VTD Consolidation Research Articles

Weekly Subcutaneous Bortezomib Is Well Tolerated and Effective As Initial Therapy Of Symptomatic Myeloma

BackgroundBortezomib became funded in New Zealand for first line therapy of myeloma in May 2011. In June 2011 North Shore and Christchurch Hospitals moved to weekly subcutaneous use. We performed a retrospective review of all untreated symptomatic myeloma patients presenting to North Shore and Christchurch Hospitals. Patients were treated with CyBorD consisting of Cyclophosphamide 300mg/m2 PO, Bortezomib 1.5 mg or 1.6mg /m2 SC (at 2.5mg/ml) and Dexamethasone 40mg PO, administered weekly. Four weeks was called one cycle. Transplant eligible patients received 4-6 cycles prior to transplant with melphalan 200mg/m2, with stem cell mobilization after the 4th cycle. At North Shore consolidation was given with 3-4 cycles of VTD starting day 100 consisting of Bortezomib 1.6mg/m2SC, Thalidomide 100mg PO and Dexamethasone 40mg. Non-transplant eligible patients were treated with a similar schedule but omitting the transplant, i.e. CyBorD x 5, VTD x4. In older patients treatment was stopped earlier.From 9th May 2011 to 8thJuly 2013, 105 patients (55 transplant eligible and 50 non-transplant eligible) with untreated symptomatic myeloma (IgG 62, IgA 19, light chain 19, IgD 4, mixed 1) received CyBorD. Steroid pretreatment was given to 25 pts. The median age was 67 years (range: 38 to 89 yrs). ISS was available in 80 pts and was 1 in 35%, 2 in 36% and 3 in 29%. Creatinine was > 200 µmol/l in 16 pts and dialysis was needed in 6 pts, using high-cut off filters in 2pts. At presentation 27 patients had hypercalcaemia >2.7 mmol/L. ResultsAt a median follow-up of 8 months (range 1 to 26 months), the Kaplan-Meier estimate of OS was 93% (± 3%) at 1 year and 88% (± 5%)at 2 years. Disease free survival was 82% (± 5%) at 1 yr and 60% (± 10%) at 2 years. There was a non-significant trend for better PFS in transplant eligible patients with 1 yr PFS 91% vs 82% and 2 yr PFS 66% vs 52%(log rank p=0.149), in transplant eligible and ineligible pts , respectively. Data on response was available for 98 patients. Overall response rate of ≥ PR was 95%, with a median time to response of 36 days. Time to PR was the same for transplant eligible and non-eligible patients (log rank p=0.56). VGPR was achieved in 59pts, with Kaplan-Meier estimates of VGPR 74% (± 6%) at 1 yr and 77% (± 6%) at 2 years. CR rates improved progressively with time, 16 patients achieved CR with Kaplan-Meier estimate of CR 25% (± 6%) at 1 yr and 34% (± 8%) at 2 years. Treatment was well tolerated. There were 8 patients who had dose reduction due to neuropathy. Painful neuropathy was rare. TransplantsOf the 55 transplant eligible patients, so far 36 have proceeded to transplant, 8 have transplant planned, and 11 have not been transplanted due to: progressive disease (2 pts), failure to mobilise (3 pts), patient choice (3 pts), and comorbidity (3 pts). The overall success rate of proceeding to transplant was high at 76% (36/47 pts), compared to other population studies. Of the 36 patients who proceeded to transplant the overall response pre-transplant was 92% (CR 3, VGPR 14, PR 16, SD 2, NR 1). This improved to 100% in 35 pts assessable post transplant (CR 8, VGPR 16, PR 11). Following transplant 18 patient have receive a median of 3 cycles VTD consolidation (Range 1 to 5). The overall survival following transplant is 100% at 2 yrs, PFS was 97%(± 3%) at 1yr and 79% (± 15%) at 2 years, with no difference yet in those receiving consolidation (1pt progressed compared to 2 in those who did not receive consolidation, Breslow p=0.13). The 1 yr Kaplan-Meier estimates of PR 100%, VGPR 75%(± 9%)and CR 28% (± 9%) increased to VGPR 88% (± 8%) and CR 39 % (± 10%) at 2 years. SummaryIn this unselected cohort, treatment with weekly subcutaneous bortezomib, as part of CyBorD or VTD, was well tolerated even in elderly patients. Neurotoxicity was low and responses are excellent and durable. Post-transplant consolidation is well tolerated but it is too soon to see if this improves PFS. Weekly subcutaneous bortezomib seems better tolerated than IV, with no evidence of reduced efficacy compared to previously published reports. Disclosures:No relevant conflicts of interest to declare.

Bortezomib Induction and Consolidation in Patients with Multiple Myeloma Who Received Frontline Autologous Stem Cell Transplant

Introduction For multiple myeloma patients who are eligible for transplant determined by age and physiological reserve, autologous stem cell transplant (ASCT) following induction chemotherapy is considered as frontline treatment due to the better depth of response, progression-free (PFS) and overall survival (OS). Bortezomib is effective as part of a multi-agent induction regimen prior to ASCT as supported by long-term analysis with survival benefit. However, the role of Bortezomib and Thalidomide consolidation remains controversial. In New Zealand, Bortezomib was funded for up to nine cycles in front line setting. To maximise Bortezomib exposure, patients were typically given four to five cycles of Cyclophosphamide-Bortezomib-Dexamethasone (CyBorD) induction and later received the remaining number of cycles as consolidation after ASCT. Here we present our real-world data on patients who had CyBorD induction followed by ASCT and VTD consolidation. Method Data from 3 centres across New Zealand (Waitemata District Health Board, Counties Manukau District Health Board and Northland District Health Board) were extracted from the patient electronic database. All patients with multiple myeloma under the age of 70 who received CyBorD induction and ASCT as frontline treatment between 1 January 2013 and 31 December 2019 were included. Treatment response was determined as per the International Myeloma Working Group criteria and survival time was determined from the time of commencement of CyBorD. All statistical analyses were performed using IBM SPSS version 20.The data cut-off date is 10th October 2019. Result A total of 263 patients were identified from the 3 centres who were aged <70 and received frontline CyBorD. 125 patients did not proceed with frontline ASCT due to comorbidities, patients' choice, or progressive disease. In total, 138 patients received ASCT following CyBorD induction from the 3 centres. The median age was 60.8 (range: 34.2 - 69.8) and 86 (62.3%) were male. 69.6% of the patients were European, 9.4% were New Zealand Maori, 10.9% were Pacific Islanders, and 5.8% were Asians. The international staging system (ISS) was able to be determined in 89.1% of the patients, and 48.0% and 21.1% of them were ISS II and III, respectively. FISH cytogenetic results were available in 91.3% of the cases, and 13.5% of these patients were deemed to have high-risk disease (del(17p) 7.9%, t(4;14) 3.2%, t(14;16) 1.6%, and concurrent del(17p) and t(4;14) 0.8%). The median number of cycles given in induction was 5 (range: 4 - 9). 60.1% of the patients achieved at least a very good partial response after induction, and this was increased to 84.1% after ASCT and 87.7% after consolidation. Complete response was increased from 22.5% after induction to 30.4% after ASCT and 40.6% after consolidation. After a median follow-up of 54.5 months (range: 1.8 - 96.9 months), the median progression-free survival was 47.8 months and the median overall survival was not reached (Figure1). The estimated 2 and 5-year survival were 93% and 84%, respectively. Thalidomide was added to the induction regimen in 19 patients and this was commonly done due to the presence of high risk clinical features or suboptimal clinical response as determined by the treating clinicians. These patients did not appear to have an inferior treatment outcome with a comparable median PFS (median 42.2 vs 49.5 months, p = 0.291). Conclusion Our real-world data shows that Bortezomib-based consolidation following ASCT improves depth of response and results in favourable long-term outcomes. Patients who required the addition of Thalidomide during induction due to suboptimal response do not appear to have an inferior long-term outcome. Figure Disclosures Jackson: Abbvie: Honoraria. Chan:AbbVie: Membership on an entity's Board of Directors or advisory committees; Roche: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau.

DART4MM: Daratumumab as Consolidation Therapy in Patients who Already Achieved Optimal Response /MRD Positivity by Next Generation Flow (NGF): Preliminary Results of a Phase 2 Multicenter Study

CR is a prerequisite for long term responses, PFS, OS and cure. In the era of novel agents, many Multiple Myeloma (MM) patients can achieve stringent CR but still will relapse and minimal residual disease (MRD) negativity will be primary objective in many future trials. Strategies such as VTD consolidation therapy after autologous stem cell transplant (ASCT) showed increased complete response from 15 % to 49 % in patients who had previously achieved very good partial response (VGPR) and progression free survivals (PFS) doubled for patients in MRD negativity.

Efficacy of daratumumab (DARA) + bortezomib/thalidomide/dexamethasone (D-VTd) in transplant-eligible newly diagnosed multiple myeloma (TE NDMM) based on minimal residual disease (MRD) status: Analysis of the CASSIOPEIA trial.

8017 Background: In TE NDMM patients (pts), the CD38 monoclonal antibody DARA significantly reduced the risk of progression/death and improved stringent CR, ≥CR, and MRD-negative rates when added to VTd in the phase 3 CASSIOPEIA study. MRD status and its association with progression-free survival (PFS) was evaluated in TE NDMM pts receiving D-VTd vs VTd as pre-transplant induction/post-transplant consolidation in Part 1 of CASSIOPEIA. Methods: In Part 1, TE NDMM pts were randomized 1:1 to 4 cycles of pre-ASCT induction and 2 cycles of post-ASCT consolidation with DARA + VTd or VTd. Landmark analyses of MRD were performed on bone marrow aspirates after induction by multiparametric flow cytometry (MFC; 10–5 sensitivity threshold) and after consolidation (at Day 100 post-ASCT) by MFC (10–5) and next-generation sequencing (NGS; 10–6) for all pts, regardless of response. Results: A cohort of 1085 pts was randomized (D-VTd, n = 543; VTd, n = 542). Post-induction and post-consolidation MRD-negative rates were significantly higher for D-VTd vs VTd (Table). Post-consolidation MRD-negative rates (MFC) were consistent across pt subgroups, including ISS stage III or high-risk cytogenetics. Multivariate analyses accounting for treatment arm and MRD negativity (MFC) showed a PFS benefit in pts reaching MRD negativity (HR, 0.31; 95% CI, 0.20-0.50; P <0.0001). Based on these analyses, D-VTd showed additional PFS benefit vs VTd (HR, 0.48; 95% CI, 0.30-0.78; P = 0.0028). Analysis of MRD based on response (per IMWG criteria) will be presented. Conclusions: Adding DARA to VTd induction and consolidation deepened responses, as demonstrated by significant increases in MRD-negative rates. MRD negativity was associated with a PFS benefit regardless of treatment group. However, deepened responses with D-VTd led to improved outcomes, with MRD negativity associated with prolonged PFS, versus VTd in pts with TE NDMM. Clinical trial information: NCT02541383. [Table: see text]

Fixed Dose Carfilzomib Triplets in Lenalidomide Refractory Myeloma

BackgroundMyeloma outcomes have improved due to the use of novel agents. However, patients who have failed bortezomib and lenalidomide represent a significant challenge. In New Zealand, myeloma patients are initially treated with CyBorD, transplant (if eligible) and VTD consolidation. Lenalidomide/dexamethasone is approved as third line therapy, or as second-line in patients with neuropathy. Compassionate access of carfilzomib became available in May 2016 for patients who have progressed after bortezomib and lenalidomide.MethodsPatients with myeloma treated with a carfilzomib triplet were identified from our database. After two initial doses of carfilzomib at 20mg/m2 patients were given a fixed dose of 60mg as a 30 minute infusion. Carfilzomib was given on Days 1, 2, 8, 9, 15 and 16 of a 28-day cycle. To streamline administration, carfilzomib was infused via a Portacath in most patients. Patients received dexamethasone 20mg PO on days of carfilzomib (1, 2, 8, 9, 15 and 16), and cyclophosphamide 300mg/m2 PO Days 1, 8, and 15, thalidomide 100mg daily, lenalidomide 25mg Days 1-21 or venetoclax 800mg daily. Routine support care was valaciclovir, cotrimoxazole and allopurinol. Aspirin 100mg was given daily to reduce cardiovascular events. A baseline echocardiogram was obtained in all patients. Treatments were continued for 9 cycles, followed by maintenance (reducing carfilzomib to only Days 1 and 2 of a 28-day cycle, but continuing oral therapy) until treatment failure. Patients who progressed by IMWG criteria continued treatment if they continued to derive benefit. Patients were followed with monthly myeloma blood monitoring but did not routinely have bone marrow assessments to assess CR status. All statistical analysis was done using IBM SPSS version 20.ResultsBetween 18/5/16 and 21/5/18, 38 patients with RRMM were treated with a triplet containing carfilzomib, dexamethasone and cyclophosphamide( KCd n=33), lenalidomide (KRd n=3) thalidomide (KTd n=1), or venetoclax (KVd n=1). All patients except one, received at least 2 cycles of treatment and 19 currently continue therapy. The median number of cycles given is 10 (range 2-27). The median age at treatment initiation was 68yrs (range 51yrs to 91yrs); there were 17 patients >70yrs and three >80yrs. Patients had a median of 3 prior therapies and 18pts had received a ABMT, Prior treatment included bortezomib (100%), thalidomide (92%), lenalidomide (95%), and pomalidomide (18%). Carfilzomib triplets were generally well tolerated. One patient discontinued due to shortness of breath after two cycles. One patient had a non-STEMI cardiac event prior to routine use of aspirin, but continued on KCd. The best response was ≥CR 8% (n=3), ≥VGPR 32% (n=12), ≥PR 74% (n=28) ≥ MR 84% (n=32), four patients had SD and two progressed without benefit.Of the 38 patients, 21 have progressed with a median PFS of 9 ± 2.4 months. PFS was better in patients aged <70yrs, 53% at 18 months vs 0% for those aged >70 (median 4 months)(p=0.008). So far 15pts have died with a median OS of 18 ± 3 months. All deaths were in patients who had progressed. Outcomes were superior in those aged <70 yrs, OS 68% at 18 months (median OS not reached), versus those aged >70 yrs, OS 17% at 18 months (Median OS 11±6 months)(p=0.008) The median survival from relapse was poor at 2 months. However, of the 6 patients alive after progression, 3 received an anti-CD38 antibody as salvage and 3 remain on treatment with KCd, the longest continues on treatment at 15 months.SummaryFixed dose carfilzomib triplets are effective salvage therapy in myeloma patients who fail bortezomib and lenalidomide therapy. Treatment is well tolerated, even in elderly patients, albeit with inferior outcomes. [Display omitted] DisclosuresSimpson:Abbvie: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Acerta: Research Funding; Merck: Honoraria, Research Funding; BeiGene: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Novartis: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; MSD: Honoraria; Amgen: Research Funding, TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Honoraria, Research Funding. Chan:Amgen: Honoraria; Karyopharm: Research Funding.

Long-term results of the GIMEMA VEL-03-096 trial in MM patients receiving VTD consolidation after ASCT: MRD kinetics' impact on survival

Polymerase chain reaction (PCR)-based minimal residual disease (MRD) analysis is a useful prognostic tool in multiple myeloma (MM), although its long-term impact still needs to be addressed. This report presents the updated results of the GIMEMA-VEL-03-096 trial. Thirty-nine MM patients receiving bortezomib-thalidomide-dexamethasone after autologous transplantation were monitored for MRD by both nested and real-time quantitative-PCR until relapse. Our data confirm the strong impact of MRD on survival: overall survival was 72% at 8 years median follow-up for patients in major MRD response versus 48% for those experiencing MRD persistence (P=0.041). In addition, MRD kinetics resulted predictive for relapse: indeed median remission duration was not reached for patients in major MRD response, 38 months for those experiencing MRD reappearance and 9 months for patients with MRD persistence (P<0.001). Moreover: (1) 26 patients achieving major MRD response (67%) benefit of excellent disease control (median TNT: 42 months); (2) MRD reappearance heralds relapse, with a TNT comparable to that of MRD persistence (9 versus 10 months, P=0.706); (3) the median lag between MRD reappearance and need for salvage treatment is 9 months. These results suggest the usefulness of a long-term MRD monitoring in MM patients and the need for maintenance or pre-emptive treatments ensuring durable responses.

Partial Response at Completion of Bortezomib-Thalidomide-Dexamethasone (VTd) Induction Regimen Upfront in Multiple Myeloma Does Not Preclude Response to VTd in Consolidation

The impact of consolidation on response rates and PFS has recently been demonstrated after induction and autotransplantation upfront in Multiple Myeloma (MM). We further showed that patients in ≥VGPR following the intensification procedure benefited most from consolidation. Question remains as to the benefit of consolidation for patients in PR at completion of induction - feature of partial resistance to the induction regimen.We collected data from 54 newly diagnosed MM treated with VTd-auto-VTd regimen that reached only PR at completion of the induction procedure.Overall, 37 patients (68%) improved depth of response (≥VGPR) at completion of consolidation, including 35% that reached CR and 38% solely related to consolidation. Of patients that remained on PR or improved depth of response after ASCT, 26% and 38% further responded to consolidation, respectively. With a median follow-up of 36 months, improved depth of response translated into lower relapse rate compared with patients remaining in PR, 19% vs. 36%. This difference was more striking in patients that reached CR vs. others, 8% and 38%, respectively (p=0.039). The median TTP was prolonged in patients that improved depth of response after consolidation (p=0.012), with a 3-year TTP of 87% vs. 18% otherwise. In multivariate analysis, lack of improved depth of response to consolidation independently predicted shorten median TTP [OR=4.4, 95%CI=1-21; p=0.039], with elevated LDH and beta2m, and adverse FISH.This study shows that VTd consolidation should be recommended to patients solely on PR at completion of induction with VTd, feature of lower sensitivity to VTd.

Persistent Improvement In Clinical Outcomes With Bortezomib-Thalidomide-Dexamethasone Vs Thalidomide-Dexamethasone Incorporated Into Double Autologous Transplantation For Multiple Myeloma: An Updated Analysis Of Phase 3 Gimema-MMY-3006 Study

▪Over the last years, incorporation of novel agents into autologous stem cell transplantation (ASCT) has improved markedly the outcomes of younger patients with newly diagnosed multiple myeloma (MM). Superior results with experimental treatments vs previous standards of care have been frequently reported after preliminary analyses and need to be confirmed with longer follow up. The randomized phase 3 GIMEMA-MMY-3006 study was designed to compare bortezomib-thalidomide-dexamethasone (VTD) vs thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double ASCT. Data from the initial analysis, with a median follow up of 36 months, demonstrated that patients randomized to the VTD arm enjoyed superior complete/near complete response (CR/nCR) rates after both induction and consolidation therapy, and had a significantly longer PFS compared to those prospectively assigned to the TD arm. We performed an updated analysis of the study after a median follow up of 59 months and results are herein reported. A persistent TTP and PFS benefit with incorporation of VTD into ASCT was confirmed. On an intention-to-treat analysis of 236 patients randomized to the VTD arm, median TTP was 62 months and median PFS was 57 months. The median values for 238 patients randomly assigned to the TD arm were 45 months for TTP (HR=0.64, p=0.001) and 42 months for PFS (HR=0.66, p=0.001) (Fig. 1). With the longer follow up of this analysis, an initial divergence between OS curves could be appreciated after 4 years, although the difference was not yet statistically significant at 6 years (75% for VTD vs 69% for TD). Superiority of VTD over TD for TTP and PFS was retained across prespecified subgroups of patients with high risk and low risk disease. In particular, PFS benefit with VTD was seen for patients age >60 years (HR=0.62, p=0.013) and younger than 60 years (HR=0.70, p=0.026), with ISS stage 1 (HR=0.59, p=0.009) and ISS stage 2-3 (HR=0.69, p=0.018), and for those with t(4;14) and/or del(17p) (HR=0.43, p<0.001) and with t(4;14) alone [t(4;14) positivity but lack of del(17p)] (HR=0.41, p=0.001). In comparison with patients with t(4;14) positivity who were randomized to TD, those assigned to the VTD arm had significantly longer PFS (median: 24 vs 53 months, HR=0.41, p=0.0007) (Fig. 2) and a trend towards longer OS (4-year estimates: 66% vs 81%, p=0.052). By the opposite, similar PFS curves were seen for patients in the VTD group regardless of the presence or absence of t(4;14) (Fig. 3). On multivariate Cox regression analysis, randomization to the VTD arm was an independent factor predicting for prolonged PFS (HR=0.64, P=0.001). Additional disease- and treatment-related variables independently affecting PFS included attainment of CR/nCR after both induction (HR=0.64, p=0.010) and consolidation therapy (HR=0.57, p<0.001), β2-m >3.5 mg/L (HR=1.7, p<0.001) and presence of t(4;14) and/or del(17p) (HR=2.0, p<0.001). On multivariate analysis, β2-m, cytogenetic abnormalities and attainment of CR/nCR after consolidation therapy were independently associated with OS. With an updated median follow-up of 49 months from the landmark of starting consolidation therapy, median PFS was 50 months for patients receiving VTD consolidation and 38 months for those treated with TD (HR= 0.69, P=0.015) (Fig. 4). Superior PFS with VTD vs TD consolidation therapy was observed for patients who failed CR/nCR after the second ASCT (HR=0.48, P=0.003) and was retained in both low risk and high risk subgroups. Finally, duration of OS from relapse or progression was similar between the two treatment groups (median, 42 for VTD vs 35 months for TD, p=0.47), even when bortezomib was incorporated into salvage therapy. In conclusion, this updated analysis of the GIMEMA-MMY-3006 study demonstrated: 1) a persistent PFS benefit with VTD vs TD in the overall population, as well as in subgroups of patients with high risk and low risk MM; 2) the ability of VTD, but not of TD, incorporated into double ASCT to overcome the adverse prognosis related to t(4;14); 3) the significant contribution of VTD consolidation to improved outcomes seen for patients randomized to the VTD arm; 4) the lack of more resistant relapse after exposure to VTD as induction and consolidation therapy compared to TD. A longer follow up is required to assess the OS benefit, if any, with VTD plus double ASCT. [Display omitted] [Display omitted] [Display omitted] [Display omitted] Disclosures:Cavo:Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Tacchetti:Janssen and Celgene: Honoraria. Zamagni:Celgene: Honoraria; Janssen-Cilag: Honoraria. Caravita:Celgene: Honoraria, Research Funding. Brioli:Celgene: Honoraria.

Impact Of Consolidation With Bortezomib-Thalidomide-Dexamethasone (VTd) Upfront In Multiple Myeloma (MM) With Partial Response (PR) At Completion Of Induction With Vtd

BackgroundSeveral studies have demonstrated the impact of VTd on response rates and PFS either as induction or consolidation regimen. However, studies have also showed that VGPR and greater was associated with a better survival prognostic at completion of intensification regimen, and that these patients benefited most from consolidation. Questions remain as to the benefit of consolidation using VTd in patients that reached solely PR at completion of VTd induction, patients that display features of resistance to VTd partially.We aimed to assess the efficacy and safety of VTd as consolidation therapy in the context of VTd as induction regimen followed by a single auto (VTd-auto-VTd regimen) in patients that reached PR at completion of Induction with VTd. MethodThis study has included a group of 121 newly diagnosed MM patients that underwent auto from 2009 to 2011 across 9 IFM centers. Patients were to be eligible for auto in first-line of treatment, aged less than 65 years old and treated with VTd-auto-VTd regimen. We then studied the 54 patients that reached PR (n=54) at completion of VTd induction. ResultsThe median age was 57 years, the sex ratio was 1,25, 58% had ISS 2 and 3, 25% had adverse FISH, including t(4;14) and/or del17p (similar in the 2 groups).Overall, 37 (68%) responded (at least VGPR) at completion of consolidation, including 33% and 35% that reached VGPR and CR, respectively. 55% and 37.5% of patients improved response rate after auto and consolidation, respectively. We then studied the role of consolidation whether or not patients responded to auto. Out of the 15 patients that remained on PR after auto (no benefit from auto), 35% responded at completion of consolidation. Out of the 31 patients that improved response rate to auto (at least VGPR), 32% further improved to CR at completion of consolidation. The median duration of response was prolonged from 10 (CI95% 10-14) months to 16 (13-20) months for patients in PR at completion of induction with VTd that further responded to consolidation VTd (p=0.24).With a median follow-up of 36 months, 30% and 11% had relapsed and died, respectively. The incidence rate of relapse was greater in patients that did not benefit from consolidation, 86% versus 14%, (p=0.27). The median TTP was 26 (95%CI 13-38) months in patients that did not benefit from consolidation versus not reached yet for the second group (p=0.012); the 3-year TTP was 18% and 87%. The 3-year PFS was 18% and 58%, respectively (p=0.03). The median OS was not reached in either group, and the 2-years OS was 75%. In univariate analysis, the variables that shortened TTP were high serum beta2m greater than 5mg/L (p=0.014), adverse FISH (p=0.05), elevated serum LDH (p<0.0001), absence of response following auto (p=0.022) and absence of response following consolidation (p=0.012). We have then sought for independent variables that impacted TTP in multivariate analysis after exclusion of LDH, beta2m and FISH known to be the most powerful predicators of short TTP and OS. The response to consolidation was then the most important marker to predict shorten median TTP [OR = 4.4, 95%CI = 1-21; p = 0.039].The safety profile of VTd consolidation in this population was similar to reports in patients that reached VGPR and greater at completion of induction with no excess toxicity. The incidence rate of hematological EIs of grade 3 and 4 was 2% with no excess and non hematological EIs related to consolidation. The incidence rate of neuropathy all grades was 7%, but only 2% occurred during the consolidation. We have also observed 9 (9%) thromboembolic events (TE), with none occurring during the consolidation phase. ConclusionThis study showed an improved response rate in relation to the VTd consolidation phase in two-third of patients that only partially responded to the induction VTd regimen. This improved quality of responses translated into a lower relapse rate with a prolonged PFS. This study demonstrates that VTd consolidation in the context of a the VTd-auto-VTd regimen upfront should be recommended to all responders to the induction phase, including patients in PR characterized with a lower sensitivity to the VTd regimen. Disclosures:Leleu:Amgen: Honoraria; Millennium : Honoraria; Leopharma: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Honoraria. Roussel:CELGENE: Honoraria; JANSSEN: Honoraria. Facon:JANSSEN: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau. Attal:JANSSEN: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau. Moreau:JANSSEN: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau.

VTD consolidation, without bisphosphonates, reduces bone resorption and is associated with a very low incidence of skeletal-related events in myeloma patients post ASCT

We prospectively evaluated the effect of bortezomib, thalidomide and dexamethasone (VTD) consolidation on bone metabolism of 42 myeloma patients who underwent an autologous stem cell transplantation (ASCT). VTD started on day 100 post ASCT; patients received four cycles of VTD (first block), were followed without treatment for 100 days and then received another four VTD cycles (second block). During this 12-month period, bisphosphonates were not administered. Best response included stringent complete remission (sCR) in 15 (35.7%) patients, complete response (CR) in 13 (30.9%), vgPR in 7 (16.6%), PR in 4 (9.5%), while 3 (7.1%) patients developed a progressive disease (PD). Importantly, 33.3% and 47.6% of patients improved their status of response after the first and second VTD block, respectively. VTD consolidation resulted in a significant reduction of circulating C-terminal cross-linking telopeptide of collagen type I (CTX), soluble receptor activator of the nuclear factor-kappa B ligand (sRANKL) and osteocalcin (OC), whereas bone-specific alkaline phosphatase (bALP) remained stable compared with pre-VTD values. During the study period, only one patient with a PD developed a skeletal-related event (that is, radiation to bone). The median time to progression (TTP) after ASCT was 34 months and the median time of next treatment was 40 months. We conclude that VTD consolidation post ASCT reduces bone resorption and is associated with a very low incidence of skeletal-related events (SREs) despite the absence of bisphosphonates; the later do not appear to be necessary in this context.

Consolidation with Vtd Significantly Improves the Complete Remission (CR) Rate Following Vtd Induction and Single Autologous Stem Cell Transplantation (auto) in Multiple Myeloma (MM).

Consolidation with Vtd Significantly Improves the Complete Remission (CR) Rate Following Vtd Induction and Single Autologous Stem Cell Transplantation (auto) in Multiple Myeloma (MM).

Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma

AbstractIn a randomized, phase 3 study, superior complete/near-complete response (CR/nCR) rates and extended progression-free survival were demonstrated with bortezomib-thalidomide-dexamethasone (VTD) versus thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double autologous stem cell transplantation for newly diagnosed myeloma patients (intention-to-treat analysis; VTD, n = 236; TD, n = 238). This per-protocol analysis (VTD, n = 160; TD, n = 161) specifically assessed the efficacy and safety of consolidation with VTD or TD. Before starting consolidation, CR/nCR rates were not significantly different in the VTD (63.1%) and TD arms (54.7%). After consolidation, CR (60.6% vs 46.6%) and CR/nCR (73.1% vs 60.9%) rates were significantly higher for VTD-treated versus TD-treated patients. VTD consolidation significantly increased CR and CR/nCR rates, but TD did not (McNemar test). With a median follow-up of 30.4 months from start of consolidation, 3-year progression-free survival was significantly longer for the VTD group (60% vs 48% for TD). Grade 2 or 3 peripheral neuropathy (8.1% vs 2.4%) was more frequent with VTD (grade 3, 0.6%) versus TD consolidation. The superior efficacy of VTD versus TD as induction was retained despite readministration as consolidation therapy after double autologous transplantation. VTD consolidation therapy significantly contributed to improved clinical outcomes observed for patients randomly assigned to the VTD arm of the study. The study is registered at www.clinicaltrials.gov as #NCT01134484.

Superior Complete Response Rate (CR) and Progression-Free Survival (PFS) with Bortezomib-Thalidomide-Dexamethasone (VTD) Versus Thalidomide-Dexamethasone (TD) As Consolidation Therapy After Autologous Stem-Cell Transplantation (ASCT) in Multiple Myeloma (MM)

