Survivorship in WM: Identification of Factors Associated with Survival of More Than a Decade and with Early WM-Related Death

Abstract Waldenström's Macroglobulinemia (WM) is a low grade lymphoma with a prolonged course and a median survival exceeding 7 years. However, there are patients who die of WM early during the course of the disease while a significant proportion of WM patients can survive ≥10 years. The characteristics of these two groups of patients may differ and their identification may augment the choice of risk adapted treatment strategies. The aim of our study was to identify and characterize patients with short survival due to WM as well as those with survival exceeding 10 years, and to compare their characteristics in order to evaluate clinical factors associated with poor or with good outcomes, based on data from a large database with long follow up. The analysis included 492 patients that have been entered in the prospectively maintained database of the Greek Myeloma Study Group, who fulfill the criteria form symptomatic WM requiring therapy. The median follow up of all the patients in the database is 10 years. For the first part of the analysis we included 292 patients who have at least 10 years of follow up (thus, they started therapy at least 10 years ago, before 2006). Among them, we identified 101 (34.5%) patients who survived ≥10 years, and 13% who died due to WM within <3 years after initiation of treatment. When compared to patients who survived less than 10 years, those with survival ≥ 10 years had lower levels of b2microglobulin (p=0.043), higher levels of serum albumin (p=0.004) and were younger (p<0.001); however, cytopenias and IgM levels were not significantly different between the two groups. We then compared the characteristics of those who survived ≥10 years to patients from the same subgroup (i.e those who started therapy before 2006) who died of WM within <3 years: 10-years survivors were younger (64% vs 16% were ≤65 years, p<0.001), had less anemia (hgb<11.5 gr/dl in 69% vs 89%, p=0.006), thrombocytopenia (platelet counts <100x109/L in 8% vs 22%, p=0.017), had less often LDH ≥250 IU/L (12% vs 29%, p=0.014), b2-microglobulin ≥3 mg/L (56% vs 76%, p=0.31), serum albumin <4 gr/dl (68% vs 83%, p=0.001) and splenomegaly (27% vs 51%, p=0.002) compared to those who survived <3 years. Per ISSWM their disposition was 30%, 35% & 35% for low, intermediate and high risk for those that survived ≥10 years and was 33% and 67% for intermediate and high risk for those that survived <3 years (no patient had low risk disease) (p<0.001). As a validation of the previous results, we evaluated the presence of the above clinical characteristics in patients with survival <3 years who started therapy between 2006 and 2012 (n=177) and thus, had a minimum follow up ≥3 years. The incidence of WM-related death within <3 years was 10%, similar to what was observed in the era before 2006. The characteristics of patients with short survival in the era 2006-2012 were similar to that of patients with short survival in the period before 2006: age >65 in 63%, hgb<11.5 gr/dl in 89%, platelet counts <100x109/L in 11%, LDH ≥250 IU/L n 39%, b2-microglobulin ≥3 mg/L in 82%, serum albumin <4 gr/dl in 89%, splenomegaly in 28% and per ISSWM, 29% were intermediate and 65% high risk. In order to further elucidate the most important characteristics of patients with short WM-related survival we performed further analysis in all patients with a minimum follow up ≥3 years. Based on ROC analysis for early death, serum albumin <4 gr/dL and b2microglobulin >4 mg/L were the two most important predictors of early WM-related death. When age >65 years was also included as a predictor, patients with 0, 1, 2 or 3 of the above factors had 3-year WM-related death rate of 3%, 4%, 16% and 25% (p<0.001). Regarding overall survival, 4 groups with significant 5-year (93%, 89%, 72% and 44%) and 10-year survival (81%, 62%, 38% and 23%) were identified (p<0.001)(figure 1). Also, this staging by b2m, serum albumin and age outperformed IPSSWM. In conclusion, 34.5% of patients with WM survive ≥10 years, but 10%-13% die of WM within < 3 years from initiation of treatment. These patients with high risk disease are older with higher tumor bulk and increased LDH. However, by applying only the presence of serum albumin < 4 gr/dl, b2 microglobulin ≥4 mg/L and age >65 years we can identify patients at very low risk of early death as well as patients with significant risk of early death and short survival. This simple staging system may also outperform IPSSWM. Figure 1 Figure 1. Disclosures Kastritis: Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Genesis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Kyrtsonis:Genesis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Katodritou:Genesis: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Delimpasi:Amgen: Honoraria; Janssen: Honoraria; Genesis: Honoraria. Terpos:Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Dimopoulos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: 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; Genesis: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Extended Follow-up of the Multi-Center Multi-National Prospective Cohort Study That Derived the “Men Continue and HERDOO2” Clinical Decision Rule Which Identifies Low Risk Patients Who May Be Able to Discontinue Oral Anticoagulants (Oac) 5-7 Months After Treatment for Unprovoked Venous Thromboembolism (VTE).

Blood ◽

10.1182/blood.v114.22.451.451 ◽

2009 ◽

Vol 114 (22) ◽

pp. 451-451 ◽

Cited By ~ 3

Author(s):

Marc Rodger ◽

Michael J. Kovacs ◽

Susan Kahn ◽

Phil Wells ◽

David Anderson ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Low Risk ◽

Advisory Committees ◽

High Risk Women ◽

Risk Patients ◽

Recurrent Vte ◽

Annual Risk

Abstract Abstract 451 Introduction: To continue or discontinue OAC after 6 months of therapy for VTE is one of the most important unanswered questions in VTE management. In 2007, we developed a clinical decision rule to identify low risk patients with unprovoked VTE who could safely discontinue OAC after 5-7 months of therapy. This clinical decision rule was developed from a large prospective cohort study of patients with unprovoked VTE who discontinued anticoagulants after 5-7 months of OAC and were subsequently followed for a mean of 18 months for recurrent VTE. The “MEN continue and HERDOO2” rule states that men and high risk women should continue anticoagulants indefinitely after unprovoked VTE. High risk women are women with ≥2 of the following 1)Hyperpigmentation, Edema or Redness (HER) on exam in either leg, 2)Vidas D-Dimer >250, 3)Obesity- BMI >30 or 4)Older age over 65. Given that the OAC treatment decision is a long-term treatment decision that needs to be counter-balanced with long-term bleeding risk from OAC (1-3% annual risk of major hemorrhage) it is important to determine long-term risks of recurrent VTE in unprovoked VTE patients, high risk patients and low risk patients. Objective: We sought to confirm that the risk of recurrent VTE in high risk patients remains elevated and conversely that the risk remains low in low risk women over longer term follow-up. Methods: Multi-centre prospective cohort study of first unprovoked VTE patients who had potential predictors collected while on OAC (including D-Dimer) enrolled from 2001 to March 2006. Patients were excluded if they had: 1) recurrent unprovoked VTE, 2) known high risk thrombophilia or 3) no consent. Symptomatic suspected VTE during subsequent follow-up (up to july 2009) off of OAC was investigated with reference to baseline imaging and then independently adjudicated. Results: 646 participants were enrolled in 11 centers. At enrolment, mean age of 53 (range 17-95) and 49% were female. During a mean 3.1 years (range 0.01-6.5) of follow-up, 131/512 suspected VTE were adjudicated as recurrent VTE resulting in an annual risk of recurrent VTE of 6.7% (95% CI 5.5-7.6%) in patients with unprovoked VTE. Men had a 9.9% (95% CI 8.3-11.8%) annual risk of recurrent VTE. High risk women with 2 or more HERDOO points had an annual risk of recurrent VTE of 8.3% (95%CI 5.7-11.3%). Low risk women (1 or 0 HERDOO points) had 1.3% (95% CI 0.5-2.8%) annual risk of recurrent VTE compared to 9.5% (8.1-11.0%) annual risk of recurrent VTE in high risk patients (men and high risk women). Conclusions: Men and high risk women with unprovoked VTE should be considered for long-term OAC therapy given a high risk of recurrent VTE over 3 year follow-up . Women with a low HER DOO 2 score may be able to safely discontinue anticoagulants. Disclosures: Rodger: Bayer: Research Funding; Leo Pharma: Research Funding; Pfizer: Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Biomerieux: Research Funding; GTC Therapeutics: Research Funding. Crowther:BI: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Research Funding; Leo Pharma: Consultancy, Honoraria, Research Funding; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Artisan Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Conventional Immunochemotherapy (R-CHOEP) Vs High-Dose Immunochemotherapy (R-MegaCHOEP) in Younger Patients with High-Risk Aggressive B-Cell Lymphoma: 10-Year Long-Term Follow-up of a German Lymphoma Alliance (GLA) Study

Blood ◽

10.1182/blood-2019-123637 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1589-1589

Author(s):

Fabian Frontzek ◽

Marita Ziepert ◽

Maike Nickelsen ◽

Bettina Altmann ◽

Bertram Glass ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

High Dose ◽

Advisory Committees ◽

Scientific Advisory Board ◽

Scientific Advisory

Introduction: The R-MegaCHOEP trial showed that dose-escalation of conventional chemotherapy necessitating autologous stem cell transplantation (ASCT) does not confer a survival benefit for younger patients (pts) with high-risk aggressive B-cell lymphoma in the Rituximab era (Schmitz et al., Lancet Oncology 2012; 13, 1250-1259). To describe efficacy and toxicity over time and document the long-term risks of relapse and secondary malignancy we present the 10-year follow-up of this study. Methods: In the randomized, prospective phase 3 trial R-MegaCHOEP younger pts aged 18-60 years with newly diagnosed, high-risk (aaIPI 2-3) aggressive B-cell lymphoma were assigned to 8 cycles of CHOEP (cyclophosphamide, doxorubcine, vincristine, etoposide, prednisone) or 4 cycles of dose-escalated high-dose therapy (HDT) necessitating repetitive ASCT both combined with Rituximab. Both arms were stratified according to aaIPI, bulky disease, and center. Primary endpoint was event-free survival (EFS). All analyses were calculated for the intention-to-treat population. This follow-up report includes molecular data based on immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) for MYC (IHC: 31/92 positive [40-100%], FISH: 14/103 positive), BCL2 (IHC: 65/89 positive [50-100%], FISH: 23/111 positive) and BCL6 (IHC: 52/86 positive [30-100%], FISH: 34/110 positive) and data on cell of origin (COO) classification according to the Lymph2CX assay (GCB: 53/88; ABC: 24/88; unclassified: 11/88). Results: 130 pts had been assigned to R-CHOEP and 132 to R-MegaCHOEP. DLBCL was the most common lymphoma subtype (~80%). 73% of pts scored an aaIPI of 2 and 27% an aaIPI of 3. 60% of pts had an initial lymphoma bulk and in 40% more than 1 extranodal site was involved. After a median observation time of 111 months, EFS at 10 years was 57% (95% CI 47-67%) in the R-CHOEP vs. 51% in the R-MegaCHOEP arm (42-61%) (hazard ratio 1.3, 95% CI 0.9-1.8, p=0.228), overall survival (OS) after 10 years was 72% (63-81%) vs. 66% (57-76%) respectively (p=0.249). With regard to molecular characterization, we were unable to detect a significant benefit for HDT/ASCT in any subgroup analyzed. In total, 16% of pts (30 pts) relapsed after having achieved a complete remission (CR). 23% of all relapses (7 pts) showed an indolent histology (follicular lymphoma grade 1-3a) and 6 of these pts survived long-term. In contrast, of 23 pts (77%) relapsing with aggressive DLBCL or unknown histology 18 pts died due to lymphoma or related therapy. The majority of relapses occurred during the first 3 years after randomization (median time: 22 months) while after 5 years we detected relapses only in 5 pts (3% of all 190 pts prior CR). 11% of pts were initially progressive (28 pts) among whom 71% (20 pts) died rapidly due to lymphoma. Interestingly, the remaining 29% (8 pts) showed a long-term survival after salvage therapy (+/- ASCT); only 1 pt received allogeneic transplantation. The frequency of secondary malignancies was very similar in both treatment arms (9% vs. 8%) despite the very high dose of etoposide (total 4g/m2)in the R-MegaCHOEP arm. We observed 2 cases of AML and 1 case of MDS per arm. In total 70 pts (28%) have died: 30 pts due to lymphoma (12%), 22 pts therapy-related (11 pts due to salvage therapy) (9%), 8 pts of secondary neoplasia (3%), 5 pts due to concomitant disease (2%) and 5 pts for unknown reasons. Conclusions: This 10-year long-term follow-up of the R-MegaCHOEP trial confirms the very encouraging outcome of young high-risk pts following conventional chemotherapy with R-CHOEP. High-dose therapy did not improve outcome in any subgroup analysis including molecular high-risk groups. