Reports

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PRIORITY PRESS - 16th Congress of the European Hematology Association (EHA)

London, UK / June 9-12, 2011

Chief Medical Editor: Dr. Léna Coïc, Montréal, Québec

Prof. Philippe Moreau, University Hospital Hôtel-Dieu, Nantes, France, told delegates here at the EHA, “Since the proteasome inhibitor bortezomib became available for the treatment of multiple myeloma (MM), bortezomib/dexamethasone (VD) has become the backbone of induction therapy prior to autologous stem-cell transplantation (ASCT) to which other more complex regimens should be compared.” As consolidation therapy post-ASCT, the proteasome inhibitor may improve complete response (CR) rate as well as depth of response leading to molecular CR and prolong the duration of response and progression-free survival (PFS) through maintenance therapy.

First-line High-dose Therapy with Novel Agents

A real-life retrospective study led by Dr. Hareth Nahi, Karolinska University Hospital, Stockholm, Sweden, underlined the importance of having a near CR (nCR) with first-line high-dose-therapy (HDT) MM patients in clinical practice. Patients receiving novel agents (bortezomib, lenalidomide, thalidomide) had a higher probability of an nCR than those who did not receive these agents (63% vs. 49%). They found that an nCR in the first line was associated with a 48% probability of at least a very good partial response (=VGPR) and a 35% probability of an nCR in second line. Median overall survival (OS) was 6.3 years in the total population and 6.9 years in patients with a first-line nCR. They concluded that the novel agents in first line improve response.

Improving Prognosis after ASCT

According to a study led by Dr. Josep-Maria Ribera, Hospital Universitari Germans Trias i Pujol, Badalona, Spain, patients who receive dexamethasone, alkylating agents and anthracyclines as first-line induction are at increased risk of death due to infections or toxicity during the first year post-ASCT compared with patients treated with bortezomib or thalidomide. In a single-centre study of newly diagnosed MM patients, the first group (1999-2005) received induction therapy with dexamethasone, alkylating agents and anthracycline before ASCT and bortezomib and/or immunomodulatory drugs (IMDs) at relapse. The second group (2005-2009) received IMDs and/or bortezomib, underwent ASCT in first response and were treated at relapse with the same or alternative agents.

Out of 141 patients, 49 in group 1 and 39 in group 2 underwent ASCT after induction. During the first year post-ASCT, in group 1, 6 patients died due to toxicity or infection, 1 of unrelated cause and 3 relapsed. In group 2, only 1 patient died due to progression. Rates of CR before and overall response rate (ORR) after ASCT were significantly greater in group 2 (6% vs. 16%, P=0.024, and 35% vs. 62%, P=0.009, respectively). The projected OS post-ASCT for group 2 at 4 years was 83%.

Induction and Consolidation Therapy

The phase III trial by the GIMEMA Italian Myeloma Network demonstrated the benefits of a bortezomib/thalidomide/dexamethasone (VTD) induction and consolidation regimen in 480 patients with newly diagnosed MM undergoing double ASCT (Lancet 2010;376:2075-85). “Long-term follow-up of the patients appears to confirm the favourable impact of post-ASCT consolidation with VTD on clinical outcomes,” Dr. Michele Cavo, Seragnoli Institute of Hematology and Medical Oncology, Bologna University School of Medicine, Italy, told delegates. Induction therapy consisted of 21-day cycles with T at 100 mg/day for 14 days then 200 mg/day, D at 320 mg/cycle (TD) or with V at 1.3 mg/m² twice weekly (VTD) followed by double ASCT. By March 20, 2011, 161 TD and 160 VTD patients had received 2 preplanned 35-day cycles of consolidation therapy (T, 100 mg/day; D, 320 mg/cycle alone; V, 1.3 mg/m² once weekly).

Median follow-up from the start of consolidation was 29 months. Significant increases in CR were seen with VTD (61% vs. 46.5%, P=0.012) and in nCR/CR (73% vs. 61%, P=0.020). In the time period before and after consolidation, the overall probability of upgrade from <CR to CR was 31% with VTD vs. 17% with TD (P=0.03). The 3-year PFS estimate from the start of consolidation therapy was significantly greater with VTD (62% vs. 44%, P=0.016) and a 36% relative reduction in risk of progression or death.

This effect was retained in poor-prognosis subgroups, including patients with del(13q) and t(4;14) ± del(17p). VTD but not TD significantly reduced minimal residual disease. Both regimens were well tolerated. However, Dr. Cavo noted, “The role of consolidation therapy needs to be prospectively addressed in the context of randomized trials. This will be one of the 2 major questions addressed by the European Myeloma Network in the upcoming phase III EMN02 trial.”

Overcoming Negative Genetic Prognostic Factors

A subgroup analysis of the HOVON-65/GMMG-HD4 phase III trial showed that the negative impact of the high-risk chromosomal abnormality del(17p13) in MM patients can be significantly improved with ASCT and maintenance therapy with the proteasome inhibitor. “Long-term administration of bortezomib should be considered as a standard of care for these patients,” remarked Dr. Kai Neben, Department of Internal Medicine V, University of Heidelberg, Germany.

In this study, 744 newly diagnosed, symptomatic MM patients were randomized to vincristine/adriamycin/dexamethasone (VinAD) or bortezomib/adriamycin/dexamethasone (VAD). Patients in the VAD treatment arm were significantly less likely to experience disease progression and showed significant improvement in OS (Blood 2010;116(21):Abstract 40).

Using fluorescence in situ hybridization (FISH) analysis in 399 German patients, 4 chromosomal abnormalities— t(4;14), del(13q14), del(17p13) and +1q21—were identified as significantly associated with poor prognosis for PFS and OS. However, for all analyzed chromosome abnormalities, median PFS and 3-year OS in patients on VAD were equal or superior to those on VinAD. “It was striking that patients with del(17p13) did significantly better when they were treated with the bortezomib-based regimen,” Dr. Neben stated. In patients with del(17p13), it improved median PFS from 12 to 26 months (P=0.024) and 3-year OS from 17% to 69% (P=0.028). “Deletion 17p was a very important prognostic factor on the standard treatment arm but not with the bortezomib-based regimen,” Dr. Neben emphasized.

Achieving Molecular Remission

Current evidence indicates that molecular remission (MolR) is an important prognostic factor for long-term survival in MM. The first data on MolR determined by allele-specific-oligonucleotide-real-time quantitative-polymerase chain reaction (ASO-RQ-PCR) in symptomatic patients who received bortezomib-based induction therapy followed by HDT-ASCT were presented here at the EHA. In this ongoing study led by Dr. Raija H. Silvennoinen, Tampere University Hospital, Finland, 36 patients received 4 cycles of VD induction therapy after which 9 were in nCR/CR and 2 in MolR. Three months after ASCT with melphalan 200 mg/m², nCR/CR was reported in 14 of 29 evaluable patients and MolR in 6 (21%). At 6 months after ASCT, 12/26 patients were in nCR/CR and 7 (27%) in MolR. Further studies will be necessary to determine the long-term outcomes associated with MolR.

Emerging Compound

The latest data from PX-171-004, an ongoing phase II study of single-agent therapy with the second-generation proteasome inhibitor carfilzomib in patients with relapsed or refractory MM, show that in bortezomib-naive patients, it is associated with high response rates with minimal neuropathy. Led by Dr. Michael Wang, University of Texas MD Anderson Cancer Center, Houston, the study evaluated carfilzomib in 129 patients who had a median of 2 prior therapeutic regimens including corticosteroids (97%), thalidomide or lenalidomide (92%), an alkylating agent (81%) and/or ASCT (73%). Patients received doses of 20 mg/m² on days 1, 2, 8, 9, 15, 16 q28 days for up to 12 cycles (cohort 1) or a stepped-up dose-escalating regimen of 20 mg/m² for cycle 1 and 27 mg/m² for all subsequent cycles (cohort 2). Significant ORR were reported: 42% and 51% in cohort 1 and 2, respectively. At a median follow-up of 17.5 months for cohort 1, the median time to progression and duration of response were 8.3 and 13.1 months. At a median duration of follow-up of 10.3 months, these had not been reached for cohort 2. The incidence and severity of adverse events was similar between the 2 cohorts. No cumulative toxicities have been noted.

Summary

The novel agents used first-line have been shown to achieve higher nCR. In consolidation and maintenance, bortezomib-based regimens significantly improve PFS and OS even in patients with high-risk chromosomal abnormalities. Through more effective induction, consolidation and maintenance regimens, bortezomib-based treatment strategies achieved improved response and survival rates.