Abstract 1871 Introduction: In a randomized phase 3 study, the use of VTD as induction therapy prior to and consolidation therapy following double ASCT increased the rate of complete or near complete response (CR/nCR) and extended PFS in comparison with TD given as induction and post-ASCT consolidation therapy in 474 newly diagnosed MM patients (Cavo et al , Lancet 2010). However, the specific impact of VTD consolidation on improved clinical outcomes was not defined. Methods: To address this issue, we performed a per-protocol analysis of 321 patients who received the entire treatment program, including the two pre-planned cycles of consolidation therapy with either VTD (160 of 236 patients, 68%) or TD (161 of 238 patients, 68%). By study design, two 35-d cycles of VTD (V 1.3 mg/m 2 on days 1, 8, 15, and 22; T 100 mg/d on days 1–35; D 40 mg on the days of and after each V administration) or TD (at the same doses as in VTD) were given as consolidation therapy to patients randomly assigned to each of the two respective induction regimens. Patient and disease characteristics at baseline were comparable in the two groups of patients. Results: The rates of CR and CR/nCR were significantly higher after consolidation therapy with VTD compared with TD (CR: 61% vs 47%; p=0.012; CR/nCR: 73% vs 61%; p=0.020). The impact of VTD consolidation on post-ASCT enhanced rates of CR and CR/nCR was confirmed by the McNemar test (CR: p=0.0009; CR/nCR: p=0.004) which conversely failed to demonstrate a significant increase in the frequencies of CR (p=0.052) and CR/nCR (p=0.110) with TD consolidation therapy. The absolute probability of upgrading from less than CR before consolidation to CR after consolidation was 31% with VTD and 17% with TD (Pearson chi-square test: p=0.03). Ninety six percent of patients who upgraded from less than CR to CR after VTD consolidation were in nCR (44%) or VGPR (52%) before starting consolidation therapy. A landmark analysis (with the landmark set as the start of consolidation therapy) was performed to compare time to progression (TTP), PFS, and overall survival (OS) between treatment groups. With a median follow-up of 30 months, the estimated 3-year probability of relapse or progression was 38% with VTD and 52% with TD (p=0.039 by Kaplan-Meier analysis) (HR: 0.68, 95% CI: 0.47–0.98, p=0.041). PFS was significantly longer for patients receiving VTD consolidation than for those treated with TD (3-year estimates: 62% vs 46%; p=0.025) (HR: 0.66, 95% CI: 0.46–0.95, p=0.027), a gain particularly evident for patients who failed to achieve CR after ASCT (3-year PFS estimates: 66% vs 43%; HR: 0.54, 95% CI: 0.32–0.91, p=0.022). Superior PFS with VTD vs TD consolidation was retained across poor prognosis subgroups, including patients with t(4;14) and/or del(17q) (HR: 0.44, p=0.004), del(13q) (HR: 0.44, p=0.002), β 2 -microglobulin >3.5 mg/L (HR: 0.57, p=0.025), lactate dehydrogenase >190 U/L (HR: 0.57, p=0.005), or ISS stage 2 and 3 (HR: 0.57, p=0.021). In a multivariate regression analysis, the most important and independent variables positively correlated with PFS were VTD consolidation therapy (p=0.002), double ASCT (p=0.001), low β 2 -microglobulin (p Conclusions: In comparison with TD, post-ASCT consolidation therapy with the triplet VTD regimen significantly increased the rates of CR and CR/nCR, and extended landmarked TTP and PFS. Superior PFS with VTD consolidation was maintained across poor prognosis subgroups, including those with advanced ISS stage and/or high-risk cytogenetic profiles. In a multivariate regression analysis VTD consolidation was confirmed to be an independent variable favorably affecting PFS. The superior activity seen with VTD versus TD as induction therapy before ASCT was retained despite the same triplet regimen being used as post-ASCT consolidation. Disclosures: Cavo: Millennium: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria; Genzyme: Honoraria. Off Label Use: Bortezomib and Thalidomide as post autotransplantation consolidation therapy in myeloma. Patriarca: Schering-Plough: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Roche: Honoraria. Petrucci: Celgene: Honoraria; Janssen: Honoraria. Di Raimondo: Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau. Palumbo: Merck: Honoraria; Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Amgen: Honoraria. Offidani: Celgene: Honoraria; Janssen: Honoraria. Baccarani: Bristol-Meyers Squibb: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees.

LONG-TERM RESULTS of the GIMEMA VTD Consolidation TRIAL In Autografted MULTIPLE Myeloma PATIENTS (VEL-03-096): IMPACT of Minimal RESIDUAL DISEASE Detection by REAL Time Quantitative PCR On LATE Recurrences and Overall SURVIVAL

Abstract 827 Background and aims:We have recently shown that a consolidation therapy with bortezomib/thalidomide/dexamethasone (VTD) in multiple myeloma (MM) patients responding to autologous transplantation (ASCT) induces major tumor shrinking assessed by real time-quantitative (RQ)-PCR. Moreover we found that low levels of minimal residual disease (MRD) associated to a better progression-free survival (PFS) [GIMEMA VEL-03-096 trial, EudraCT Number 2004-000531-28: Ladetto et al, J Clin Oncol 2010]. We here present the updated results of this study at a median follow-up of 65 months. In the present analysis the following additional issues have been addressed: a) impact of MRD on PFS over time, with special interest to the role of MRD kinetics on outcome; b) impact of MRD on overall survival (OS). Patients and methods:Inclusion criteria and treatment schedule for this study have been already reported [Ladetto et al., J Clin Oncol 2010] and included: 1) a documented complete or very good partial remission following ASCT delivered as first line treatment; 2) no previous therapy with thalidomide or bortezomib; 3) presence of a molecular marker based on the immunoglobulin heavy chain rearrangement (IGH). MRD was assessed on bone marrow samples at diagnosis, study entry, after two VTD courses, at the end of treatment and then at six months intervals, up to clinical relapse. Patients underwent MRD detection using either qualitative nested PCR and RQ-PCR, employing IGH-derived patient specific primers as already described [Voena et al., Leukemia 1997; Ladetto et al., Biol Bone Marrow Transpl 2000]. For outcome analysis patients were grouped according to following definitions: a) MRD negativity on two consecutive samples by the most sensitive PCR method (nested PCR): full molecular remission (FMR); b) MRD negativity on two consecutive samples by RQ-PCR (less sensitive but currently better standardized, according to European Study Group on MRD detection guidelines [van der Vendel et al., Leukemia 2007]): standard molecular remission (SMR); c) post-treatment tumor load above the median by RQ-PCR: high tumor burden (HTB); d) post-treatment tumor load below the median by RQ-PCR: low tumor burden (LTB); e) recurrence of detectable MRD after FMR/SMR: molecular relapse (M-rel); f) increase of MRD levels of at least one log: active disease (AD). Results:Feasibility, toxicity and clinical outcome of the trial have been already reported [Ladetto et al., J Clin Oncol 2010]. Thirty-nine patients were enrolled and median clinical follow-up from start of first line treatment is 65 months. 270 of the planned samples for MRD monitoring (86%) were actually received by the centralized lab. So far 17 relapses and six deaths have been reported. Following VTD consolidation, 7/38 evaluable patients achieved FMR (18%) and 15/38 achieved SMR (39%). Three M-rel were observed, two of them followed by clinical relapse within six months. Achievement of SMR proved highly predictive for PFS (5-years (y) PFS 82% vs 44%, p=0.009, figure 1A), as well as the presence of HTB and AD (5-y PFS 35% vs 87%, p<0.001, figure 2). Interestingly, patients with LTB and no evidence of M-rel or AD had an excellent outcome with a 5-y PFS of 87%, (even considering that molecular follow-up was incomplete due to lack of samples in the two events observed in the low risk group, figure 2). Most notably, none of the patients achieving FMR or SMR has so far died and both SMR and AD proved to be significant predictors for OS (respectively, 5y-OS 100% vs 74%, p=0.012, figure 1B, and 5y-OS 86% vs 100%, p=0.037, data not shown). [Display omitted] [Display omitted] Conclusions:Our long-term results indicate that: 1) the achievement of SMR following VTD consolidation in MM patients is associated with a better outcome in terms of PFS and OS; 2) a dynamic increase in molecular tumor burden (AD), detectable by RQ-PCR, predicts late disease relapses several months before clinical recurrence. Taken together these results suggest the importance of developing tailored treatment for patients with high residual burden or showing increasing levels of MRD during follow-up, as already pursued for example in mantle cell lymphoma [Andersen et al., J Clin Oncol 2009]. Disclosures:Ladetto:Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Bayer: Honoraria; Mundipharma: Honoraria; Janssen-Cilag: Research Funding; Italfarmaco: Research Funding. Cavallo:celgene: Honoraria. Guglielmelli:celgene: Honoraria; Janssen-Cilag: Honoraria. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Palumbo:Merck: Honoraria; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria.

Molecular Remission After Bortezomib-Thalidomide-Dexamethasone Compared with Thalidomide-Dexamethasone as Consolidation Therapy Following Double Autologous Transplantation for Multiple Myeloma: Results of a Qualitative and Quantitative Analysis

AbstractAbstract 861The high rate of complete response (CR) effected by novel agents as induction and consolidation/maintenance therapy in multiple myeloma (MM) has renewed interest in the evaluation of minimal residual disease (MRD) after these combined treatment strategies. For this purpose, a useful molecular marker is represented by the immunoglobulin heavy-chain (IgH) rearrangement which can be carefully detected by means of polymerase chain reaction (PCR). We designed a molecular sub-study to the phase 3 GIMEMA trial of bortezomib-thalidomide-dexamethasone (VTD) vs. thalidomide-dexamethasone (TD) incorporated into double autologous stem cell transplantation (ASCT) for newly diagnosed MM. By study design, patients randomized at diagnosis to VTD or TD as induction therapy before ASCT received two 35-day cycles of consolidation therapy with VTD or TD starting 3 months after ASCT(s), independently from prior response. Doses of study drugs were the following: V, 1.3 mg/m2 once weekly; T, 100 mg/d through d 1 to 70; D, 320 mg/cycle. Aim of the molecular study was to compare the activity of VTD consolidation with that of TD by qualitative and quantitative PCR analysis. Patients who were planned to receive consolidation with either VTD or TD and who were in confirmed CR or near CR before the start of consolidation therapy were eligible for entry into the molecular study. A qualitative and quantitative PCR analysis with patient-specific primers was performed on bone marrow samples collected at day 0 and at day +70 after the two preplanned cycles of either VTD or TD. At this time, 84 patients were included in the study; of these, 67 patients were analyzed for MRD detection based on the availability of: 1) a molecular marker (e.g. IgH rearrangement) assessed at diagnosis; 2) both pre- and post-consolidation bone marrow samples. According to randomization at diagnosis, 35 out of 67 patients received VTD consolidation, while TD consolidation was given to 32 patients. Qualitative PCR analysis performed on bone marrow samples collected at day 0 showed that MRD before the start of VTD consolidation therapy was undetectable in 15 out of 35 patients, or 43%; the corresponding value before the start of TD consolidation was 37.5% (or 12 out of 32 patients). In comparison with the pre-consolidation status, analysis of bone marrow samples collected at day +70 revealed an upgrade in PCR-negativity from 37.5% to 52% with TD consolidation and from 43% to 67% with VTD consolidation (p=0.05, according to McNemar's test). By using the Fisher's exact test, the proportion of patients with post-consolidation PCR-negativity was significantly higher with VTD vs. TD consolidation (p=0.05). These data were furtherly extended by a Real-time quantitative PCR analysis, which could be performed in 45 out of the 67 patients initially included in the study (22 in the TD arm and 23 in VTD). In comparison with residual tumor mass at day 0, quantitative PCR analysis of bone marrow samples collected at day +70 revealed a median 1 log reduction in tumor burden with TD consolidation vs. a median 5 log reduction with VTD consolidation. By using the Wilcoxon test, the overall reduction in residual tumor burden effected by VTD consolidation therapy was statistically significant (p=0.05). In conclusion, in comparison with TD consolidation, two 35-day cycles of consolidation therapy with VTD following double ASCT significantly increased the rate of molecular remissions and significantly reduced the burden of residual myeloma cells persisting after ASCT. Superior activity of VTD over TD consolidation was retained although prior exposure to the same regimen given as induction therapy in preparation for ASCT. Additional data on molecular follow-up analyses of bone marrow samples collected after day +70 and comparisons of the prognostic relevance of PCR-negativity with PCR-positivity, as well as of PCR-negativity induced by VTD with that induced by TD will be presented during the meeting.Supported by: Progetto di Ricerca Finalizzata Orientata (to M.C), BolognAIL, Fondazione del Monte di Bologna e Ravenna. Disclosures:Baccarani:NOVARTIS: Honoraria; BRISTOL MYERS SQUIBB: Honoraria. Cavo:jansen-cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, no; celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, no; novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, no.

Consolidation with Bortezomib, Thalidomide and Dexamethasone After High Dose Therapy Is Feasible, Safe and Effective In De Novo Multiple Myeloma Patients Who Already Received New Drugs Containing-Induction Regimen

AbstractAbstract 3041High dose therapy (HDT) with autologous stem cell transplantation (ASCT) is a standard treatment option for frontline myeloma patients (pts). However, after a single or a double transplantation, almost all pts ultimately relapse. Thus, new strategies are required to control the residual disease after HDT. Consolidation therapy, given early after HDT, could enhance the depth of response and further improve progression free survival (PFS) and overall survival (OS). The IFM (Intergroupe Francophone du MyeÃŒlome) previously reported that either Thalidomide or Lenalidomide, administered after HDT, was able to reduce this residual disease (IFM 99-02 and 2005-02 trials, Attal M et al. Blood 2006 and ASCO 2010). Ladetto M et al. (JCO 2010) also reported a major shrinking of residual tumor cell burden in myeloma pts undergoing early consolidation with Bortezomib, Thalidomide and Dexamethasone (VTD) after ASCT. None of these pts had previously received treatment with Thalidomide and/or Bortezomib during induction. The aim of this study was to evaluate the feasibility, safety and efficacy of early consolidation therapy in pts who had received new drugs containing-induction therapies before ASCT. Patients and Methods:In this prospective monocenter study,patients were eligible if they had the following: 1) at least partial response (PR) after HD melphalan (HDM), 2) no grade ≥ 2 peripheral neuropathy (PNY). The consolidation therapy with vTD had to be started within 3 months from ASCT for a total of 2 cycles. Each 4-week cycle consisted of: a) Bortezomib: 1mg/m2 as an IV injection twice weekly (on days 1, 4, 8, 11); b) oral Thalidomide: 100 mg/day; c) oral Dexamethasone 40 mg/day once a week (on days 1, 8, 15 and 22). Pts did not receive maintenance therapy after vTD consolidation. A systematic prophylactic anticoagulation therapy was given either by aspirin or low molecular weight heparin. Pts also received systematic anti herpes zoster prophylaxis with valacyclovir. Toxicities were graded according to the CTAECv4 at each cycle. Response was assessed according to modified European group for Blood and Marrow Transplantion criteria including very good partial response (VGPR), 1 month after the last cycle of vTD. As no immunophenotypic analysis was available routinely in our institute, we did not evaluate stingent complete response. Results:From August 2008 to May 2010, 90 newly diagnosed multiple myeloma pts under 65 received HDM followed by ASCT in the Toulouse's hospital bone marrow transplant unit, FRANCE. Forty-six pts were eligible for this study and started on consolidation. Two pts are ongoing their treatment and 41 received the whole planned treatment. Two pts withdrawn thalidomide and 1 pt did not receive the second cycle of consolidation because of toxicities. Forty-four pts were excluded mainly because of PN (27%). Initial characteristics were: age=58 years (range,44-65); ISS: 1= 50%, 2= 23%, 3=18%, NA= 9%; DS stage: I=4,5%, II=4,5%, III=91%; median beta-2microglobulin=2,9 mg/l (1,3-11,3); FISH analysis: t(4-14) and/or del 17p= 4/29 evaluable pts. The induction regimen was: Bortezomib/Dexamethasone (82%), vTD (11%), or another regimen (7%).Before consolidation therapy, response rates were: PR=16%, VGPR=48%, near complete response (nCR)=14% and CR=23%. In an Intend to treat basis, 17 pts (39%) improved their responses after consolidation with vTD: 3 pts (7%) from PR to VGPR, 8 pts (18%) from VGPR to nCR, and 6 pts (14%) from VGPR to CR. Response improvement was also reported in the 5 pts who already received induction therapy with vTD; three pts (60%) improved their response: 1 pt from PR to VGPR and 2 pts from VGPR to nCR. As immunophenotypic analysis was not avalaible, response improvement might be underestimate for CR pts. Overall, consolidation therapy with 2 cycles of vTD was efficient; 16 pts (36%) acheived CR, 30 pts (68%) CR+nCR and 40 pts (91%) VGPR or better.Considering the safety profile, there was no toxic death or grade 3/4 hematological toxicity. Non-hematological toxicities reported were: fatigue=18%, PNY (all grades)= 9%, pneumonia=7%, vertigo= 7%, constipation= 6%, and deep-vein thrombosis= 4,5%. Conclusions:Early consolidation with vTD in pts who already received Thalidomide and/or Bortezomib as induction therapy is feasible, safe and effective. Response rates improved in almost 40% of pts. Disclosures:Roussel:Janssen: Consultancy, Research Funding, orator; celgene: Consultancy, Orator, Research Funding. Off Label Use: bortezomib and thalidomide as consolidation therapy after High Dose Melphalan. Attal:celgene: Consultancy, Research Funding; janssen: Consultancy, Research Funding.

Bortezomib-Thalidomide-Dexamethasone Compared with Thalidomide-Dexamethasone as Induction and Consolidation Therapy Before and After Double Autologous Transplantation In Newly Diagnosed Multiple Myeloma: Results From a Randomized Phase 3 Study

AbstractAbstract 42We prospectively compared thalidomide-dexamethasone (TD) with bortezomib-thalidomide-dexamethasone (VTD) as induction therapy before, and consolidation after, double autologous stem-cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma (MM). Three 21-d cycles of either VTD (V, 1.3 mg/m2 twice-weekly; T, 200 mg/d through d 1 to 63; D, 320 mg/cycle) or TD were given as induction therapy. Consolidation therapy comprised two 35-d cycles of VTD (V, 1.3 mg/m2 once-weekly; T, 100 mg/d through d 1 to 70; D, 320 mg/cycle) or TD. 474 patients randomized to the VTD (n=236) or TD (n=238) arm were analyzed on an intention-to-treat basis for response rate, PFS and OS. Centrally reassessed CR/nCR rate was significantly higher in the VTD compared with the TD arm after all treatment phases, including induction therapy (30% vs 10%, p<0.0001), double autotransplantation (54% vs 42%, p=0.008) and consolidation therapy (60% vs 44%, p=0.001). Best confirmed overall CR/nCR rate was 71% in the VTD arm compared with 52% in the TD arm (p<0.0001); the corresponding values for VGPR or better were 89% vs 72%, respectively (p<0.0001). To evaluate the role of consolidation therapy we performed a per-protocol analysis of 323 patients, 161 treated with VTD and 162 with TD. Overall, upgraded responses with VTD and TD as consolidation therapy were observed in 55% vs 37% of patients, respectively (p=0.01; OR:1.15-3.77). Furthermore, the probability to improve responses from less than CR before consolidation to CR after consolidation was 28% with VTD vs 15% with TD (p=0.02; OR:1.07-4.57) (p=0.003 using the Mc Nemar's test). Post-consolidation molecular detection of minimal residual disease was the objective of a substudy; detailed results are reported in a separate abstract. Briefly, both qualitative and quantitative analyses confirmed the statistically significant superiority of VTD over TD in effecting higher rates of molecular remissions and reducing the burden of residual myeloma cells after ASCT. Any grade 3–4 non-hematologic adverse events were 10% with VTD (peripheral neuropathy: 1.3%, skin rash: 0.6%) vs 12% with TD. With a median follow-up of 31 months, median PFS was 42 months in the TD arm and was not yet reached in the VTD arm (44-month projected rate: 61%) (HR: 0.62 [CI: 0.45–0.87], p=0.006). Superior PFS in the VTD vs TD arm was retained across patient subgroups with poor prognosis, including those with t(4;14) and/or del(17p). Randomization to VTD overcome the adverse influence of t(4;14) on PFS (40-month projected rates: 69% vs 67% according to the presence or absence of this abnormality, respectively; p=0.6). By the opposite, in the TD arm corresponding median PFS values were 24.5 vs 41.5 months, respectively (p=0.01). The small numbers of patients with del(17p) in both arms of the study precluded a statistical comparison with del(17p)-negative group. In a multivariate analysis, variables favorably influencing PFS were beta2-m lower than 3.5 mg/L (HR:0.47; p=0.000), absence of t(4;14) and/or del(17p) (HR:0.52; p=0.000), randomization to VTD arm (HR:0.57; p=0.002), attainment of at least VGPR (HR:0.50; p=0.009) and CR (HR:0.8; p=0.01). No statistically significant difference between the overall treatment protocols was seen in terms of OS, although curves seemed to initially diverge after 40 months (44-month projected rates: 84% vs 74% for VTD and TD arms, respectively). A multivariate analysis showed the independent role of absence of t(4;14) and/or del(17p) (HR:0.42; p=0.003), ISS stage1-2 (HR:0.49; p=0.02) and randomization to VTD (HR:0.53; p=0.04) in prolonging OS. When time-dependent CR entered the model, absence of t(4;14) and/or del(17p) and less advanced ISS stage retained their positive prognostic value; attainment of CR (strictly related to VTD randomization) was an additional favorable variable. In conclusion, in comparison with the TD arm of the study, 1) VTD induction emerges as a new standard of care for maximizing the degree and speedy of tumor reduction in preparation for ASCT; 2) VTD consolidation effected significantly higher rates of upgraded responses, including CR, and of molecular remissions; 3) double ASCT incorporating VTD as induction and consolidation therapy resulted in significantly longer PFS, a benefit confirmed in a multivariate regression analysis and maintained in the subgroup of patients with adverse cytogenetic abnormalities. Disclosures:Cavo:Janssen-Cilag: 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; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Use of bortezomib and thalidomide as induction therapy before, and consolidation after, autologous transplantation in newly diagnosed multiple myeloma. Baccarani:NOVARTIS: Honoraria; BRISTOL MYERS SQUIBB: Honoraria.

Major Tumor Shrinking and Persistent Molecular Remissions After Consolidation With Bortezomib, Thalidomide, and Dexamethasone in Patients With Autografted Myeloma

PURPOSE We investigated the effect on minimal residual disease, by qualitative and real-time quantitative polymerase chain reaction (RQ-PCR), of a consolidation regimen that included bortezomib, thalidomide, and dexamethasone (VTD) in patients with multiple myeloma (MM) responding to autologous stem-cell transplantation (auto-SCT). PATIENTS AND METHODS Patients achieving at least very good partial response who had an available molecular marker based on the immunoglobulin heavy-chain rearrangement received four courses of treatment every month: four infusions per month of bortezomib at 1.6 mg/m(2), thalidomide at 200 mg/d, and dexamethasone at 20 mg/d on days 1 to 4, 8 to 11, and 15 to 18. Patients were studied with tumor-clone-specific primers by qualitative nested PCR and RQ-PCR. Results Of 39 patients enrolled, 31 received the four VTD courses. Immunofixation complete responses increased from 15% after auto-SCT to 49% after VTD. Molecular remissions (MRs) were 3% after auto-SCT and 18% after VTD. Median time to maximum response was 3.5 months. So far, no patient in MR has relapsed (median follow-up, 42 months). VTD consolidation induced an additional depletion of 4.14 natural logarithms of tumor burden by RQ-PCR. Patients with a tumor load less than the median value after VTD had outcomes better than those who had tumor loads above the median value after VTD (at median follow-up: progression-free survival, 100% v 57%; P < .001). CONCLUSION To the best of our knowledge, this study is the first to document the occurrence of persistent MRs in a proportion of MM patients treated without allogeneic transplantation. Moreover, the major reduction in tumor load recorded by RQ-PCR after VTD suggests that unprecedented levels of tumor cell reduction can be achieved in MM thanks to the new nonchemotherapeutic drugs.

Consolidation Therapy with Bortezomib, Thalidomide and Dexamethasone (VTD) Regimen After ASCT in Myeloma Patients Who Do Not Receive Bisphosphonates Reduces Bone Resorption and RANKL/OPG Ratio but Seems to Have No Effect On Bone Formation and Angiogenesis.

Abstract 3863Poster Board III-799Bortezomib (V) monotherapy is associated with increased osteoblastic activity, reduced osteoclast function and decreased angiogenesis in relapsed/refractory myeloma (MM). The co-administration of zoledronic acid in all reported studies to-date may suggest a synergistic stimulation on osteoclast/osteoblast interactions by the two agents but has not allowed the independent evaluation of V on bone metabolism. Furthermore, the combination of V with other agents, such as thalidomide (T), melphalan (M) and dexamethasone (D), although it reduced osteoclast activity, it did not enhance osteoblast function. We evaluated the effect of VTD consolidation on bone metabolism and angiogenesis in MM patients who underwent high-dose M followed by ASCT. In this prospective study, only patients in first remission or with primary refractory disease to one frontline treatment were included. Patients did not receive any bisphosphonate during or post-ASCT as well as throughout the period of VTD consolidation. VTD started on day 100 after ASCT: V was administered at a dose of 1.0 mg/m2 on days 1,4,8,11; T was given at a dose of 100 mg/day, po, on days 1-21 and D at a dose of 40 mg/day on days 1–4 of a 21-day cycle. Patients received 4 cycles of VTD (first block), were followed without treatment for 100 days and then received another 4 cycles of VTD (2nd block). Patients were assessed for skeletal-related events (SREs) throughout the period of the study (12 months). Bone remodeling was studied by the measurement of the following serum indices before and after each block of VTD (4 measurements for each patient): i) osteoclast regulators [sRANKL and osteoprotegerin (OPG)], ii) osteoblast inhibitor dickkopf-1 (Dkk-1), iii) bone resorption markers (CTX and TRACP-5b) and iv) bone formation markers [bone-specific alkaline phosphatase (bALP) and osteocalcin (OC)]. Angiogenic cytokines such as VEGF, angiogenin (ANG), angiopoietin (Angp)-1 and -2, and bFGF were also studied on the same dates. So far, 32 patients have completed the first block of VTD, while 16 patients have completed both VTD blocks. Just before VDT administration, 10 patients were in CR (4 in sCR), 14 in vgPR and 8 in PR. Although most of these patients were rated as vgPR or better, they had increased serum levels of sRANKL (p=0.037), Dkk-1 (p=0.001), CTX (p=0.002), TRACP-5b (p<0.001), VEGF (p<0.001), bFGF (p<0.001), ANG (p=0.006) and reduced levels of Angp-1/Angp-2 ratio (p<0.001) compared to 18 healthy controls of similar age and gender, indicating sustained osteoclast and angiogenic activity despite minimal tumor load. Levels of sRANKL and Dkk-1 positively correlated with resorption markers (p<0.01). The first block of VTD resulted in a significant reduction of sRANKL (p=0.001), sRANKL/OPG (p=0.005), CTX (p=0.001), TRACP-5b (p=0.032), but also of bALP (p=0.022) and OC (p=0.02), while Dkk-1 and the majority of angiogenic cytokines showed no alterations (only Angp-1/Angp-2 ratio had a borderline increase, p=0.044). After the first block of VTD, 39% of patients improved their status of response; however alterations of the studied molecules were irrespective of further response or not improvement. Before the administration of the 2nd block of VTD, RANKL, RANKL/OPG and CTX were reduced compared to values after the first block of VTD (p=0.01, p=0.027 and p=0.005, respectively). These parameters were further reduced after the completion of the study (p<0.05). On the contrary, Dkk-1 was increased between the end of the first block of VTD and the initiation of the 2nd (p=0.008) but was reduced after the 2nd block of VTD (p=0.037). OC had no further alterations, while bALP was increased before the 2nd block of VTD (p=0.012) and showed no changes thereafter. VEGF, ANG, and Angp-1/Angp-2 were increased during the resting period between the two VTD blocks and remained unchanged thereafter. During the study period, only one patient developed a SRE (i.e. radiation to bone). As of July 2009, 8 of 32 patients have developed progressive disease. The median TTP after ASCT was 27 months (CI 95% 16.3-37.6). The results of this ongoing study suggest that VTD consolidation post-ASCT, without the presence of bisphosphonates, reduces RANKL and bone resorption and is associated with a very low incidence of SREs. However, bortezomib was not able to produce a significant anabolic effect on bones when combined with TD even in these patients with low myeloma burden, while its effect on angiogenic cytokines was modest. Disclosures:Terpos:Janssen-Cilag: Consultancy, Honoraria. Dimopoulos:Janssen-Cilag: Honoraria; Celgene: Honoraria.

Major Shrinking of Residual Tumor Cell Burden and Achievement of Molecular Remissions in Myeloma Patients Undergoing Post-Trasplant Consolidation with Bortezomib, Thalidomide and Dexamethasone: A Qualitative and Quantitative PCR Study

Background and aims. In multiple myeloma (MM) molecular remission (MR) is usually not achieved with autologous transplantation (ASCT) as opposed to allogeneic transplantation where it occurs frequently and associates to an improved outcome. Aim of this study was to assess, by qualitative and quantitative PCR, the impact of a consolidation treatment, including Bortezomib/Thalidomide/Dexamethasone (VTD) on residual MM cells in patients achieving a good clinical response after ASCT.Patients and methods: Inclusion criteria were:a documented complete or very good partial remission (CR or VGPR) following ASCT delivered as first line treatment;no previous treatment with thalidomide and bortezomib;presence of a molecular marker based on the immunoglobulin heavy chain rearrangement (IgH-R).VTD had to be started within 6 months from ASCT. Each cycle consisted of:Bortezomib 1.6 mg/m2 as an IV injection once weekly (on days 1, 8, 15, 22) followed by a 13-day rest period (days 23–35);Thalidomide at the initial dose of 50 mg/day PO once daily, with increments of 50 mg every 7 days up to 200 mg;Dexamethasone 20 mg/day PO once daily, on days 1 to 4, 8 to 11 and 15 to 18 followed by a 17-day rest period (days 19–35).A total of 4 cycles were delivered. MRD was assessed on bone marrow (BM) samples at diagnosis, study entry, after two VTD courses, at the end of treatment and then at six months intervals. Qualitative and quantitative PCR analysis were carried out using IgH-R-derived patient-specific primers as already described (Voena et al, Leukemia 1997; Ladetto et al, Biol Bone Marrow Transpl 2000).Results: Forty pts were enrolled and are evaluable at study entry. 20% of patients did not receive the whole planned treatment, but were nevertheless included in MRD analysis. Median follow-up from study entry is currently 21 months. Qualitative PCR has been performed on the whole population (overall 198 samples). Six patients converted to MR (defined as two consecutive PCR-negative samples, spaced at least three months) while two patients had an isolated PCR-negative result. Patients in MR persisted in their status with the exception of one molecular relapse at 24 months. No clinical relapse has been so far observed in MR patients at a median follow-up of 26 months (18–30). Among patients not achieving MR we observed eight relapses occurring at a median time of 12 months (4–26). Quantitative PCR has been performed on 20 patients (overall 105 samples). Median tumor bulk at diagnosis was 157000 (35-925000) IgH-R/106 diploid genomes (dg). It shrunk to 440 (3-420000) following ASCT and to 17 (0-113000) following VTD. The effect of VTD was detectable both in patients in VGPR and CR. Follow-up analysis by real time PCR at six, 12 and 18 months in persistently PCR-positive patients revealed stable MRD levels in 66% of patients and a growth greater than one log in 33%. Notably, patients who already relapsed were characterized by a tumor load persistently greater than 100 IgH-R/106dg except one who showed a transient tumor cell reduction after 2 VTD courses followed by a sharp increase in his MRD level.Conclusions: Post-transplant VTD consolidation is active on residual plasma cells surviving ASCT. Moreover a proportion of CR/VGPR MM enters MR which might persist up to 30 months. Thus, new non-chemotherapeutic agents can substantially improve the quality of remission in MM patients even in case of optimal response to ASCT.