the proteasome. Previous presentations have included phase I dose and schedule finding trials.

The phase II trials have included patients with relapsed multiple myeloma, some of whom were bortezomib naïve and others who had previously received bortezomib. Dr Luhua Wang from M. D. Anderson Cancer Center presented updated results from 1 of the phase II studies of carfilzomib in bortezomib-naïve patients with relapsed/refractory myeloma. These 57 patients had received from 1-3 prior therapies including alkylators, SCT, thalidomide, lenalidomide, and anthracyclines. Carfilzomib was administered on days 1 and 2 weekly for 3 weeks out of 4.

Fifty-four patients were evaluable, and 23 patients (46%) experienced a response. This included 1 CR, 5 VGPRs, and 19 PRs. Median TTP was 7.6 months. Fatigue, nausea, dyspnea, thrombocytopenia, infections, and anemia were the most common adverse events. Grade 1-2 peripheral neuropathy was seen in 12%. Grade 3 peripheral neuropathy was rare and there was no grade 4 peripheral neuropathy.

Abstract 429
Martha Lacy from the Mayo Clinic presented results of her phase II study of the novel immunomodulatory agent, pomalidomide, plus dexamethasone in lenalidomide-refractory myeloma. A previous phase II study in patients with relapsed/refractory myeloma had demonstrated a 63% response rate with pomalidomide. Thirty-four patients with myeloma who were resistant or refractory to lenalidomide were enrolled. Seventy percent had received 3 or more prior regimens. Sixty percent had received bortezomib, and 68% had undergone SCT.

There were 9 responses, and 18 patients experienced stable disease. Grade 3-4 neutropenia was seen in 21%. Peripheral neuropathy (all grade 1-2) occurred in 18%. There were no thromboembolic events seen.

References
Harousseau JL, Avet-Loiseau H, Attal M, et al. High complete and very good partial response rates with bortezomib-dexamethasone as induction prior to ASCT in newly diagnosed patients with high-risk myeloma: Results of the IFM2005-01 Phase 3 trial. Blood. 2009;114(22). Abstract 353 and oral presentation at: American Society of Hematology Annual Meeting; December 5-8, 2009; San Francisco, CA.

Attal M, Haroussseau JL, Marit G, et al. Lenalidomide after autologous transplantation for myeloma: First analysis of a prospective, randomized study of the Intergroupe Francophone Du Myelome (IMF2005 02). Blood. 2009;114(22). Abstract 529 and oral presentation at: American Society of Hematology Annual Meeting; December 5-8, 2009; San Francisco, CA.

Einsele H, Liebisch P, Langer C, et al. Velcade, intravenous cyclophosphamide and dexamethasone (VCD) induction for previously untreated multiple myeloma (German DSMM Xia Trial). Blood. 2009;114(22). Abstract 131 and oral presentation at: American Society of Hematology Annual Meeting; December 5-8, 2009; San Francisco, CA.

Kumar S, Flinn IW, Hari PN, et al. Novel three– and four–drug combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide, for newly diagnosed multiple myeloma: Encouraging results from the multi-center, randomized, phase 2 EVOLUTION study. Blood. 2009;114(22). Abstract 127 and oral presentation at: American Society of Hematology Annual Meeting; December 5-8, 2009; San Francisco, CA.

Mateos MV, Oriol A, Martinez J, et al. A prospective, multicenter, randomized, trial of bortezomib/melphalan/prednisone (VMP) versus bortezomib/thalidomide/prednisone (VTP) as induction therapy followed by maintenance treatment with bortezomib/thalidomide (VT) versus bortezomib/prednisone (VP) in elderly untreated patients with multiple myeloma older than 65 years. Blood. 2009;114(22). Abstract 3 and oral presentation at: American Society of Hematology Annual Meeting; December 5-8, 2009; San Francisco, CA.

Mateos MV, López-Corral L, Hernández M, et al. Multicenter, randomized, open-label, phase II trial of lenalidomide-dexamethasone (Len/dex) vs therapeutic abstention in smoldering multiple myeloma at high risk of progression to symptomatic MM: Results of the first interim analysis. Blood. 2009;114(22). Abstract 614 and oral presentation at: American Society of Hematology Annual Meeting; December 5-8, 2009; San Francisco, CA.

Palumbo A, Bringhen S, Rossi D, et al. Bortezomib, melphalan, prednisone and thalidomide (VMPT) followed by maintenance with bortezomib and thalidomide for initial treatment of elderly multiple myeloma patients. Blood. 2009;114(22). Abstract 128 and oral presentation at: American Society of Hematology Annual Meeting; December 5-8, 2009; San Francisco, CA.

Palumbo A, Dimopoulos MA, Deforge M, et al. A phase III study to determine the efficacy and safety of lenalidomide in combination with melphalan and prednisone (MPR) in elderly patients with newly diagnosed multiple myeloma. Blood. 2009;114(22). Abstract 613 and oral presentation at: American Society of Hematology Annual Meeting; December 5-8, 2009; San Francisco, CA.

Wang L, Siegel D, Kaufman JL, et al. Updated results of bortezomib-naïve patients in PX-171-004, an ongoing open-label, phase II study of single-agent carfilzomib (CFZ) in patients with relapsed or refractory myeloma (MM). Blood. 2009;114(22). Abstract 302 and oral presentation at: American Society of Hematology Annual Meeting; December 5-8, 2009; San Francisco, CA.

Lacy MQ, Gertz MA, Hayman SR, et al. Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma. Blood. 2009;114(22). Abstract 429 and oral presentation at: American Society of Hematology Annual Meeting; December 5-8, 2009; San Francisco, CA.

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