Very Good Partial Response Rate Research Articles

Combined Treatment of Bortezomib, Continuous Low-Dose Cyclophosphamide and Dexamethasone Followed By One Year of Maintenance Treatment for Refractory or Relapsed Multiple Myeloma Patients: A Prospective Phase II Study

Introduction: Combination therapy for longer periods but at low dose, also called metronomic scheduling, might be an effective manner to treat patients with relapsing myeloma. In particular if the used agents attack the malignant clone in an alternative manner. Therefore we used the combination of bortezomib, dexametasone and daily low dose of oral cyclophosphamide as an induction regimen followed by one year of maintenance therapy consisting of bortezomib and cyclophosphamide.Methods: Relapsing myeloma patients, bortezomib naïve, were treated with three cycles of 1.3 mg/m2 bortezomib at day 1, 4, 8 and 11, cyclophosphamide 50 mg daily, and 20 mg dexamethasone at day 1, 2, 4, 5, 8, 9, 11 and 12 followed by three cycles of bortezomib 1.6 mg/m2 (day 1, 8, 15 and 2), cyclophosphamide (50 mg) daily and dexamethasone (20 mg) at day 1, 2, 8, 9, 15, 16, 22 and 23. Maintenance therapy consisting of bortezomib 1.3 mg/m2 every two weeks and daily dose of 50 mg cyclophosphamide for one year was applied to patients in partial or complete remission. Primary endpoints were toxicity during re-induction and maintenance therapy. Secondary endpoints were response to treatment and progression free and overall survival.Results: 59 patients with relapsing multiple myeloma were included of whom 69% were in first relapse (Table 1). The upfront treatment consisted mainly of thalidomide-based and vincristine-based chemotherapy and 40% of the patients have been treated with an autologous stem cell transplantation. All 6 cycles of induction chemotherapy could be given in 49% of the patients. Premature discontinuation before starting maintenance therapy was due to toxicity (31%), progressive disease (7%), death (7%) or other reasons (6%). Myelosuppression was the most common side effect with WHO grade 3-4 in 31% of the patients. Neuropathy grade 3-4 was observed in 16% of patients, partially due to the fact that bortezomib was given intravenously during the first 2 yrs of the protocol which included 76% of the patients. Maintenance therapy was started in 47% of the patients with a median duration of 7.3 months (range 0.36.-13.4). Grade 3-4 toxicity was observed in 25% of the patients including infections (n=3) and myelosuppression (n=3) which did not resulted in discontinuation of therapy. Median follow up time was 29 months with an overall response of 62%, and a very good partial response (VGPR), complete remission (CR) in 21% and 7% of the patients respectively. During the maintenance phase an improvement in responsiveness was observed in 25% of the patients. The CR rate increased with 9% to a total of 16%. VGPR rate was 20% and 16% of the patient had a PR. At end of the maintenance therapy 50% of patients started with maintenance had stable disease. The median progression free survival (PFS) was 17.2 months (range 0.13 – 43.5) as depicted in figure 1. and the median overall survival was 21.6 months (range 0.46-54.4, figure 2). During follow up 33 % of the patients died due to progression of MM.Conclusion: The present study demonstrates that combination therapy with bortezomib, continuous low dose cyclophosphamide and dexamethasone is an effective and manageable regimen. Adding a year of maintenance was feasible with limited side effects and an increase in CR rate.Table 1:patient characteristicsPatients (%)Age, mean (min,max)69 (46-86)SexMale56Female44Relapse numberFirst relapse75Second relapse20Third relapse5Performance status06512925M-protein heavy chainIgA18IgG65Light chain disease18PolyneuropathyNo61Yes39 [Display omitted] [Display omitted] DisclosuresWaal de:Jansen Cilag: Research Funding. Munck de:Jansen Cilag: Research Funding. Woolthuis:Jansen Cilag: Research Funding. velden Van Der:Jansen Cilag: Research Funding. Tromp:Jansen Cilag: Research Funding. Hoogendoorn:Jansen Cilag: Research Funding. Vellenga:Jansen Cilag: Research Funding. Hovenga:Jansen Cilag: Research Funding.

Superior Efficacy of VTD over VCD As Induction Therapy for Autotransplantation-Eligible, Newly Diagnosed, Myeloma Patients

Superior Efficacy of VTD over VCD As Induction Therapy for Autotransplantation-Eligible, Newly Diagnosed, Myeloma Patients

The role of transplant in multiple myeloma.

Over the past decades significant therapeutic advances have been made in the treatment of multiple myeloma (MM). A population-based study of 45,595 patients showed substantial incremental increases in myeloma-specific survival in patients younger than 80 years treated between 1973 and 2009. Depth of response to therapy has long been associated with improved long-term outcomes. Autologous stem cell transplantation (ASCT) was previously the only modality capable of inducing a very good partial response (VGPR) or complete response in a substantial proportion of patients. The introduction of 2 classes of novel agents, immunomodulatory drugs and proteasome inhibitors, resulted in induction regimens that achieve VGPR rates exceeding 60% even before transplant, thus challenging the role of ASCT. Allogeneic stem cell transplantation (allo-SCT) has also been tested in patients with MM; however, its current role remains undefined given the high rates of transplant-related mortality and chronic graft-versus-host disease. Posttransplant consolidation and maintenance strategies have further improved progression-free and overall survivals. This article discusses the current roles of ASCT, allo-SCT, and consolidation and maintenance therapies in the management of MM.

Autologous Stem Cell Transplantation for Multiple Myeloma in the Era of Novel Agents

Autologous Stem Cell Transplantation for Multiple Myeloma in the Era of Novel Agents

Maintenance Therapy With Lenalidomide Significantly Improved Survival Of Yong Newly Diagnosed Multiple Myeloma Patients

▪ BackgroundHigh-dose chemotherapy (HDT) with autologous stem cell transplant improves outcome of multiple myeloma (MM) patients in comparison to conventional chemotherapy. The incorporation of new drugs into induction, consolidation and maintenance therapy is changing the treatment paradigm and is questioning the role of HDT in newly diagnosed MM (NDMM) patients <65 years. Previous finding have been presented (Boccadoro, ASCO 2013) and this analysis provides a longer follow-up. AimsTo compare in a prospective randomized trial melphalan-prednisone-lenalidomide (MPR) with tandem melphalan (200 mg/m2) (MEL200) both followed by maintenance with lenalidomide or no maintenance in NDMM patients. MethodsA 2x2 factorial randomized trial was designed. The induction treatment consisted of four 28-day cycles of lenalidomide (25 mg d 1-21) and low-dose dexamethasone (40 mg d 1,8,15,22) (Rd). As consolidation, patients were randomized to MPR (N=202) [six 28-day cycles of melphalan (0.18 mg/k g d 1-4), prednisone (2 mg/kg d 1-4) and lenalidomide (10 mg d 1-21)] or MEL200 (N=200)[tandem melphalan 200 mg/m2 with stem-cell support]. Patients were further randomized, within each group, to receive lenalidomide maintenance (10 mg, days 1-21, N=198) or no maintenance (N=204). Primary study endpoint was progression free survival (PFS). The secondary study endpoints included response rates, safety and overall survival (OS). Data were analyzed in the intent-to-treat (ITT) population. ResultsFrom November 2007 to July 2009, 402 patients with NDMM <65 years of age were enrolled. All patients were stratified according to International Staging System (ISS) and age. Patient characteristics were well balanced in all groups. In the MPR group, the Very Good Partial Response (VGPR) rate was 50% with 13% of Complete Response (CR) while the VGPR rate was 52% including 19% of CR in the MEL200 group. In the MPR group the CR rate improved from 13% after consolidation to 17% after maintenance. In the MEL200 group the CR rate improved from 19% after consolidation to 25% after maintenance.After a median follow-up of 48 months, the median PFS was 24.2 months in MPR group and 38.6 months in MEL200 group ( P< 0.0001).A multivariate analysis confirms the PFS benefit associated with MEL200 across all subgroups of patients defined by stratification factors and baseline characteristics.The 5-year OS rate was similar between MPR (62%) and MEL200 (71%; P= 0.27). In a landmark analysis, lenalidomide maintenance significantly extended PFS from the start of maintenance (median 42,7 months) compared with no maintenance (median 17.5 months; P<.0001). The 4-year OS rate from the start of maintenance was higher in patients who received lenalidomide maintenance (80%) compared with patients who did not (62%; P= 0,01). No significant interaction was detected between MPR/MEL200 (P=0.704) and maintenance/observation (P=0.984) effects.During consolidation, the incidence of grade 3-4 adverse events (AEs) between MPR and MEL200 were as follow: neutropenia (50% vs. 90%), thrombocytopenia (8% vs. 89%), infections (1% vs. 15%) and gastrointestinal (0% vs. 18%), with complications being higher with MEL200.During the maintenance phase, grade 3-4 hematologic AEs were reported in 17% of patients receiving lenalidomide (16% neutropenia). For individual group comparisons during maintenance, grade 3-4 hematologic AEs were observed in 20% of patients receiving MPR plus lenalidomide maintenance compared with 15% receiving MEL200 plus lenalidomide maintenance. Second primary malignancies were observed in 11 patients (3%), and were mainly solid tumors. Four solid tumors were observed in the MEL200 group and one in the MPR group in the maintenance arm, while three solid tumors were observed in the MEL200 group and three in the MPR group in no maintenance arm. ConclusionThe administration of MPR was significantly inferior to MEL200 in terms of PFS. Toxicities were significantly higher in MEL200 group, but manageable. OS is similar between MPR and MEL200. Lenalidomide maintenance significantly reduced the risk of progression and of death independently from the previous treatment. Disclosures:Gay:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavallo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Caravita:Celgene: Honoraria, Research Funding. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Palumbo:Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria.

Car-Bird [Carfilzomib, Clarithromycin(Biaxin(R)), Lenalidomide/(Revlimid(R)), Dexamethasone) For Newly-Diagnosed Multiple Myeloma

BackgroundCarfilzomib (Cfz) synergizes with lenalidomide and dexamethasone (Len-dex) to provide impressive response rates as upfront treatment of multiple myeloma (MM) (Jakubowiak et al 2012). The addition of clarithromycin to Len-dex has shown superior time to progression compared to Len-dex alone (Gay et al 2010). We hypothesized that sequential treatment with Cfz-dex and BiRD would lead to enhanced efficacy, response duration, and tolerability. We thus tested a sequential approach of upfront carfilzomib / dexamethasone, consolidation with BiRd, and lenalidomide maintenance to evaluate overall response and safety as first line therapy for MM. MethodsTwenty-four patients (pts) with symptomatic untreated MM were enrolled in a single institution study to evaluate the efficacy and tolerability of Car-BiRd. Car-BiRd therapy is: Cfz IV over 30 minutes on Days 1, 2, 8, 9, 15, 16 of a 28-day cycle at a dose of 20mg/m2 on days 1, 2 of the 1st cycle only and 45mg/m2 for each successive dose thereafter and dex 40mg on D1, 8, 15, 22. Cfz-dex was continued until plateau in disease response defined as unchanged M-protein for 2 cycles. Elective autologous stem cell collection was then performed per physician and patient discretion and consolidation with BiRd initiated. Transplant ineligible pts proceeded directly to BiRd. BiRd is: Clarithromycin 500mg BID, lenalidomide 25mg daily on D1-21, and dex 40mg daily D1, 8, 15, 22 of 28-day cycle. Therapy was continued until a 2nd plateau in disease response after which lenalidomide maintenance at a dose of 10mg daily D1-21 of 28 day cycle was continued until disease progression or intolerability. Results24 pts have currently been enrolled; 23 have completed at least 1 cycle of therapy and were evaluable for response. Sixteen pts (67%) harbored high-risk cytogenetics, as defined by the presence of one or more of the following on iFISH: del 17p, gain 1q, del 1p, t(4;14), t(14;16), or complex karyotypic abnormalities. Median study follow-up was 30.8 weeks (range 4.5-62.2). Response to the Car-BiRD regimen was: overall response rate (ORR) 87%, stringent complete response (sCR) 13%, very good partial response (VGPR) 48%, partial response (PR) 26%, stable disease (SD) 13%. Maximum response to the Cfz-dex induction was: ORR 87%, sCR 9%, VGPR 39%, PR 35%, SD 13%. Median time to PR and maximum response with Cfz-dex was 2 cycles (range 1-2) and 4 cycles (range 1-5) respectively. Median M-spike percentage decrease with Cfz-dex was 92% (range 13-100%). Twelve pts thereafter received BiRD consolidation with 5 pts (41%) further decreasing the M-spike by a median of 8% (range 1-45%). A median of 3 cycles (range 2-7) of BiRD was given until a 2nd response plateau was achieved. Seven pts subsequently received lenalidomide and all have maintained their response after a median of 5 cycles (range 1-8) of follow-up.Seven pts (30%) have come off study, 2 (8%) secondary to disease progression (1 during Car-Dex and 1 during BiRD) and 5 pts (22%) due to toxicity (2 pts due to Grade III renal failure, both attributable to Cfz, and 2 pts due to Grade III CHF during Cfz-Dex, 1 attributable to Cfz; 1 pt with Grade III Thromboembolic event during BiRD, attributable to Len-dex). DiscussionThis is the first prospective study evaluating the response to induction Cfz/Dex in treatment-naïve MM. Cfz/Dex therapy appears safe and effective in newly diagnosed myeloma patients. Responses deepen with subsequent IMiD(R)-based consolidation and maintenance. Toxicities due to each component of the regimen were manageable. The ORR of 87% and rate of VGPR or better of 61% in group with a high percentage of unfavorable cytogenetics compares favorably to similar studies using 1st generation proteasome inhibitor combinations, and may continue to improve with longer study follow-up. Disclosures:Mark:Onyx: Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Carfilzomib is not approved for front line use in myeloma. Rossi:Celgene: Speakers Bureau. Zafar:Onyx: Speakers Bureau; Millennium: Speakers Bureau; Celgene: Speakers Bureau. Pekle:Millennium: Speakers Bureau; Celgene: Speakers Bureau. Niesvizky:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium: The Takeda Oncology Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Low Level Of NF-Kb Activity Is Associated With Higher Response Rate To Bortezomib-Based Induction Therapy In Patients With Newly Diagnosed Multiple Myeloma

PurposeActivation of canonical and noncanonical NF-kB pathways plays a key role in multiple myeloma (MM) pathogenesis. Recent studies have shown that constitutive activation of NF-kB pathways is present in ∼15-20 % of newly diagnosed MM patients. Bortezomib is a potent selective inhibitor of NF-kB activation; however its cytotoxicity is mainly due to inhibition of the noncanonical NF-kB pathway. We have previously shown that the achievement of very good partial response (VGPR) after induction therapy prior to frontline autologous stem cell transplantation (ASCT) was a favourable prognostic factor for progression-free survival (Moreau et al, Blood 2011;117:3041-3044). Our aim was to correlate NF-kB activity, reflected by a gene signature of well-known NF-kB targets, with the response rate achieved with a bortezomib-based induction regimen prior to high-dose therapy and ASCT performed as part of frontline treatment in patients with symptomatic multiple myeloma. Patients and methodsOne hundred and ninety-nine patients with symptomatic MM were enrolled in the prospective randomized IFM2007-02 trial comparing 4 cycles of bortezomib-dexamethasone (VD) induction therapy versus 4 cycles of the triplet combination bortezomib-thalidomide-dexamethasone (VTD) prior to ASCT. Among these 199 patients, 114 included in the present study were available for gene expression profile testing and therefore analysed for NF-kB activity. For each patient, the NF-kB(10) index, a reliable measure of NF-kB activity in MM tumor cells (Demchenko et al, Blood 2010; 115: 3541-3552) was calculated. NF-kB(10) index is based on a transcription signature of 10 genes: IL2RG, NFKB2,TNFAIP3, NFKBIE, NFKBIA, RELB, CD74, PLEK, MALT1 and WNT10. Gene expression signature was obtained from Affymetrix Exon1.0 normalized data. A high level of NF-kB activity was defined by the NF-kB(10) index found in a cohort of 20 MM patients with biallelic deletions, identified by using Affymetrix SNP6.0 data, that inactivate negative regulators (cIAP1/2) of NF-kB pathways. Response to induction therapy was evaluated according to the IMWG criteria. ResultsResponses to induction therapy are shown in Table 1. In this subgroup analysis, the CR plus VGPR rates were not statistically different in both arms of the trial: 24 / 54 (44%) in the VTD arm versus 21 / 60 (35%) in the VD arm, P = .35. We subsequently analyzed the correlation between NF-kB activity and response in the whole cohort of 114 patients regardless of induction treatment.Table 1Table patient's responseVD (n = 60)VTD (n = 54)CR1414VGPR710PR3023stable63progression34We found that the level of NF-kB activity, based NF-kB(10) index, tested as a continuous variable, was strongly correlated with the quality of response, i.e. VGPR or better (P = .007 Wilcoxon test). We also investigated the cut-off value of NF-kB(10) index that could impact the response rate. Since high NF-kB(10) index was found in MM cells with known NF-kB mutations, we calculated the NF-kB(10) index in a control cohort of MM patients deleted in cIAP1/2. Patients of IFM2007-02 trial with a NF-kB(10) index (< 70.5) lower than the index of the control cohort were assigned to the low NF-kB activity group (50/114, 44%); therefore the remaining cases (64/114, 56%) presented with a high NF-kB activity. We found that patients with a reduced NF-kB(10) index displayed a significantly higher response rate (27/50; 54% vs 18/64; 28%, P= .007), as shown in Figure 1, indicating that the vast majority of patients with high NF-kB were not able to achieve at least VGPR. [Display omitted] ConclusionOur results show that a low level NF-kB activity is associated with a higher response rate (>VGPR) to bortezomib-based induction regimen. Patients with low NF-kB(10) index represent 44% of the cohort studied. Since NK-kB activity is related to both canonical and noncanonical pathways, and knowing that bortezomib-induced cytotoxicity is mostly due to the inhibition of the noncanonical pathway only, our data strongly suggest that bortezomib should be combined with drug also targeting the canonical pathway in order to induce a high response rate in patients with increased NF-kB activity, as shown in preclinical studies (Fabre et al, Clin Cancer Res. 2012;18:4669-4681. Disclosures:Moreau:CELGENE: Honoraria, Speakers Bureau; JANSSEN: Honoraria, Speakers Bureau. Off Label Use: FRONTLINE TREATMENT WITH CARFIZOMIB. Attal:CELGENE: Honoraria, Speakers Bureau; JANSSEN: Honoraria, Speakers Bureau. Facon:Janssen and Celgene: Speakers Bureau; Millennium, Onyx, Novartis, BMS, Amgen: Membership on an entity's Board of Directors or advisory committees.

ClaPD (Clarithromycin, Pomalidomide, Dexamethasone) Therapy in Relapsed or Refractory Multiple Myeloma

Abstract 77 Background:The addition of clarithromycin has been reported to enhance anti-myeloma activity of lenalidomide+dexamethasone in the upfront treatment of multiple myeloma (MM). Pomalidomide is a distinct IMiD® immunomodulatory agent with a significant response rate in subjects with relapsed or refractory MM (RRMM), including those with prior lenalidomide treatment. We have shown initial results that clarithromycin may similarly enhance the activity of pomalidomide + dexamethasone in patients with RRMM after prior lenalidomide therapy (Rossi et al, ASCO 2012). We now report updated results from a phase 2 trial of large group of patients treated with ClaPD in RRMM. Methods:One hundred patients with heavily pretreated RRMM were enrolled into a single-institution study to investigate the effectiveness and tolerability of ClaPD. Eligible subjects had at least 3 prior lines of therapy, one line of which must have included lenalidomide. ClaPD is clarithromycin 500mg twice daily; pomalidomide 4mg for days 1–21 of a 28-day cycle, and dexamethasone 40mg on days 1,8,15,22. All subjects had thromboprophylaxis with 81mg aspirin daily. Disease response evaluation was performed monthly with immunoelectrophoresis and free light chain analysis; bone marrow biopsy with skeletal imaging was used to confirm MM progression or complete response (CR). Treatment was continued as tolerated by the patient until disease progression. Results:Ninety-seven patients had completed at least 1 cycle of ClaPD and were eligible for disease response and safety analysis. Patients had undergone a median of 5 (range 3–15) prior lines of therapy. The proportion of patients who were refractory to lenalidomide, refractory to bortezomib, and double (lenalidomide +bortezomib) refractory were 73%, 70%, and 64% respectively. The median number of ClaPD cycles received was 4 (range 1–23). Response to ClaPD was progressive disease (PD): 9.3%, stable disease (SD): 32%, minimal response (MR): 5.2%, partial response (PR): 32%, very good partial response (VGPR): 17.5%, stringent complete remission (sCR): 4.1%, giving an overall response rate (ORR, ≥PR) of 53.6% and a ≥VGPR rate of 21.6%. Clinical benefit (≥SD) was achieved in 90.7%. Median time to PR and maximum response was 1 (range 1–7) and 2 (range 1–14) cycles, respectively. After a mean follow up time of 10.1 months, 41 patients (42%) remain on study free from disease progression, with a median progression free survival of 8.2 months (95% CI: 5.1, 10.3). Median overall survival has not been reached with 72 patients (74%) alive at last follow-up. The most common grade 3 and 4 toxicities included anemia (25%), neutropenia (40%), hyperglycemia (11%), and fatigue (6%). Febrile neutropenia was uncommon at 2%. There were 4 cases of lower extremity venous thrombosis (4.1%, 1 at grade 1, 3 at grade 2) and no instances of pulmonary embolism. There was no treatment related mortality. Conclusions:ClaPD is a highly effective regimen for heavily treated RRMM that has progressed after prior treatments. Response to ClaPD is rapid and sustained at > 8 months in the majority of subjects. The tolerability profile is comparable to lenalidomide and incidence of thromboembolic events was low with low-dose aspirin prophylaxis. These data support the use of pomalidomide therapy in RRMM that has progressed after lenalidomide. Disclosures:Mark:Celgene Corp: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium Inc.: Speakers Bureau. Off Label Use: Pomalidomide is not indicated to treat multiple myeloma. This drug is a next-generation immunomodulatory agent. We are investigating its activity and safety for use in relapsed or refractory myeloma. Zafar:Celgene Corp: Speakers Bureau. Pekle:Celgene Corp: Speakers Bureau. Coleman:Celgene Corp: Speakers Bureau. Niesvizky:Onyx, Millenium, Celgene. Speakers bureau: Millenium and Celgene: Consultancy, Research Funding.

Treatment patterns and outcomes in elderly patients with multiple myeloma

Treatment patterns and outcomes in elderly patients with multiple myeloma

Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma

AbstractThe Intergroupe Francophone du Myelome conducted a randomized trial to compare bortezomib-dexamethasone (VD) as induction before high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) to a combination consisting of reduced doses of bortezomib and thalidomide plus dexamethasone (vtD) in patients with multiple myeloma. Overall, a total of 199 patients were centrally randomly assigned to receive VD or vtD. After 4 cycles, the complete response (CR) rate was the same in both groups (13% in the vtD arm, 12% in the VD arm, P = .74). However, the CR plus very good partial response (VGPR) rate was significantly higher in the vtD arm (49% vs 36%, P = .05). After ASCT, the CR plus VGPR rate was significantly higher in the vtD arm (74% vs 58%, P = .02). The reduced doses of bortezomib and thalidomide translated into a reduced incidence of peripheral neuropathy (PN): grade ≥ 2 PN were reported in 34% in the VD arm versus 14% in the vtD arm (P = .001). vtD, including reduced doses of bortezomib and thalidomide, yields higher VGPR rates compared with VD and can be considered a new effective triplet combination before HDT/ASCT. This study was registered with www.clinicaltrials.gov as #NCT00910897 and EudraCT as #2007-005204-40.

Bortezomib Plus Dexamethasone As Induction Treatment Followed by Autologous Peripheral Blood Stem Cell Transplantation in Patients with Multiple Myeloma: A Study From India

Abstract 4584 Background and Objectives –Multiple myeloma (MM) is an incurable hematological malignancy, afflicting 25000 patients each year in India. Complete remission in myeloma is a surrogate marker for improved survival. The objective of induction regimen, using novel agents such a bortezomib, and Autologous Peripheral Blood Stem Cell Transplantation (APBSCT) is to increase the number of patients achieving CR. Here, we report a retrospective evaluation of the efficacy and response rates of induction with Bortezomib (Velcade) plus Dexamethasone (VD Regimen) followed by APBSCT and its effect on stem cell collection and final outcome of the transplant. Methods –Ten patients with symptomatic MM who had received VD induction before stem cell collection were evaluated. VD Induction comprised of Bortezomib (1.3 mg/m2) and Dexamethasone (40 mg) administered on days 1, 4, 8, 11 for four 21-day cycles.Peripheral blood stem cell collection technique involved administration of granulocyte stimulating factor (G-CSF); 300 mg/kg administered twice daily for 5 days. Adequate number of stem cells was collected in nine patients by a single harvest. One patient required apharesis twice for adequate stem cell collection. These cells were cryo-preserved. High dose Melphalan (200 mg/m2) was given followed by stem cell transfusion. Results –The median CD34-positive stem cell count was 5.6 × 106/kg. All the patients engrafted post transplant. The median time for engraftment i.e. Absolute Neutrophil Count (ANC) > 500/mL was 10 days and Platelet Count > 50000/mL was 16 days. The median length of hospital stay was 21 days. They were successfully managed for fever and infections with antibiotics, antifungals and supportive treatment. Irradiated blood (median - 4 units) and platelet apharesis (median – 3 units) were given.Response was assessed according to International Myeloma Working Group uniform response criteria. After induction with VD protocol, the overall response rate (ORR) was 90%. 2 patients (20%) had a complete response (CR), 7 patients (70%) had very good partial response (VGPR) and 1 patient (10%) had progressive disease.Post – APBSCT, the patient with progressive disease achieved VGPR and 6 out of 7 patients (85.7%) with VGPR achieved CR making the total responses as 8 CRs and 2 VGPRs. Thus, ORR was 100%, including 80% CR rate and 20% VGPR rate.All patients were put on maintenance therapy, 6 patients were on thalidomide (50 mg/day) and 4 patients received lenalidomide (10 mg/day) therapy.In the analysis, the median progression-free survival (PFS) was not reached at 22 months. The median overall survival (OS) was not reached after a median follow-up of 25 months, and the 2-year OS rate was 70%. Three patients (30%) had a relapse post-APBSCT, after 5 months, 9 months and 18 months respectively. Two patients (20%) expired, one due to myeloma and the other due to unrelated cause. All three patients with renal insufficiency experienced improvement in renal function and did not require dialysis post-APBSCT. Two patients (20%) developed neuropathy and two patients (20%) developed Herpes Zoster infection due to bortezomib therapy. Conclusions –The induction regimen of bortezomib plus dexamethasone is effective and well tolerated in symptomatic myeloma patients. It significantly improves post-induction and post-transplantation CR and VGPR rates and does not affect stem cell mobilization and collection procedure. Disclosures:No relevant conflicts of interest to declare.

ClaPD (Clarithromycin/[Biaxin®], Pomalidomide, Dexamethasone) Therapy in Relapsed or Refractory Multiple Myeloma

Abstract 635▪▪This icon denotes a clinically relevant abstract Background:The addition of clarithromycin has been reported to enhance anti-myeloma activity of lenalidomide+dexamethasone in the upfront treatment of multiple myeloma (MM). Pomalidomide is a distinct IMiD® immunomodulatory agent with a significant response rate in subjects with relapsed or refractory MM (RRMM), including those with prior lenalidomide treatment. We hypothesized that clarithromycin may similarly enhance the activity of pomalidomide + dexamethasone in patients with RRMM after prior lenalidomide therapy. We now report the initial results from a phase 2 trial of ClaPD (Clarithromycin/[Biaxin®], Pomalidomide, Dexamethasone) therapy in RRMM. Methods:Fifty-two patients with heavily pre-treated RRMM were enrolled into a single-institution study and received ClaPD. Eligible subjects had at least 3 prior lines therapy, one line of which must have included lenalidomide. ClaPD is clarithromycin 500mg twice daily; dexamethasone 40mg on days 1,8,15,22; and pomalidomide 4mg for days 1–21 of a 28-day cycle. All subjects had thromboprophylaxis with aspirin. Disease response evaluation was performed monthly with immunoelectrophoresis and free light chain analysis; bone marrow biopsy with skeletal imaging was used to confirm MM progression or complete response (CR). Treatment was continued as tolerated by the patient until disease progression. Results:Forty-six patients had completed at least 1 cycle of ClaPD and were eligible for analysis. The median number of cycles received was 6 (range 2–10). ClaPD responses were progressive disease (PD): 20%, stable disease (SD): 15%, minimal response (MR): 7%, partial response (PR): 33%, very good partial response (VGPR): 20%, stringent complete remission (sCR): 7%, giving an overall response rate (ORR) of 60% and a ≥VGPR rate of 27%. In responding patients, time to PR was rapid at a median of 1.5 cycles (range 1–7). After a median follow up time of 6.7 months, 28 patients (61%) remain on study free from disease progression and 39 patients (85%) are alive. Two patients withdrew from treatment due to regimen toxicity (one due to Grade 3 fatigue, another due to Grade 4 muscular weakness). Conclusions:ClaPD is a highly effective regimen for heavily treated RRMM, particularly in patients with disease progression after prior lenalidomide therapy. When compared to other published Phase 2 data, the addition of clarithromycin in ClaPD appears to enhance the efficacy of Pomalidomide-Dexamethasone in lenalidomide-relapsed patients, (ORR 60% versus 40% - Lacy et. al JCO 2009) without induction of excess toxicity. Response to ClaPD is rapid, well tolerated, and sustained at > 6 months in the majority of subjects. These data support the use of pomalidomide therapy in RRMM that has progressed after lenalidomide. Disclosures:Mark:Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: There is no FDA indication for pomalidomide at this time. Zafar:Celgene Corp: Speakers Bureau. Pekle:Celgene Corp: Speakers Bureau. Coleman:Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Niesvizky:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Research Funding.

Complete and Very Good Partial Responses Are Attainable Endpoints in Elderly Patients (>75 years) with AL Amyloidosis and Are Associated with Improved Overall Survival,

Abstract 3975 Background:Elderly patients with AL amyloidosis present a unique therapeutic challenge. Both the disease itself and other co-morbidities contribute to organ dysfunction, potentially limiting treatment options. Despite this, durable responses can be achieved leading to both improvements in quality and longevity of life. Here we present our experience with patients > 75 years (yrs) enrolled in the UK-wide ALchemy study.Patients and Methods: ALchemy was designed to collect comprehensive treatment, outcome and toxicity data in newly diagnosed patients attending the National Amyloidosis Centre in the UK. Analysis of prospectively collected data revealed 46 pts > 75 yrs who were enrolled in the study beginning in 2009. 8 patients still alive at last assessment but having < 3m follow-up were excluded. Haematologic response was defined as per the 2005 consensus criteria. The dFLC response (difference between the involved and uninvolved free light chain) was defined as the percent difference in the dFLC at the start of therapy and at response assessment and was considered assessable if the baseline dFLC was >50mg/L. A dFLC between 50–90% defined a partial response (PR) and a dFLC of >90% defined a very good partial response (VGPR). The analysis was performed on an intention-to-treat basis and patients who died prior to response assessment were defined as non-responders. Overall survival (OS) was calculated by the Kaplan-Meier method and calculated from diagnosis until death or last follow-up. Results:The final cohort comprised 38 patients. Median age was 78.0 years. Median follow-up was 8.7 months (m). 37 patients had complete information for Mayo staging and 37% were stage III. 3 patients did not receive therapy. 20 patients received CTD as first line therapy, 4 received Mel/Dex, 4 received MPT, 1 received CVD, 3 received CD, 1 received RCD and 2 received CVP-R given baseline IgM secreting clonal B-cell lymphoproliferative disorders. 46% received less than 4 cycles of the planned upfront therapy. Overall response rate (RR) was 68% (11% attained a CR). 65% attained a partial dFLC response and 22% attained a VGPR. 9 patients received second line therapy. 5 were treated for relapsed disease, none of whom bettered their previous haematologic response but 2 patients attained a VGPR. Of the 4 patients who were treated for sub-optimal response none bettered their previous response. A correlation between receiving at least 3 cycles of therapy and attaining a CR or VGPR was observed (correlation coefficient 0.23, P = 0.09 and 0.42, P = 0.009 respectively). Median OS for the entire cohort was 10.7m. 45% died within one year of diagnosis. Median OS for Mayo stage III patients was 6.2 months. Attaining a VGPR by dFLC criteria correlated with a statistically significant improvement in OS compared with patients who did not achieve this milestone (median not reached vs 9.8m respectively; P = 0.016). A similar trend in OS was seen in patients who attained a CR but this did not reach statistical significance (median not reached vs 9.8m respectively; P = 0.192). Discussion:Treatment of elderly patients with AL amyloidosis remains a challenge. From our analysis despite receiving standard of care, median OS is < 1 year. However, based on this study appropriate treatment resulted in both attainment of CRs and VGPRs. Both endpoints are important treatment milestones previously shown to correlate with improved survival, and this is further corroborated here. Median OS was not reached in patients achieving either a CR or VGPR. Unfortunately, CR and VGPR rates remain < 25% in this population and it appeared that at least one factor is the inability to complete 3 cycles of treatment. Further study examining this distinct group of patients is warranted with the aim to develop therapeutic regimens balancing both effectiveness and tolerability. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Evolving role of high dose stem cell therapy in multiple myeloma

Conventional chemotherapy has been used in the treatment of multiple myeloma. However the development of autologous stem cell transplant represented a major advance in its therapy. Complete response (CR) rates to the tune of 40-45% were seen and this translated into improvements in progression-free survival and also overall survival in some studies. As a result the autologous stem cell transplants (ASCT) is the standard of care in eligible patients and can be carried out with low treatment-related mortality. Allogenic transplant carries the potential for cure but the high mortality associated with the myeloablative transplant has made it unpopular. Reduced Intensity Stem Cell Transplants (RIST) have been tried with varying success but with a high degree of morbidity as compared to the ASCT. Introduction of newer agents like thalidomide, lenalidomide, bortezomib and liposomal doxorubicin into the induction regimens has resulted in higher CR and very good partial response rates (VGPR) as well as improvement in ease of administration. These drugs have also proved useful in patients with adverse cytogenetics. Recent trials suggest that this has translated into improvements in response rates post-ASCT. There is a suggestion that patients achieving CR/nCR or VGPR after induction therapy should be placed on maintenance and ASCT then could be used as a treatment strategy at relapse. All these trends however await confirmation from further trials. Tandem transplants have been used to augment the results obtained with ASCT and have demonstrated their utility in patients who achieved only a partial response or stable disease in response to the first transplant as well as patients with adverse cytogenetics. Incorporation of bortezomib along with melphalan into the conditioning regimen has also been tried. RIST following ASCT has been tried with varying success but does not offer any major advantage over ASCT and is associated with higher morbidity. It is hoped that recent advances in therapy will contribute greatly to improved survival.

A Phase III Study to Compare Melphalan, Prednisone, Lenalidomide (MPR) Versus Melphalan 200 Mg/m2 and Autologous Transplantation (MEL200) In Newly Diagnosed Multiple Myeloma Patients

AbstractAbstract 3573 Background:In this randomized study we question the role of HDT, when new drugs are incorporated in the conventional treatment or in the autologous transplant setting in newly diagnosed multiple myeloma (MM) patients. Aims:To compare melphalan, prednisone and lenalidomide (MPR) with tandem melphalan (200 mg/m2) (MEL200) in MM patients younger than 65 years. Methods:The induction treatment consisted of four 28-day cycles of lenalidomide (25 mg d 1–21) and low-dose dexamethasone (40 mg d 1,8,15,22) (Rd). Cyclophosphamide plus G-CSF was used to mobilize stem cells. As consolidation, patients were randomized to MPR (N=202) [six 28-day cycles of melphalan (0.18 mg/k g d 1–4), prednisone (2 mg/kg d 1–4) and lenalidomide (10 mg d 1–21))] or MEL200 (N=200)[tandem melphalan 200 mg/m2 with stem-cell support]. All patients were also randomized to receive either aspirin or low-molecular weight heparin (enoxaparin) as thromboprophylaxis during Rd and MPR. Primary study endpoint was progression free survival (PFS). Data were analyzed in intention-to-treat. Results:From november 2007 to july 2009, 402 patients with newly diagnosed symptomatic MM younger than 65 years of age were recruited and randomized. All patients enrolled were stratified according to International Staging System (ISS) (stages 1 and 2 vs stage 3) and age (<60 vs ≥60 years). Results:On an intention to treat basis, best responses after Rd induction, were: partial response (PR) rate was 87%, very good partial response (VGPR) rate was 52%, including 13% complete responses (CR). The median yields of stem cells harvested was 8.7 ×106 CD34+ cells/Kg; 91% of patients collected the minimum dose of 4×106/kg CD34+ cells. As of August 10th, 257 patients are evaluable for response after at least 3 cycles of MPR (124) and after the first MEL200 (133); best responses to consolidation: in the MPR group, the VGPR rate was 60% including 20% CR; in the MEL200 group the VGPR rate was 58% including 25% CRs. No differences in responses were reported according to chromosomal abnormalities, such as del13, t(4;14), t(14;16) or del17p. After a median follow-up of 14 months, the projected 2-year PFS and OS were similar in the two groups (table). The achievement of at least VGPR after consolidation was a predictive factor of longer PFS in both groups: in the MEL200 group, the 2-year PFS was 92% for patients with at least VGPR vs 70% for those with PR (p<.0001); in the MPR group 86% vs 61% respectively (p<.0001). MPR and MEL200 were equally effective in patients with chromosomal abnormalities (2-year PFS was 71% vs 77%; p=.39) or ISS 3 (2-year PFS was 58% vs 66%; p=.48). Induction with Rd was well tolerated: the most frequent grade 3–4 adverse events were neutropenia (8%), anemia (7%), infections (4%) and skin rash (5%). The incidence of thromboembolic events was similar in patients randomized to aspirin (2%) or low molecular weight heparin (1%) as thromboprophylaxis (p=.45). During consolidation, the incidence of grade 3–4 neutropenia (97% vs 32%;p <.001), thrombocytopenia (59% vs 5%; p<.001), infections (10% vs 1%, p<.001) and gastrointestinal (15% vs 1%, p<.001) complications was higher in MEL200 patients.TableClinical outcome after MPR or MEL200 consolidationMPRMEL200P valueCR20%25%0.49≥VGPR60%58%0.242-year PFS73%78%0.482-year OS95%97%0.18 Conclusion:Our study confirms the efficacy and safety of Rd induction. Both MPR and MEL200 improved the quality of response, achieved by Rd induction. At present, PFS and OS are not significantly different in the two groups, but longer follow-up is needed. These data will be updated at the meeting. Disclosures:Palumbo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janseen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavallo:Celgene: Honoraria. Patriarca:Celgene: Honoraria; Roche: Honoraria; Janssen-Cilag: Honoraria; Merck: Membership on an entity's Board of Directors or advisory committees. Caravita:Celgene: Consultancy. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janseen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

A Phase 3 Prospective Randomized International Study (MMY-3021) Comparing Subcutaneous and Intravenous Administration of Bortezomib In Patients with Relapsed Multiple Myeloma

