Impact of Response to Thalidomide, Lenalidomide or Bortezomib Containing Induction Chemotherapy on Outcomes of Multiple Myeloma Patients Undergoing Autologous Transplantation – A Multicenter Analysis

Abstract Abstract 1351 Introduction: High dose therapy and autologous transplantation (HDT-AT) has shown survival benefit for (at least) young, transplant eligible multiple myeloma (MM) patients. Transplant ineligible patients who achieve complete remission (CR) with novel chemotherapy agents, have recently been shown to have superior overall survival (OS) (Harousseau JL. Blood:2010). However transplant eligible MM patients who have refractory disease in response to induction chemotherapy (not containing novel agents) before HDT-AT do not have inferior outcomes post-transplantation. A recent single institution, retrospective study has shown that <50% reduction in ‘serum M-protein’ following induction with thalidomide (T) or lenalidomide (L)-based induction therapies, predicts poor outcomes following HDT-AT (Gertz M, Blood:2010). These findings require further validation in order to refine patient selection for HDT-AT. We report here the impact pre-transplant remission status on outcomes of HDT-AT in MM patients receiving induction chemotherapy with novel agents. Methods: This multicenter outcomes study includes 121 consecutive patients who underwent a planned, single autograft within 1-year of starting induction chemotherapy with regimens containing T, L, or bortezomib (B), from 2003–2009. Peripheral blood stem cells were mobilized using a cyclophosphamide/G-CSF combination. All patients with normal renal function received uniform conditioning with Mel200 (MEL140 if serum creatinine was >2 mg/dl). The disease response pre- and post transplant was determined by using the IMWG criteria. SPSS version 13.0 was used for statistical analysis. Kaplan-Meier method was used to calculate OS and progression free survival (PFS). In order to assess the impact of chemosensitive disease, outcomes of patients achieving at least a partial remission (PR) (≥PR-group; n=105) before HDT-AT were compared with one not achieving at least a PR (<PR-group; n=16). We also compared outcomes of patient achieving at least a very good partial response (VGPR) (≥VGPR-group; n=48) with ones not achieving at least a VGPR (<VGPR-group; n=73). Results: The median age of the patients at transplant was 57yrs (range 35 –76yrs). Eighty (65%) patients were male. At diagnosis 84 (68%) had Salmon-Durie stage III disease, while 37 (31%) had stage I/II disease. At transplantation median Karnofsky performance status was 90, median number of prior therapies was 1 (range 1–4), and 31 (25%) had received radiation previously. Median follow-up of surviving patients is 24 months. KM estimates of 3 year OS of patients in ≥PR-group and <PR-group was 74% vs. 77% (p=0.94) respectively. The 3 year PFS in similar order was 44.8% vs. 45% (p=0.87). The 3 year OS of patients in ≥VGPR-group and <VGPR-group (73% vs. 75%) was also not significantly different (p=0.83). Respective figures of 3 year PFS are 54% vs. 38% (p=0.97) respectively. Of the 53 patients that entered an HDT-AT with a PR, 23 improved to a CR post transplant, 2 improved their status to a VGPR whereas 28 remained in a PR. On the other hand of the 8 patients who entered an HDT-AT with a VGPR, 2 improved to a CR whereas the rest maintained their status. Conclusion: Our limited, multicenter retrospective outcomes data suggest that response to induction chemotherapy with novel agents may not reliably predict outcome of MM patients undergoing HDT-AT. Until data from prospective studies prove otherwise, MM patients who are refractory to therapy with T/L or B-based agents should not routinely be considered ineligible for HDT-AT. Disclosures: Abraham: Genentech: Membership on an entity's Board of Directors or advisory committees. Craig:Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hamadani:celgene: Honoraria, Speakers Bureau; otsuka: Research Funding, Speakers Bureau.

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Analysis of Immunophenotypic Response (IR) by Multiparameter Flow Cytometry In 516 Myeloma Patients Included In Three Consecutive Spanish Trials

Blood ◽

10.1182/blood.v116.21.1910.1910 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1910-1910 ◽

Cited By ~ 2

Author(s):

Bruno Paiva ◽

María-Belén Vidriales ◽

María-Angeles Montalbán ◽

María-Victoria Mateos ◽

Laura Rosiñol ◽

...

Keyword(s):

Flow Cytometry ◽

Board Of Directors ◽

Residual Disease ◽

Young Patients ◽

Novel Agents ◽

Multiparameter Flow Cytometry ◽

High Dose ◽

Newly Diagnosed ◽

Advisory Committees ◽

The Impact

Abstract Abstract 1910 The outcome of multiple myeloma (MM) patients has markedly improved in the last decade. Thus, overall response rates between 85%-95%, with 30%-50% complete remission (CR) rates are now being reported in young patients treated with novel agents plus high-dose therapy/autologous stem cell transplantation (HDT/ASCT). A similar scenario is also emerging in the elderly (non-transplant candidates) population. Accordingly, more sensitive techniques are needed to assess patients’ response; these may contribute to compare the efficacy of different treatment schemas, to monitor minimal residual disease (MRD) and for prognostication. In the present study we have assessed the frequency and the prognostic value of IR by multiparameter flow cytometry in a total of 516 newly diagnosed MM patients included in three consecutive PETHEMA/GEM Spanish trials: two designed for transplant candidate patients - GEM 2000 (n=157) and GEM2005<65y (n=206) - and one for elderly patients - GEM2005>65y (n=153). The GEM2000 trial was based on 6 induction cycles of VBMCP/VBAD followed by HDT/ASCT; the GEM2005<65y included three arms with 6 cycles each (Thalidomide/Dexamethasone -TD-, Bortezomib/Thalidomide/Dexamethasone -VTD- and, VBMCP/VBAD with Bortezomib in the two final cycles -VBMCP/VBAD/Bortezomib) followed by HDT/ASCT; and the GEM2005>65y compared 6 cycles of Bortezomib/Melphalan/Prednisone -VMP- vs. Bortezomib/Thalidomide/Prednisone -VTP-. All three trials had in common that patients received 6 induction cycles and IR was evaluated at this time point. In addition, IR was assessed on day +100 after HDT/ASCT in the first two trials. Patients were defined to be in IR when myelomatous plasma cells (MM-PCs) were undetectable by MFC or when less than one phenotypically aberrant PC was detected among 104 cells analyzed. Patients were referred for MRD studies if they were mainly in CR or VGPR. The IR rates reported here were calculated on intention to treat analysis. Figure 1 summarizes the IR rates after induction. The lowest IR rates corresponded to the VBMCP/VBAD and TD schemes (5% and 6%, respectively) while with the bortezomib-based regimens an approximately 3-fold increment in the IR rates was observed: VTP (12%), VBMCP/VBAD/Bortezomib (15%), VMP (16%) and VTD (17%). After HDT/ASCT, IR rates were found to be significantly increased (p<.001) in the GEM2000 protocol (14%) and in all arms of the GEM2005<65y trial: TD (18%), VBMCP/VBAD/Bortezomib (30%) and VTD (34%). Thus, a minimum 2-fold increment of IR rates was further achieved after HDT/ASCT. In addition, IR rates achieved after HDT/ASCT in patients included in all three arms of the GEM2005<65y trial were significantly superior (p≤.008) to cases treated according to the GEM2000 protocol, indicating that induction regimens with novel agents improved post-transplantation rates of IR. Moreover, bortezomib-based regimens vs. TD were associated with increased IR rates not only before but also after HDT/ACSCT (p=.06 and p=.02 for VBMCP/VBAD/Bortezomib and VTD, respectively). We further compared the impact of achieving an IR after induction and at day+100 after HDT/ASCT in the progression-free (PFS) and overall survival (OS) within the three protocols. Patients in IR status after an induction regimen according to the GEM2000, GEM2005<65y and GEM2005>65y protocols showed significantly longer (p<.001) 3-year PFS rates (100%, 100% and 90%, respectively) compared to patients in a no-IR status (61%, 59% and 35%, respectively). Similarly, 3-year OS rates were significantly longer (p=.01) in IR vs. no-IR patients status (100%, 100% and 94% vs. 84%, 90% and 76% for the GEM2000, GEM2005<65y and GEM05>65y protocols, respectively). Likewise, an IR vs. no-IR status after HDT/ASCT in both the GEM2000 and GEM05<65y trials was also associated with significantly increased 3-year PFS (p<.001) and OS (p=.007) rates. In summary, this study demonstrates that the achievement of an IR is a strong prognostic factor regardless of the type of treatment; thus, higher IR rates may help to identify optimal therapeutical schemes. In this sense, HDT/ASCT is able to markedly increase IR rates after induction even in the era of novel agents, and this translates into extended survival. Disclosures: Off Label Use: VTP is not approved for the treatment of newly diagnosed myeloma patients and VT and VP are not approved for maintenance therapy. None of the combinations proposed, VBCMP/VBAD plus bortezomib, VT and VTD are approved as induction therapy in newly diagnosed myeloma patients. Mateos:Janssen Cilag: Honoraria; Celgene: Honoraria. Rosiñol:Janssen-Cilag: Honoraria; Celgene: Honoraria. Cibeira: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. Oriol:Janssen-Cilag: Honoraria; Celgene: Honoraria. de Arriba:Janssen-Cilag: Honoraria; Celgene: Honoraria. Palomera:Janssen Cilag: Honoraria. De La Rubia:Janssen-Cilag: Honoraria; Celgene: Honoraria. Díaz-Mediavilla:Janssen-Cilag: Honoraria; Celgene: Honoraria. Garcia-Laraña:Janssen Cilag: Honoraria; Celgene: Honoraria. Sureda:Janssen-Cilag: Honoraria; Celgene: Honoraria. Alegre:Janssen-Cilag: Honoraria; Celgene: Honoraria. Blade:Janssen cilag: Honoraria; Celgene: Honoraria. Lahuerta:Janssen-Cilag: Honoraria; Celgene: Honoraria. San Miguel: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; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Response to Induction Chemotherapy with Novel Agents Does Not Predict Outcomes of Multiple Myeloma Patients Undergoing Autologous Hematopoietic Cell Transplantation

Blood ◽

10.1182/blood.v116.21.1347.1347 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1347-1347

Author(s):

Salman Osman ◽

Abraham Sebastian Kanate ◽

Pamela Bunner ◽

Sonia Leadmon ◽

William Tse ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Cell Transplantation ◽

Induction Chemotherapy ◽

Hematopoietic Cell Transplantation ◽

High Dose ◽

High Dose Therapy ◽

Advisory Committees ◽

Remission Status ◽

Autologous Hematopoietic Cell Transplantation

Abstract Abstract 1347 Introduction: High dose therapy and autologous hematopoietic cell transplantation (AHCT) is a standard therapy option for at least young (<65 years) and otherwise transplant eligible multiple myeloma (MM) patients. While outcomes of AHCT in Hodgkin's and non-Hodgkin lymphoma patients showing evidence of chemo-sensitive disease pre-transplant are clearly superior, the prognostic significance of pre-AHCT remission status in MM is controversial. Failure to achieve at least a partial remission (PR) in response to induction chemotherapy before AHCT has not been shown to negatively impact transplant outcomes, at least in the pre-thalidomide (Thal)/lenalidomide (Len)/bortezomib (Bor) era (Kumar S, BMT 2004 & Singhal S, BMT 2002). Whether this paradigm holds true for novel agent-containing induction therapies is not known. Recently <50% reduction in ‘serum M-protein’ following induction with Thal or Len based induction therapy has retrospectively been shown to predict poor outcome after AHSCT (Gertz M, Blood 2010). However, data evaluating transplant outcomes relative to pre-transplant remission status assessed by strict IMWG criteria, and data in Bor-based regimens is still scant. We report here the impact pre-transplant remission status on outcomes of AHCT after chemotherapy with novel agents. Methods: The study involves 63 consecutive patients who underwent a planned, single AHCT within 1-year of starting induction chemotherapy with regimens containing Thal, Len, or Bor, between 2000–2009. All patients with normal renal function received uniform conditioning with Mel200 (MEL140 if serum creatinine was >2 mg/dl). The disease response pre- and post transplant was determined by using the IMWG criteria. SPSS version 16.0 was used for statistical analysis. Kaplan-Meier method was used to calculate overall survival (OS) and progression free survival (PFS). Outcomes of patients achieving at least a PR (P-group; n=54) before AHCT were compared with one not achieving at least a PR (NO-P-group; n=9). As an exploratory analysis outcomes of patient achieving at least a very good partial response (VGPR) (V-group; n=40) with ones not achieving at least a VGPR (NO-V-group) was also performed (no-V group; n=23). Results: The mean age of the patients at transplant was 53yrs (range 44 –72yrs). 68 % (n=43) of patients were male. At diagnosis 42 patients (66%) had Salmon-Durie stage III disease, while 21 (34%) had stage I/II disease. Median Karnofsky performance status was 90. At the time of AHCT, the median HCT-CI score was 0. 33 % (n=21) of the patients received radiation therapy prior to transplant. At a median follow-up of 36 months, the 3 year OS of patients in P-group and NO-P-group was 58% vs. 60% (p=0.93) respectively. The 3 year PFS in similar order was 22% vs. 31% (p=0.74). The 3 year OS of patients in V-group and NO-V-group (44% vs. 62%) was also not significantly different (p=0.53). Respective figures of 3 year PFS are 22% vs. 24% (p=0.72) respectively. 3yr non relapse mortality was 5% for the whole cohort. Of the 31 patients that entered an AHCT with a PR, 15 improved to a CR post transplant, 2 improved their status to a VGPR whereas 14 remained in a PR. A total of 9 patients entered an AHCT with a stable disease (SD) of which 5 advanced to a CR, 3 a PR and one remained in SD. On the other hand of the 6 patients who entered an AHCT with a VGPR, 2 improved to a CR whereas the rest maintained their status. Finally, all the 17 patients entering an AHCT with a CR maintained their status. Conclusion: Our limited, retrospective data suggest acceptable AHCT outcomes in MM patients who do not achieve at least a PR in response to novel induction chemotherapies pre-transplantation. Failure to achieve a PR following novel induction therapies should not ‘routinely’ preclude consideration for high-dose therapy and AHCT. Disclosures: Abraham: Genentech: Membership on an entity's Board of Directors or advisory committees. Craig:Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hamadani:celgene: Honoraria, Speakers Bureau; otsuka: Research Funding, Speakers Bureau.

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Daratumumab, Carfilzomib, Lenalidomide and Dexamethasone (Dara-KRd) Induction, Autologous Transplantation and Post-Transplant, Response-Adapted, Measurable Residual Disease (MRD)-Based Dara-Krd Consolidation in Patients with Newly Diagnosed Multiple Myeloma (NDMM)

Blood ◽

10.1182/blood-2019-123170 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 860-860 ◽

Cited By ~ 26

Author(s):

Luciano J. Costa ◽

Saurabh Chhabra ◽

Kelly N. Godby ◽

Eva Medvedova ◽

Robert F. Cornell ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Autologous Transplantation ◽

Newly Diagnosed ◽

Advisory Committees ◽

Post Transplant ◽

Post Induction ◽

Best Response

Background: The CD38-targeting antibody daratumumab, when combined with a proteasome inhibitor or with an immunomodulatory agent (IMiD) increases depth and duration of response in multiple myeloma (MM). Depth of remission post initial therapy as assessed by MRD predicts long term outcome in NDMM. We hypothesized that the combination of daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd) would be safe and highly active in patients with NDMM. In addition, we assessed the feasibility of using MRD by next generation sequencing (clonoSEQ® method, sensitivity 10-6) to inform the use and duration of post-transplant Dara-KRd consolidation. Methods: Eligible patients (pts) had NDMM requiring treatment, creatinine clearance >40 ml/min, adequate liver and cardiac function, ECOG performance status 0-2 with no age limit. Treatment cycles consisted of daratumumab 16 mg/kg IV days 1,8,15,22 (with typical reduction in frequency with subsequent cycles), carfilzomib 56 mg/m2 IV days 1,8,15, lenalidomide 25 mg PO days 1-21 and dexamethasone 40 mg PO/IV days 1,8,15,22 repeated every 28 days. Patients received 4 cycles of Dara-KRd as induction, autologous transplantation, and received 0, 4 or 8 cycles of Dara-KRd consolidation, according to MRD status at each phase of therapy. MRD was evaluated by clonoSEQ® (NGS-MRD; Adaptive Biotechnologies, Seattle, WA) at end of induction, post-transplant, and during each 4-cycle block of Dara-KRd consolidation. Primary endpoint was achievement of MRD negative remission (<10-5) as defined by IMWG consensus. Secondary endpoints included MRD <10-6, complete response (CR) by IMWG criteria at end of induction and upon completion of consolidation, and rate of imaging (assessed by PET/CT scan) plus MRD-negative CR. Patients received therapy until achievement of two consecutive MRD reads <10-5 (confirmed MRD-negative remission; e.g., post-induction and post-transplant or post-transplant and during consolidation). Confirmed MRD-negative pts received no further therapy and were observed with surveillance for MRD resurgence 6 and 18 months after treatment discontinuation. Patients completing consolidation without confirmed MRD-negative remission received standard lenalidomide maintenance (NCT03224507). Results: Currently 69 pts have been enrolled, 38 have completed induction and 22 have completed post-transplant assessment. Median age was 61 (range 38-79) years, 13 (19%) had ISS 3, and 20 (29%) had high-risk chromosomal abnormalities [del17p, t(4;14) or t(14;16)]. Sixty-six (96%) pts had MRD trackable by clonoSEQ® and 100% of the expected MRD datapoints were successfully obtained. All patients responded by end of induction cycle 2, 92% of pts obtained VGPR or better after induction and 91% of patients who have reached transplant obtained CR/sCR as best response on therapy (Figure). MRD-negative remission (<10-5) rate was 34%, 70% and 80% after induction, transplant and at best response, respectively (Figure). Rates of MRD <10-6 were 28%, 45% and 65% respectively. No patient discontinued therapy due to toxicity. One patient died from metapneumovirus pneumonia post-transplant, considered not related to investigational agents. Most common grade 3 and 4 AEs were neutropenia (n=7), infection (n=6), insomnia (n=4), hyperglycemia (n=2) and rash (n=2). There were 15 serious AEs including pneumonia (n=5), fever and neutropenia (n=2), pulmonary embolism (n=1), and atypical hemolytic uremic syndrome (n=1). All 11 patients who have achieved confirmed MRD-negative remission and discontinued therapy also achieved imaging plus MRD-negative CR and none had relapse or resurgence of MRD with short follow up (0.8-7.3 months). Longer follow-up, post-induction and post-transplant MRD assessment for at least 69 and 41 pts, respectively, will be presented at the meeting. Conclusion: This is the first report of monoclonal antibody-based quadruplet regimen with MRD-based response-adapted therapy in NDMM. Dara-KRd induction, autologous transplant and Dara-KRd consolidation guided by MRD is feasible, safe and leads to high proportion of patients achieving CR/sCR, IMWG MRD-negative CR, imaging plus MRD-negative CR and MRD <10-6. This approach can form the basis for clinical efforts to reduce the burden of continuous therapy in those with confirmed MRD-negative remissions. Figure Disclosures Costa: Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; Karyopharm: Consultancy; Fujimoto Pharmaceutical Corporation Japan: Other: Advisor. Cornell:Takeda: Consultancy; KaryoPharm: Consultancy. Silbermann:Janssen, Sanofi: Other: Consultant/Advisor. Dhakal:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Omel:Celgene, Takeda, Janssen: Other: Patient Advisory Committees. Hari:Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria; Cell Vault: Equity Ownership; Sanofi: Honoraria, Research Funding; Spectrum: Consultancy, Research Funding; Amgen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Carfilzomib for newly diagnosed multiple myeloma

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A Risk Stratification Model Using Quantification of Circulating Plasma Cells in Multiple Myeloma Prior to Autologous Stem Cell Transplantation in the Era of Novel Agents

Blood ◽

10.1182/blood.v128.22.996.996 ◽

2016 ◽

Vol 128 (22) ◽

pp. 996-996

Author(s):

Rajshekhar Chakraborty ◽

Eli Muchtar ◽

Shaji Kumar ◽

Dragan Jevremovic ◽

Francis K Buadi ◽

...

Keyword(s):

Risk Stratification ◽

Board Of Directors ◽

Research Funding ◽

Plasma Cells ◽

Disease Status ◽

Novel Agents ◽

Advisory Committees ◽

Post Transplant ◽

Risk Stratification Model ◽

The Impact

Abstract Background: The presence of circulating plasma cells (CPCs) is associated with an adverse prognosis in multiple myeloma along the entire spectrum of disease. However, the impact of CPCs prior to autologous stem cell transplantation (ASCT) has not been defined in the era of novel agents. The objective of this study is to assess the impact of the presence and number of CPCs before transplant using 6-color multiparameter flow cytometry (MFC). We also explored the additional prognostic implications of CPCs over the current paradigm for risk stratification at transplant, including high-risk (HR) cytogenetics and disease status at transplant by the IMWG criteria. Methods: A total of 1113 consecutive patients transplanted between 2007 and 2015 in Mayo Clinic were included in the study. Flow-cytometry of peripheral blood to identify clonal CPCs is routinely performed in all patients before ASCT in Mayo Clinic, Rochester. The mononuclear cells from peripheral blood samples are isolated by Ficoll gradient and subsequently stained with antibodies to CD19, CD38, CD45, CD138 and cytoplasmic kappa (κ) and lambda (λ) immunoglobulin light chains. Clonality is assessed by light chain restriction (κ:λ expression ratio of 4:1 [κ restricted] or <1:2 [λ restricted]). The target for collection is >150,000 cellular events. For samples where less than 150,000 clonal events are examined, the number of final clonal events is adjusted to 150,000 events. HR cytogenetics by fluorescence in situ hybridization (FISH) on bone marrow (BM) plasma cells was defined by one of the following abnormalities: t(4;14), del(17p), t(14;16), t(14;20) or +1q, detected at any time point from diagnosis to transplant. Patients who had insufficient plasma cells for FISH analysis in BM specimens were not included in the denominator to calculate the percentage of patients with HR cytogenetics. The primary end-points of this study were post-transplant response, PFS and OS. Result: CPCs were detected in 238 out of 1113 (21.4%) patients, with the median number of CPCs being 82 (range, 1-102381) per 150,000 events. The median age of patients at transplant was 62 years. A total of 1097 (99%) patients had received novel agent based induction therapy with PIs and IMiDs, including 458 (41%) patients who had received both PIs and IMiDs. 401 (36%) patients had received post-transplant maintenance or consolidation therapy. The frequency of t(4;14) in BMPCs was significantly higher in patients with CPCs compared to those without [15.2 vs 7.0% for t(4;14); P<0.001]. The median follow-up from transplant for survivors was 45 months. The 5-year OS rate in patients with and without CPCs was 34% (95% CI, 27-42) and 70% (95% CI, 66-74) respectively (P<0.001). After exploring several cut-offs for the number of CPCs per 150,000 events, we chose a simple pre-transplant risk stratification model: No CPCs (n=874; 78.5%), 0<CPCs≤400 (n=188; 16.9%) and CPCs>400 (n=51; 4.6%). The number of patients achieving stringent complete response post-transplant in groups with no CPCs, 0<CPCs≤400 and CPCs>400 was 310 (36%), 31 (16%) and 3 (6%) respectively (P<0.001). The median PFS in the 3 groups was 27 months (95% CI, 25-30), 15 months (95% CI, 13-18) and 6 months (95% CI, 4-10) respectively (P<0.001) and 5-year OS rates were 70% (95% CI, 66-74), 42% (95% CI, 34-51) and 12% (95% CI, 5-26) respectively (P<0.001). Kaplan-Meier curves for PFS and OS are depicted in Figure I (A and B). In a multivariate model (Table I), the groups with 0<CPCs≤400 and CPCs>400 had an increased risk of death, independent of the presence of HR cytogenetics and disease status at transplant. Conclusion: Our study shows the strong negative prognostic impact of CPCs prior to transplant on post-transplant response and survival in MM in the era of novel agents. The proposed risk stratification model can be easily employed with simple equipment and should be routinely incorporated in the pre-transplant workup. Detailed epigenomic, genomic and transcriptomic analysis of CPCs is urgently needed to uncover the biological basis of resistance to both high-dose cytotoxic therapy and novel agents and identify potential avenues of targeted therapy against CPCs. Disclosures Kumar: Onyx: Consultancy, Research Funding; Kesios: Consultancy; Celgene: Consultancy, Research Funding; Glycomimetics: Consultancy; AbbVie: Research Funding; BMS: Consultancy; Sanofi: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding. Dispenzieri:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; pfizer: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Jannsen: Research Funding. Kapoor:Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Gertz:Sandoz Inc: Honoraria; NCI Frederick: Honoraria; Celgene: Honoraria; Alnylam Pharmaceuticals: Research Funding; GSK: Honoraria; Novartis: Research Funding; Research to Practice: Honoraria, Speakers Bureau; Med Learning Group: Honoraria, Speakers Bureau; Ionis: Research Funding; Prothena Therapeutics: Research Funding; Annexon Biosciences: Research Funding.

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VTE Rates and Safety Analysis of Newly Diagnosed Multiple Myeloma Patients Receiving Carfilzomib-Lenalidomide-Dexamethasone (KRD) with or without Rivaroxaban Prophylaxis

Blood ◽

10.1182/blood-2019-124403 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1835-1835 ◽

Cited By ~ 4

Author(s):

Katrina M Piedra ◽

Hani Hassoun ◽

Larry W. Buie ◽

Sean M. Devlin ◽

Jessica Flynn ◽

...

Keyword(s):

Multiple Myeloma ◽

Venous Thromboembolism ◽

Board Of Directors ◽

Research Funding ◽

High Dose ◽

Newly Diagnosed ◽

Advisory Committees ◽

Cancer Trial ◽

Oncology Research ◽

Increased Risk

Introduction Immunomodulatory agents (IMiD's) are associated with an increased risk of venous thromboembolism (VTE), particularly when combined with high dose steroids. Studies evaluating the use of lenalidomide-bortezomib-dexamethasone (RVD) and carfilzomib-lenalidomide-dexamethasone (KRD) in the frontline setting for multiple myeloma (MM) have reported a 6% and 24% incidence of thrombosis, respectively, despite primary thrombotic prophylaxis with aspirin (ASA) (Richardson, et al. Blood. 2010; Korde, et al. JAMA Oncol 2015). Recent data, including the Hokusai VTE Cancer Trial, have suggested that safety and efficacy of direct oral anticoagulants (DOACs) are preserved in the setting of treatment of solid malignancy-associated thrombosis (Raskob, et al. N Engl J Med. 2018; Mantha, et al. J Thromb Thrombolysis. 2017). Despite this data, there is limited experience and use of DOACs in prevention of thromboses in the setting of hematologic malignancies, specifically MM. After careful review of literature, since early 2018, we changed our clinical practice and routinely placed newly diagnosed MM (NDMM) patients receiving KRD at Memorial Sloan Kettering Cancer Center (MSKCC) on concomitant rivaroxaban 10 mg once daily, regardless of VTE risk stratification. In the following abstract, we present VTE rates and safety data for newly diagnosed MM patients receiving RVD with ASA vs. KRD with ASA vs. KRD with rivaroxaban prophylaxis. Methods This was an IRB-approved, single-center, retrospective chart review study. All untreated patients with newly diagnosed MM, receiving at least one cycle of RVD or KRD between January 2015 and October 2018 were included. The period of observation included the time between the first day of therapy until 90 days after completion of induction therapy. Patients were identified by querying the pharmacy database for carfilzomib or bortezomib administration and outpatient medication review of thromboprophylaxis with rivaroxaban or ASA. VTE diagnoses were confirmed by ICD-10 codes and appropriate imaging studies (computed tomography and ultrasound). Descriptive statistics were performed. Results During the observation period, 241 patients were identified to have received RVD or KRD in the frontline (99 RVD with ASA; 97 KRD with ASA; 45 KRD with rivaroxaban). Baseline characteristics were well distributed among the three arms, with a median age of 60 (30-94) in the RVD ASA arm, 62 (33-77) in the KRD ASA arm, and 60 (24-79) in the KRD rivaroxaban arm. Patients had International Staging System (ISS) stage 3 disease in 13% (N=13), 9.3% (N=9), and 11% (N=5) of the RVD ASA, KRD ASA, and KRD rivaroxaban arms, respectively. Median weekly doses of dexamethasone were higher in both KRD arms, 40 mg (20-40) vs. 20 mg (10-40) in the RVD ASA arm. The average initial doses of lenalidomide were 22 mg in the RVD ASA arm compared to 25 mg in both the KRD ASA and KRD rivaroxaban arms. After querying the pharmacy database, no patients were identified to have a history or concomitant use of erythropoietin stimulating agent (ESA) use. Treatment-related VTE's occurred in 4 patients (4.0%) in the RVD ASA arm, 16 patients (16.5%) in the KRD ASA arm, and in 1 patient (2.2%) in the KRD rivaroxaban arm. Average time to VTE was 6.15 months (Range 5.42, 9.73) after treatment initiation in the RVD ASA group, while it was 2.61 months (Range 0.43, 5.06) in the KRD ASA group and 1.35 months in the KRD rivaroxaban group. Minor, grade 1 bleeding events per the Common Terminology Criteria for Adverse Events (CTCAE) were identified in 1 (1.1%) patient in the RVD ASA arm, 5 (5.2%) patients in the KRD ASA arm, and 1 (2.2%) patient in the KRD rivaroxaban arm. Conclusion More efficacious MM combination therapies have been found to increase the risk of VTE when using ASA prophylaxis, indicating better thromboprophylaxis is needed. We found patients receiving ASA prophylaxis with KRD were more likely to experience a VTE and these events occurred earlier compared to patients receiving ASA prophylaxis with RVD. Importantly, the rate of VTE was reduced to the same level as ASA prophylaxis with RVD when low-dose rivaroxaban 10 mg daily was used with KRD, and without necessarily increasing bleeding risk. Our retrospective data support the development of prospective clinical trials further investigating DOAC use in thromboprophylaxis for NDMM patients receiving carfilzomib-based treatments. Figure Disclosures Hassoun: Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; Genentech: Research Funding; Juno: Consultancy, Honoraria. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Landgren:Theradex: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Sanofi: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Off-label use of rivaroxaban for outpatient prophylaxis of venous thromboembolism (VTE) will be explicitly disclosed to the audience.

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Secondary Chromosomal Abnormalities Appear to Be Less Prognostic for Children with Philadelphia Chromosome Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) Treated with Intensified Imatinib and Chemotherapy: Results of the Children's Oncology Group (COG) Study AALL0031.

Blood ◽

10.1182/blood.v114.22.2606.2606 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2606-2606

Author(s):

Andrew J. Carroll ◽

Nyla A. Heerema ◽

Meenakshi Devidas ◽

W. Paul Bowman ◽

Chenguang Wang ◽

...

Keyword(s):

Children And Adolescents ◽

Board Of Directors ◽

Chromosomal Abnormalities ◽

Lymphoblastic Leukemia ◽

Prognostic Significance ◽

High Dose ◽

Unrelated Donor ◽

Intensive Chemotherapy ◽

Advisory Committees ◽

The Impact

Abstract Abstract 2606 Poster Board II-582 Background: Secondary chromosomal aberrations at diagnosis occur frequently in both pediatric and adult patients with Ph+ ALL. Several studies have shown that the presence of additional cytogenetic abnormalities is a major negative prognostic factor among children and adults with Ph+ ALL. A Japanese study in adults with Ph+ ALL indicated that the adverse prognostic significance of secondary rearrangements was seen even in patients treated with imatinib-combined chemotherapy including consolidation with blood and marrow transplantation (BMT) (Haematologica 92:287, 2008). Two-year EFS in that study was 48.5±5.7%, and the 50 patients with secondary chromosomal abnormalities had a 35% - 40% lower EFS than those with t(9;22) only (p=0.003). COG AALL0031 treated children with imatinib in combination with intensive chemotherapy. This study had an overall 3 year EFS of 80±11% for those receiving chemotherapy only, an outcome similar to those receiving allogeneic BMT. We evaluated the impact of secondary chromosomal abnormalities in children and adolescents receiving this regimen. Methods: Children and adolescents (age 1–21 years) with Ph+ ALL enrolled on AALL0031 after completing 3- or 4-drug induction therapy. Imatinib was given at 340mg/m2/day for an increasing number of days in combination with an intense chemotherapy backbone. Cohort 4 received imatinib for 126 (N=12) and cohort 5 for 280 continuous days (N=50) prior to maintenance therapy. The first two cycles of the intensive chemotherapy included ifosfamide and etoposide (cycle 1) and high dose (HD) methotrexate and HD cytarabine (cycle 2). Patients were non-randomly assigned to an HLA-identical related donor BMT, if a donor was available, or to an intensive chemotherapy regimen that continued for approximately 2.2 years. Unrelated donor BMT was not allowed; these patients were taken off protocol but included in survival evaluation by an intent-to-treat evaluation. Results: Satisfactory cytogenetic results were available for 71 (76%) of 93 enrolled children. Secondary aberrations were present in 46 (65%) patients. The most frequent secondary aberrations were +der(22) (N=21), =50 chromosomes (N=14), −7/del(7p) (N=11), abnormal (9p) (N=7), and +8 (N=5). The overall 3 year CCR was 79±6% for patients in cohorts 4/5, including those with non evaluable cytogenetics (N=55). When outcome analyses were limited to Ph+ ALL patients in cohorts 4/5 (N=43), three-year CCR for patients with Ph+ alone (N=14) was 86±10% versus 71±9% for those with Ph+ and secondary abnormalities (N=29) (p=0.19). Conclusions: In this study, the lower 3 year CCR seen in patients with Ph+ ALL with secondary chromosomal abnormalities was not significantly different than for children with Ph+ alone possibly reflecting small patient numbers. The lower 3 year CCR for Ph+ ALL with secondary chromosomal abnormalities in those treated on AALL0031 (∼15% lower) appeared to be less than that seen in the previous adult trial (∼35%). This may be the result of the addition of imatinib to intensified chemotherapy reducing the poor prognostic significance of additional chromosome abnormalities seen in previous studies. Larger patient numbers and longer follow-up will be necessary to answer this question. Disclosures: Schultz: DOR Biopharma: Membership on an entity's Board of Directors or advisory committees; Genzyme Canada: Membership on an entity's Board of Directors or advisory committees.

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The Introduction of Novel Agents Improves Outcomes of Young Patients with Myeloma (MM) Treated with Autologous Stem Cell Transplant (ASCT)

Blood ◽

10.1182/blood.v116.21.1348.1348 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1348-1348

Author(s):

Radovan Saso ◽

Kevin D Boyd ◽

Kabir Mohammed ◽

Ping Wu ◽

Jennifer Treleaven ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Survival Rates ◽

