Abstract
The following report will focus on nine important presentations given during the 50th annual meeting of the American Society of Hematology. Interesting new data on the latest drugs, treatment of patients younger or older than 65 years, and new combinations were discussed.
New drugs
Sundar Jagannath (St Vincent’s Comprehensive Cancer Center, NY, USA; abstract 864) presented data on the efficacy of carfilzomib, a new proteasome inhibitor, in patients with relapsed or refractory multiple myeloma.
In this Phase II PX-171-003 trial, 46 patients were treated. They received a median number of five lines of therapy prior to carfilzomib administration. Carfilzomib was infused intravenously 20 mg/day on days 1–2, 8–9 and 15–16, in 28-day cycles. Overall, 26% of the patients experienced either partial responses (PRs) or minimal responses with carfilzomib monotherapy. The toxicity was acceptable, with 30% experiencing grade 3/4 anemia, 25% experiencing grade 3/4 thrombocytopenia and 5% experiencing grade 3/4 neutropenia. Interestingly, no cases of neuropathy were observed.
Ravi Vij (Washington University School of Medicine, MO, USA; abstract 865) also presented results of another Phase II trial of carfilzomib (PX-171-004) in patients with relapsed/refractory multiple myeloma.
Patients received a higher dose of carfilzomib (20 mg/m2) according to the same schedule on days 1–2, 8–9 and 15–16, in 28-day cycles. A total of 14 out of 31 patients were bortezomib-naive at the time of therapy. The overall response rate was 35%; 18% in patients previously treated with bortezomib and 57% in bortezomib-naive patients. One case of tumor lysis was reported. No cases of neuropathy were observed.
These two presentations confirmed the interest of this new proteasome inhibitor in the treatment of relapsed/refractory multiple myeloma.
Martha Q Lacy (Mayo Clinic, MN, USA; abstract 866) reported the efficacy of the combination of polamidomide plus low-dose dexamethasone in patients with relapsed and refractory multiple myeloma. Polamidomide is a novel immunomodulatory drug, available orally, with higher in vitro anti-inflammatory, antiangiogenic and immunomodulatory effects, compared with thalidomide. A Phase I trial indicated that 2 mg/day was the maximal tolerated dose.
In this Phase II trial, 60 patients were treated with pomalidomide 2 mg/day orally continuously and dexamethasone 40 mg/day on days 1, 8, 15 and 22. Prophylactic anti-thrombotic administration of aspirin was given. The overall response rate was 58%, with 25% with complete response (CR) or very good partial response (VGPR). The response rate was 29% in PR to lenalidomide. Grade 3 and 4 neutropenia was observed in 32%, and grade 3/4 fatigue in 28% of the cases, respectively. Overall, this combination is very promising.
Treatment of patients older than 65 years of age or not eligible for high-dose therapy
Jesus F San Miguel (Hospital Universitario Salamanca, Salamanca, Spain; abstract 650) presented the updated results of the Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone (VISTA) trial comparing melphalan–prednisone (MP) with melphalan–prednisone–bortezomib (MPV) in patients who are older than 65 years of age or are not eligible for high-dose therapy. With a median follow-up of 26 months, the median time-to-progression was 24 months in the MPV arm versus 15.5 months in the MP arm. This was translated into a clear survival advantage of treatment with the MPV combination, with a 72% probability of survival at 3 years versus 59% in the MP arm. The superiority of MPV over MP was observed in all subgroups of patients, that is, patients older or younger than 75 years of age, patients with low or high β-2-microglobulin levels, patients with an injury severity score of 1, 2 or 3, or patients with creatinine clearance of less than or above 60 ml/min. Although the number of patients studied was relatively small, it seemed that the MPV combination had a similar efficacy in patients with poor cytogenetics, such as t(4;14), t(14;16) or del 17 p, compared with others. These results confirmed that MPV can be considered as a standard of care in the frontline treatment of patients with de novo multiple myeloma who are older than 65 years of age.