AbstractAbstract 312 Background:Bortezomib (VELCADE®) is approved in the US and Europe for the treatment of patients with multiple myeloma (MM) in both the frontline and the relapse settings. The recommended dose of bortezomib is 1.3 mg/m2 administered as a 3- to 5-second bolus intravenous (IV) injection. As an alternative to IV delivery, subcutaneous (SC) administration of bortezomib may be a good option for some patients, particularly those with poor venous access, since it would eliminate the need for repeated IV access or insertion of long-term central venous access devices, improving convenience for some patients and physicians. In a randomized phase 1 trial of SC versus IV bortezomib in 24 relapsed or refractory MM patients, both routes of administration demonstrated similar systemic drug exposure and proteasome inhibition, good local tolerability and, importantly, comparable response rates and safety profiles (Moreau et al. Haematologica 2008). A large, multicenter, international, randomized, phase 3 open-label trial was therefore undertaken to compare SC and IV administration in patients with previously treated MM to confirm these preliminary findings. Methods:Eligible patients were aged ≥18 years with measurable secretory MM who had relapsed or progressed following prior systemic therapy and had a Karnofsky performance status of ≥70%. Patients who had received prior bortezomib or >3 previous lines of therapy, or who had peripheral neuropathy or neuropathic pain of NCI CTCAE grade ≥2 were excluded. Patients were randomized 2:1 to receive SC or IV bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 every 21 days for a total of eight cycles. SC injection sites were the thighs or abdomen, and the injection site was rotated for subsequent injections within a cycle. IV injections were administered at a concentration of 1 mg/ml as a 3- to 5-second IV push, and SC injections were administered at 2.5 mg/ml. For cycles 1–4, patients received bortezomib monotherapy. After 4 cycles, if a patient had no change or partial response (PR) as the best response and had not progressed, oral dexamethasone 20 mg could be added on the day of and day after bortezomib dosing (days 1, 2, 4, 5, 8, 9 and 11, 12) in the next 4 cycles. At the end of 8 cycles, patients who had an unconfirmed PR or who were evolving steadily to a delayed PR could receive two additional cycles of study medication. The primary endpoint was overall response rate (ORR; complete response [CR + PR]) after 4 cycles. Response was evaluated using EBMT response criteria, modified with the addition of the response categories of near CR (nCR) and very good partial response (VGPR). Secondary endpoints were CR, nCR and VGPR rates after 4 cycles, ORR after 8 cycles including the effect of adding dexamethasone, duration of response (DOR), time to progression (TTP), progression-free survival, 1-year survival, and time to response. Safety and tolerability of the two administration routes, including local tolerability of SC administration, were also assessed. Pharmacokinetics (PK) and pharmacodynamics (PD) (via whole blood 20S proteasome inhibition assay) were evaluated in a subset of patients. Results:Between July 2008 and February 2010, 222 patients from 53 centers in 10 countries across Asia, Europe and South America were enrolled and randomized to SC or IV bortezomib (148 SC, 74 IV). 32 patients (18 SC, 14 IV) in 8 centers participated in the PK/PD substudy. The primary study analysis will occur in October 2010. Conclusion:Final data for all primary and secondary endpoints will be presented during the meeting, including time-to-event data for DOR, TTP and 1-year survival rate, as well as PK/PD data. Disclosures:Moreau:Jansen-Cilag: Honoraria; Millennium Pharmaceuticals, Inc.: Advisory board, Honoraria; Celgene: Honoraria. Off Label Use: Discussion of Velcade administered as an SC rather than an IV bolus is included. Leleu:Jansen-Cilag: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Co-Pharma: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Robak:Johnson & Johnson: Research Funding. Kropff:ORTHO BIOTECH: Honoraria; Celgene: Honoraria. Cavet:OrthoBiotech: Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Research Funding. Parasuraman:Millennium Pharmaceuticals, Inc.: Employment, Equity Ownership. Feng:Johnson & Johnson: Employment. Skee:Johnson & Johnson: Employment. van de Velde:Johnson & Johnson: Employment, Equity Ownership. Deraedt:Johnson & Johnson: Employment, Equity Ownership. Harousseau:Jansen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Maintenance Treatment with Lenalidomide After Transplantation for MYELOMA: Final Analysis of the IFM 2005-02.

AbstractAbstract 310High dose therapy with autologous stem cell transplantation (ASCT) is a standard treatment for young patients with myeloma. Some residual disease responsible for relapse is always present after ASCT. Effective maintenance treatment would be required to prevent relapse. However, such treatment is still to be defined. This phase 3, placebo-controlled trial investigated the efficacy of lenalidomide (LEN) for maintenance after transplantation.Patients, under 65 years of age, with non-progressive disease after a first line ASCT (performed within the last 6 months) were randomized to receive consolidation with LEN (25 mg/d, 21 days/month, for 2 months) followed by maintenance with either placebo (Arm A) or LEN (10 to 15 mg/d) until relapse (Arm B). From July 2006 to August 2008, 614 patients were randomized. Patient's characteristics of each group were similar with regard to age (57 years), ISS stage, FISH analysis, induction regimen (VAD / bortezomib-dex / others = 49%/44%/7%), diagnosis-randomization interval (10 months), and response at time of randomization.The first pre-planned interim analysis was performed on the 4th of September 2009 with a median follow up of 24 months from randomization (ASCO 2010, abstract 8018). The independent data and safety monitoring committee recommended to unblind the trial due to the PFS superiority of arm B (primary end point). On the 6th of July 2010, the trial was unblinded and the final analysis was performed with a median follow up of 34 months from randomization and 44 months from diagnosis. Consolidation with LEN improved the very good partial response rate (VGPR) (p<0.0001). Maintenance with LEN improved the progression-free survival: median 24 months from randomization and 34 months from diagnosis in arm A, versus 42 months from randomization and 52 months from diagnosis in arm B (HR=0.5, p<10−8). This benefit was observed across all stratified subgroups of patients including beta-2 microglobulin level, (< or > 3 mg/l) cytogenetic profile (del 13, + or -), and response after transplantation (CR/VGPR or not). In multivariate analysis, PFS was related to maintenance with LEN (p<0.0001), and to the achievement of CR/VGPR after consolidation with LEN (p<0.01). Maintenance treatment with LEN was not associated with resistance of the disease at time of progression: the median interval between progression and death was similar in both arms (12 months). With the current follow-up, the 5-year post diagnosis overall survival remains extremely high and similar in the 2 treatment groups: 83%. Maintenance treatment with LEN was well tolerated. The definitive interruption rate for serious adverse events during maintenance was similar in both arms (Arm A=5%, Arm B=8%, NS).The IFM 2005-02 trial demonstrates that lenalidomide is an effective and well tolerated maintenance treatment after transplantation for multiple myeloma patients. Disclosures:Attal:celgene: Consultancy, Research Funding; johnson and johnson: Consultancy, Research Funding. Off Label Use: maintenance treatment with Revlimid. Facon:celgene: Consultancy, Research Funding; johnson and johnson: Consultancy. Roussel:celgene: Consultancy; johnson and johnson: Consultancy. Avet-Loiseau:celgene: Consultancy, Research Funding; johnson and johnson: Consultancy, Research Funding. Harousseau:celgene: Consultancy; johnson and johnson: Consultancy.