Young Patients ◽

Novel Agents ◽

Cell Transplant ◽

Advisory Committees ◽

Younger Patients ◽

Response To Chemotherapy ◽

The Impact

Abstract Abstract 1348 Background: There has been an improvement in the population based survival of patients with MM in the UK (Office of National Statistics), however, because of the way the data is collected it is uncertain what has happened to the outcome of younger patients. High dose melphalan with ASCT has formed an integral part of the treatment of younger patients with myeloma for more than 20 years. During this time the context within which this treatment has been delivered has changed. Peripheral blood stem cell harvesting has replaced bone marrow harvesting, and importantly, novel agents have become available at induction and at relapse. It is not known how these changes have affected patient outcome. We analysed the survival of patients undergoing ASCT for MM in a single referral centre over an 18 year period to assess the impact of these changes. Patients: 1291 patients with myeloma were registered on the Royal Marsden Hospital Database in the period between 1981–2009, of which 875 patients underwent autologous transplantation. Bone marrow transplant (BMT) was performed in 191 patient, while 684 patients had peripheral blood stem cell transplant (SCT). Prognostic Factors: The following factors were found to be associated with improved overall survival (OS) in univariate analysis: Salmon Durie Stage A vs Stage B (p<0.004), ISS Stage I vs II vs III (p<0.001), response to chemotherapy CR vs PR vs Other (p<0.007), Platelets >130 vs <130 × 109/L (p<0.001), Hb >10 vs <10 g/dl (p<0.001), Calcium <10 vs >10mg/dl, Albumin >35 vs <35g/L (p<0.034), B-2M >3.5 vs <3.5 mg/l (p<0.001), IgG vs IgA vs BJ (p<0.038). Variables significant in multivariate testing were: Response to chemotherapy CR vs <CR (HR 1.4; 95% CI 1.0–2.0), Platelets >130 (HR 0.52; 95% CI 0.3–0.9), Calcium (HR1.7; 95% CI 1.2–2.5) and B2M (HR2.1; 95% CI 1.5–2.9). These variables were significantly associated with OS in the overall dataset, and in the subgroup of younger patients under the age of 60. Response and Survival: The overall response (OR) rate following induction chemotherapy was 84%, including 22% complete responses (CR). Following autologous SCT, CR rates improved to 42%, with an OR of 91%. Analysis of actuarial survival for the whole group of patients who had SCT showed that young patients had significantly longer survival (Median survival: <60yrs vs. >60yrs; 8.7yrs vs 6.2yrs, p<0.009). In order to assess the impact of the introduction of new therapeutic agents in, we defined groups of patients treated in five year periods: 1991–1996, 1997–2003, 2004–2009. 5 year OS was unchanged when comparing the first two cohorts. However, the cohort of patients treated from 2004–2009 were associated with significant improvement in 5 year survival rates, from 61% for the earlier quinquennia to 82% for those treated in 2004-9 (p<0.001). We also assessed the impact of the introduction of SCT compared to BMT. SCT entered routine use at this centre in 2002, and patient outcomes did not improve from 2002–2004. The improved survival after 2004 is therefore unlikely to be due to the introduction of SCT. Summary: We found that patient survival following ASCT did not change significantly during the period 1991–2004. However, since 2004 survival rates have improved significantly, and the group that benefitted most were patients under the age of 60. This time period corresponds to the incorporation of novel agents such as thalidomide, bortezomib and lenalidomide into induction and relapse regimens, and suggests that novel agents have significantly improved the outcome of younger patients with myeloma in the context of treatment with ASCT. Disclosures: Boyd: celgene: Honoraria. Davies:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ortho Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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A Comparison of Chemotherapy + G-CSF Versus Plerixafor (Mozobil®) + G-CSF for Stem Cell Mobilization In Patients with Multiple Myeloma Treated with Lenalidomide

Blood ◽

10.1182/blood.v116.21.2258.2258 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2258-2258

Author(s):

Tomer M Mark ◽

Adriana C Rossi ◽

Roger N Pearse ◽

Morton Coleman ◽

David Bernstein ◽

...

Keyword(s):

Stem Cells ◽

Multiple Myeloma ◽

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Yield ◽

High Dose ◽

Advisory Committees ◽

Cd34 Cells ◽

Stem Cell Collection

Abstract Abstract 2258 Background: Prior use of lenalidomide beyond 6 cycles of therapy in the treatment of multiple myeloma (MM) has been shown to negatively impact stem cell yield, but this phenomenon can be overcome with the addition of high-dose cyclophosphamide to standard G-CSF mobilization. We hypothesized that the use of plerixafor (Mozobil®) would compare similarly to chemotherapy in rescuing the ability to collect stem cells in lenalidomide-treated myeloma. Methods: We performed a retrospective study comparing the efficacy of plerixafor + G-CSF mobilization (PG) to chemotherapy + G-CSF (CG) (either high-dose cyclophosphamide at 3g/m2 or DCEP [4-day infusional dexamethasone/ cyclophosphamide/ etoposide/cisplatin]) in 49 consecutive stem cell collection attempts in patients with MM exposed to prior lenalidomide. The primary endpoint was the ability to collect sufficient stem cells for at least two transplants (minimum 5×106 CD34+ cells/kg), comparing results in terms of total exposure to lenalidomide and time elapsed from lenalidomide exposure until the mobilization attempt. The secondary endpoint was number of apheresis days required to meet collection goal. Resilts: Twenty-four patients underwent PG mobilization and twenty-five with CG (21 with G-CSF + cyclophosphamide, 4 with G-CSF+DCEP). The two groups did not differ in terms of total amount of lenalidomide exposure: median number of lenalidomide cycles for patients mobilized with PG was 6.5 (range 1.2–86.6), vs. 6 (range 2–21.6), for patients mobilized with CG (P = 0.663). The median time between mobilization and last lenalidomide dose was also similar between the two groups: 57.5 (range 12–462) days for PG vs. 154 (range 27–805) days for CG (P = 0.101). There was an equivalent rate of successful collection of 100% for PG and 96% for CG, P = 0.322. One patient failed collection in the CG group due to emergent hospitalization for septic shock during a period of neutropenia; no patient collected with PG had a serious adverse event that interrupted the collection process. Stem cell yield did not differ between the two arms (13.9 vs. 18.8 × 106 million CD34+ cells/kg for PG vs. CG respectively, P = 0.083). Average time to collection goal was also equal, with a median of time of 1 day required in both groups, (range 1–2 days for PG, 1–5 days for CG, P = 0.073). There was no relationship between amount of lenalidomide exposure and stem cell yield with either PG (P = 0.243) or CG (P = 0.867). Conclusion: A plerixafor + G-CSF mobilization schedule is equivalent in efficacy to chemotherapy + G-CSF in obtaining adequate numbers of stem cells for two autologous stem cell transplants in patients with MM exposed to lenalidomide; however, PG may be a less toxic approach than chemomobilization. Number of lenalidomide cycles has no impact on chances of stem cell collection success using either method. Disclosures: Mark: Celgene Corp: Speakers Bureau; Millenium Corp: Speakers Bureau. Zafar: Celgene Corp: Speakers Bureau. Niesvizky: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Research Funding.

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Achievement of Complete Response Is a Strong Prognostic Factor In Elderly Newly Diagnosed Myeloma: Retrospective Analysis of 1175 Patients

Blood ◽

10.1182/blood.v116.21.1949.1949 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1949-1949

Author(s):

Francesca Gay ◽

Alessandra Larocca ◽

P.W. Wijermans ◽

Sara Bringhen ◽

Tommasina Guglielmelli ◽

...

Keyword(s):

Board Of Directors ◽

Complete Response ◽

New Drugs ◽

Response To Treatment ◽

Maximal Response ◽

High Dose ◽

Newly Diagnosed ◽

Advisory Committees ◽

Best Response ◽

The Impact

Abstract Abstract 1949 Introduction: There is extensive evidence from numerous studies in the transplant setting that achievement of complete response (CR) or at least very good partial response (VGPR) is significantly associated with prolonged progression-free survival (PFS) and overall survival (OS). In elderly myeloma patients CR was a rare event since new drugs has been added to standard melphalan-prednisone (MP). After the introduction of novel agents, CR represents an achievable goal, also outside of the transplant setting. Aims: to assess the impact of response to treatment on time-to-event parameters (PFS and OS) in elderly myeloma patients. Methods: We retrospectively analysed newly diagnosed myeloma patients, older than 65 years old, or younger but not eligible for high-dose chemotherapy and transplant. Patients were enrolled in 3 multicentre randomized European trials of the GIMEMA and Hovon groups, and were treated with MP (n=332), MP plus thalidomide (MPT, n=332), MP plus bortezomib (VMP, n=257) or MP plus bortezomib-thalidomide followed by bortezomib-thalidomide maintenance (VMPT-VT, n=254). PFS, OS and duration of CR were analysed by the Cox proportional hazards model, comparing the two arms by the Wald test and calculating 95% confidence interval (CI). Univariate and multivariate analyses were performed for the following variables: age at diagnosis (>75 vs. ≤75 yrs), International Staging System (ISS) stages, type of chemotherapy and best response achieved. Best response was treated as a time-dependent variable. Results: A total of 1,175 patients, enrolled from November, 2001 to January, 2009, were retrospectively analysed. The best response to treatment was available in 1,136 patients: CR was reported in 195, VGPR in 212, PR in 397. Baseline characteristics according to best response achieved in patients who obtained CR, VGPR or PR were similar. Since response rates vary according to treatment regimens the proportion of patients who received MP, MPT, VMP, and VMPT-VT was different in the different response categories. After a median follow-up of 29 months, PFS was significantly higher in patients who achieved CR compared to those who obtained VGPR (HR 0.16; 95% CI 0.10–0.24; p<0.001) or PR (HR 0.07; 95% CI 0.04–0.13; p<0.001). The advantage in PFS translated into an advantage in OS: patients obtaining CR have a significantly prolonged OS than patients who achieved VGPR (HR 0.15; 95% CI 0.08–0.28; p<0.001) or PR (HR 0.08; 95% CI 0.04–0.16, p<0.001), (table). In multivariate analysis CR achievement was as an independent predictor of longer PFS and OS, regardless of age, ISS stage, and treatment administered. In patients > 75 years, both PFS and OS were shorter as compared to younger patients. Despite these differences, the impact of CR on outcome was identical. In the subgroup of patients > 75 years, PFS was significantly prolonged in patients who achieved CR, compared with those who obtained VGPR (HR 0.26; 95% CI 0.12–0.58, p = 0.001) or PR (HR 0.20; 95% CI 0.10–0.41, p < 0.001). Accordingly, OS was significantly higher in patients who achieved CR, compared with those who obtained VGPR (HR 0.13; 95% IC 0.03–0.58; p = 0.007), or PR (HR 0.12; 95% IC 0.03–0.51, p = 0.004), (table). No significant PFS differences between patients obtaining CR during the first 6 months of treatment or later were seen (HR 1.06; 95% IC 0.49–2.27; p=0.878). Similarly, no OS differences between these two groups were detected (p = 0.676). Duration of CR was comparable in patients who obtained CR during or after the first 6 months of treatment (HR 0.66; 95% CI 0.30–1.45; p = 0.305). Patients whose CR lasted more than 18 months have a significant OS benefit compared to patients who did not (p=0.006). Conclusions: These finding highlight the importance of CR, also outside of the transplant setting, regardless of age, ISS and treatment administered, and support the use of new drugs, also in patients older than 75 years, to achieve and maintain maximal response. Disclosures: Gay: Celgene: Honoraria. Bringhen:Calgene: Honoraria; Janssen-Cilag: Honoraria. Guglielmelli:Celgene: Honoraria; Janssen Cilag: Honoraria. Boccadoro:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Sonneveld:Celgene: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson : Membership on an entity's Board of Directors or advisory committees. Palumbo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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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

Blood ◽

10.1182/blood.v116.21.42.42 ◽

2010 ◽

Vol 116 (21) ◽

pp. 42-42 ◽

Cited By ~ 4

Author(s):

Michele Cavo ◽

Giulia Perrone ◽

Silvia Buttignol ◽

Elisabetta Calabrese ◽

Monica Galli ◽

...

Keyword(s):

Multiple Myeloma ◽

Multivariate Analysis ◽

Board Of Directors ◽

Induction Therapy ◽

Autologous Transplantation ◽

Consolidation Therapy ◽

Newly Diagnosed ◽

Advisory Committees ◽

Significant Difference

Abstract Abstract 42 We 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.

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