Pier Wijermans (Haga Hospital, The Hague, The Netherlands; abstract 649) reported the result of the HOVON49 trial comparing MP with melphalan–prednisone–thalidomide (MPT) in elderly patients. A total of 344 patients were included in this trial comparing melphalan 0.25 mg/kg/day for 5 days plus prednisone 1 mg/kg/day for 5 days every 4 weeks, with or without thalidomide 200 mg/day. The overall response rate was clearly in favor of the MPT arm: 62 versus 47%, including 29% CR or VGPR versus 9%. The event-free survival (EFS) was also clearly superior in the MPT arm but this did not translate into a survival benefit, since the overall survival rate was 76% in the MPT arm versus 81% in the MP arm at 1 year, 67% in the MPT arm versus 60% in the MP arm at 2 years, and 36% in the MPT arm versus 25% in the MP arm at 4 years. This lack of survival advantage was attributed to a higher toxicity of the MPT combination, associated with a high rate of treatment discontinuation. These results were not surprising, since more than 50% of the patients included in the trial were older than 75 years of age and a high number of patients presented with poor performance status at the time of diagnosis.
These results are different from those obtained by the French Intergroupe Francophone du Myélome group, with a clear survival advantage of the MPT combination, even in very elderly patients, indicating that doses of MPT need to be adjusted according to age and performance status, with reduced doses of both melphalan and thalidomide in patients over 75 years of age.
Antonio Palumbo (Divisione di Ematologia dell’Universita di Torino, Torino, Italy; abstract 159) reported the results of a Phase II trial in patients with de novo multiple myeloma aged between 65 and 75 years. Induction therapy consisted of four cycles of bortezomib–pegylated doxorubicin–dexamethasone (PAD) PS341, followed by autologous stem cell harvest after cyclophosphamide mobilization, double autologous stem cell transplant (ASCT) prepared by melphalan 100 mg/m2, consolidation using four monthly cycles of lenalidomide 25 mg/day, day 1–21 plus prednisone, followed by maintenance treatment using lenalidomide 10 mg/day on days 1–21, every 28 days.
A total of 102 patients, with a median age of 67 years, were included in the trial. The response rates were impressive: the CR and VGPR rate was 60% after induction treatment, 87% (including 43% CR) after the double ASCT and 95% (including 73% CR) at the end of therapy. The follow-up was short but the projected overall survival was 84% at 2 years and the projected progression-free survival (PFS) rate was 78% at 2 years. The toxicities were manageable, and the results compared favorably with those of historical controls treated with bortezomib–dexamethasone followed by melphalan 200 mg or vincristine–doxorubicin–dexamethasone (VAD) followed by melphalan 200 mg.
These provocative results outline the feasibility of ASCT using reduced doses of melphalan and incorporation of novel agents, both as part of induction treatment and as consolidation/maintenance treatment. Of note, the median age was 67 years in this Phase II trial.
Treatment of multiple myeloma in patients younger than 65 years of age
Michele Cavo (Seragnoli Institute of Hematology, Bologna, Italy; abstract 158) presented the results of the GIMEMA 268650138-MMY-3006 trial, which prospectively compared upfront velcade–thalidomide–dexamethasone (VTD) with thalidomide–dexamethasone (TD) in newly diagnosed multiple myeloma.
Patients were randomized upfront to receive either VTD or TD, followed by a double ASCT and consolidation therapy consisting of either VTD or TD, followed by maintenance treatment with dexamethasone alone. The primary end point of the study was the CR and near-CR rate with VTD versus TD as induction therapy, and secondary end points were CR and near-CR (nCR) after ASCT and consolidation therapy in VTD and TD arms, while clinical outcomes were in terms of PFS and overall survival and toxicity. In total, 460 patients were randomized: 226 in the VTD arm and 234 in the TD arm. Response to induction therapy was evaluated according to European Group for Blood and Marrow Transplant criteria (with added nCR and VGPR categories). Response rates were clearly in favor of the VTD combination, with a CR and nCR rate of 32 versus 12%, a VGPR rate of at least 62 versus 29% and partial response rates of at least 94 versus 79%, respectively. The superiority of VTD over VD was also observed in poor cytogenetic subgroups, such as chromosome 13 deletion, t(4;14) and del17p. This superiority after induction treatment did translate into a better response rate after the first ASCT, with a CR plus nCR rate of 55% in the VTD arm versus 32% in the TD arm after melphalan 20 mg/m2, and a VGPR rate of 76 versus 58%. Grade 3/4 nonhematologic adverse events during induction therapy were higher in the VTD arm, with 9% peripheral neuropathy versus 2% in the TD arm, and 8% skin rash versus 1% in the TD arm. The deep vein thrombosis rate was similar in the two arms of the trial. With a median follow-up of 15 months, the 2-year PFS rate was 90% in the VTD arm versus 80% in the TD arm (p = 0.009), without any difference for overall survival (96% in the VTD arm vs 91% in the TD arm; p = 0.2, due to the short follow-up).