Bortezomib Plus Dexamethasone Is Superior to Vincristine Plus Doxorubicin Plus Dexamethasone As Induction Treatment Prior to Autologous Stem-Cell Transplantation in Newly Diagnosed Multiple Myeloma: Results of the IFM 2005-01 Phase III Trial

To compare efficacy and safety of bortezomib plus dexamethasone and vincristine plus doxorubicin plus dexamethasone (VAD) as induction before stem-cell transplantation in previously untreated myeloma. Four hundred eighty-two patients were randomly assigned to VAD (n = 121), VAD plus dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) consolidation (n = 121), bortezomib plus dexamethasone (n = 121), or bortezomib plus dexamethasone plus DCEP (n = 119), followed by autologous stem-cell transplantation. Patients not achieving very good partial response (VGPR) required a second transplantation. The primary end point was postinduction complete response/near complete response (CR/nCR) rate. Postinduction CR/nCR (14.8% v 6.4%), at least VGPR (37.7% v 15.1%), and overall response (78.5% v 62.8%) rates were significantly higher with bortezomib plus dexamethasone versus VAD; CR/nCR and at least VGPR rates were higher regardless of disease stage or adverse cytogenetic abnormalities. Response rates were similar in patients who did and did not receive DCEP. Post first transplantation, CR/nCR (35.0% v 18.4%) and at least VGPR (54.3% v 37.2%) rates remained significantly higher with bortezomib plus dexamethasone. Median progression-free survival (PFS) was 36.0 months versus 29.7 months (P = .064) with bortezomib plus dexamethasone versus VAD; respective 3-year survival rates were 81.4% and 77.4% (median follow-up, 32.2 months). The incidence of severe adverse events appeared similar between groups, but hematologic toxicity and deaths related to toxicity (zero v seven) were more frequent with VAD. Conversely, rates of grade 2 (20.5% v 10.5%) and grades 3 to 4 (9.2% v 2.5%) peripheral neuropathy during induction through first transplantation were significantly higher with bortezomib plus dexamethasone. Bortezomib plus dexamethasone significantly improved postinduction and post-transplantation CR/nCR and at least VGPR rates compared with VAD and resulted in a trend for longer PFS. Bortezomib plus dexamethasone should therefore be considered a standard of care in this setting.

Autologous Stem Cell Transplantation—An Important Step Toward Improving Survival in Multiple Myeloma

Conventional chemotherapy has been used in the treatment of multiple myeloma; however, the development of autologous stem cell transplantation (ASCT) represented a major advance in the therapy. Complete response (CR) rates of 40–45% were seen and this translated into improvements in progression-free survival (PFS) and overall survival (OS) in some studies. As a result, ASCT is the standard of care in eligible patients and can be carried out with low treatment-related mortality. The introduction of newer agents such as thalidomide, lenalidomide, bortezomib, and liposomal doxorubicin into induction regimens has resulted in higher CR rates, very good partial response rates (VGPR), and improvements in the ease of administration. These drugs have also proved useful in patients with adverse cytogenetics. Recent trials suggest that this has translated into improvements in response rates post-ASCT. There is a suggestion that patients achieving CR/near-CR (nCR) or VGPR after induction therapy should be placed on maintenance and ASCT could then be used as a treatment strategy at relapse; however, all of these trends await confirmation from further trials. Tandem transplants have been used to augment the results obtained with ASCT and have demonstrated their utility in patients who achieved only a partial response or stable disease in response to the first transplant and patients with adverse cytogenetics. Incorporation of bortezomib along with melphalan into the conditioning regimen has also been tried. It is hoped that recent advances in therapy will contribute greatly to improved survival.

A Prospective, Randomized Study of Melphalan, Prednisone, Lenalidomide (MPR) versus Melphalan (200 Mg/M2) and Autologous Transplantation (Mel200) in Newly Diagnosed Myeloma Patients: An Interim Analysis.

Abstract 350▪▪This icon denotes an abstract that is clinically relevant. Background.The incorporation of new drugs as induction therapy before autologous transplantation appears to produce a high proportion of complete responses, slightly superior to those achieved by conventional chemotherapy with new drugs. Randomized trials are needed to directly compare current best chemotherapeutic approach with best autologous transplantation strategy. Aims.To compare melphalan, prednisone and lenalidomide (MPR) with tandem melphalan (200 mg/m2) (MEL200) in patients younger than 65 years. Methods.As induction, all (N=402) patients received four 28-day cycles of lenalidomide (25 mg days 1-21) and low-dose dexamethasone (40mg days 1,8,15,22) (Rd). Cyclophosphamide (4 g/m2) plus granulocyte-colony stimulating factor was used to mobilize stem cells. As consolidation, patients (N=202) randomized to MPR received six 28-day cycles of melphalan (0.18 mg/kg days 1-4), prednisone (2 mg/kg days 1-4) and lenalidomide (10mg days 1-21); patients (N=200) randomized to MEL200 received tandem melphalan 200 mg/m2 with stem-cell support. All patients were also randomized to receive either aspirin or low-molecular weight heparin (enoxaparin) as thromboprophylaxis. Primary end point was progression-free survival; data were analyzed in intention-to-treat. Results.Patient characteristics were similar in both groups, median age was 58 years. After Rd induction, at least partial response (PR) rate was 84%, at least very good partial response (VGPR) was 32% including 5% complete response (CR). The median yields of CD34+ cells harvested was 10 ×106 CD34+ cells/Kg; 94% of patients collected the minimum dose of 2×106/kg CD34+ cells. After 3 cycles of MPR, at least VGPR rate was 51% and CR 11%. After the first MEL200, at least VGPR rate was 56% and CR 14%. No difference in responses were reported according to cytogenetic abnormalities, such as del13, t(4;14) and t(14;16). After a median follow-up of 12 months, 1-year progression-free survival was 96% for MPR and 94% for MEL200 (p=.92) 1-year overall survival was 98% for MPR and 99% for MEL200 (p=.94). During Rd induction, the most frequent grade 3-4 adverse events were neutropenia (9%), anemia (8%), infections (4%), skin rash (4%), fatigue (2%) and thromboembolic events (1%). During consolidation, the incidence of grade 3-4 neutropenia (97% vs 34%, p <.001) thrombocytopenia (97% vs 16%, p<.001), infections (21% vs 3%, p<.001) and gastrointestinal (17% vs 1%, p<.001) complications was higher in MEL200 patients The incidence of thromboembolic events was similar in patients randomized to receive aspirin (2%) or enoxaparin (1%) as thromboprophylaxis (p=.42). Conclusion.Rd is an effective and safe induction regimen. Both MPR andMEL200 improved the quality of response, achieved by Rd induction. At present, progression-free and overall survival are not significantly different in the two groups, but longer follow-up is needed. Both aspirin and enoxaparin were equally effective as thromboprophylaxis. These data will be updated at the meeting. Disclosures:Palumbo:CELGENE: Honoraria. Cavallo:CELGENE: Honoraria. Patriarca:CELGENE: Honoraria. Caravita:CELGENE: CONSULTANCY. Boccadoro:CELGENE: CONSULTANCY, ADVISORY COMMITTEES, Research Funding.