The conclusions of this trial were the following: VTD as induction therapy significantly increased the CR and VGPR rate up to values seen previously with single or double ASCT preceded by conventional treatments without new agents. The superiority of VTD was maintained across all subgroups, including patients with poor cytogenetic abnormalities; the benefit with VTD versus TD translated into significantly higher response rates following ASCT and significantly improved PFS.
This study showed that effective combinations of novel induction agents can have a remarkable impact on pre- and post-ASCT outcomes.
Pieter Sonneveld (HOVON and Erasmus MC, Rotterdam, The Netherlands; abstract 653) reported the preliminary results of a randomized Phase III trial HOVON65-GMMG-HD4 comparing bortezomib–adriamycin–dexamethasone (BAD) versus VAD as part of induction treatment prior to ASCT in patients younger than 65 years of age. After ASCT, patients received a maintenance treatment with thalidomide 50 mg/day when they were included in the VAD arm, or bortezomib 1.3 mg/m2 intravenous infusion every 2 weeks when they were randomized in the PAD arm, during a 2-year period.
Overall, 825 patients were randomized within 3 years. Results were presented on the first 300 patients included (150 per arm). The two groups of patients were identical regarding disease characteristics at diagnosis. During induction treatment, 29% of patients in the PAD arm presented with neuropathy grade 2–4 versus 23% in the VAD arm. The overall grade 3 and grade 4 adverse events were identical in both arms of the trial. A total of 54% of the patients experienced infections in the PAD arm versus 42% in the VAD arm. Overall, 88% of the patients in the VAD arm were able to receive a first ASCT versus 87% in the PAD arm. The response rate was higher with the PAD combination, with at least 42% VGPR after induction versus 15%, and at least 83% PR versus 59% in the VAD arm. After the first ASCT prepared by melphalan 200 mg/m2, the PR rate was 93% in the PAD plus melphalan 200 mg versus 80% in the VAD plus melphalan 200 mg arm.
The follow-up and the number of patients evaluated is still too short to draw definite conclusions, however, the combination of PAD plus ASCT seems to be superior to the combination of VAD and ASCT in terms of response. The impact of the maintenance treatment in this study will be evaluated with a longer follow-up.
New combination
Paul Richardson (Dana-Farber Cancer Institute, MA, USA; abstract 92) presented the updated results of a Phase I–II study of the combination of lenalidomide, bortezomib and dexamethasone in patients with newly diagnosed multiple myeloma.
The Phase I study revealed that the dose schedule of the combination was the following: lenalidomide 25 mg/day for 14 days, bortezomib 1.3 mg/m2 on day 1, 4, 8 and 11, and dexamethasone 20 mg/day on days 1–2, 4–5, 8–9 and 11–12, up to eight 21-day cycles.
Overall, 65 patients were evaluable for both efficacy and toxicity. The overall response rate, at least PR, was 100%, with at least VGPR in 74% and CR/nCR in 44% of the patients. In total, 70% of the patients completed eight cycles, and some of them stayed on treatment for up to 35 cycles. The percentage of patients proceeding to ASCT was 23%. Stem cell collection has proceeded successfully in 21 out of 23 patients with a median of 6.2 × 106 CD34+ cells after a median of six cycles of therapy. The combination was well tolerated and only two patients experienced grade 3 neuropathy. After a median follow-up of 8 months, the median PFS and overall survival have not yet been reached.
These preliminary results indicate that this velcade–revlimid–dexamethasone combination is effective with 100% PR and well-tolerated. Longer follow-up is still require in order to evaluate PFS.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.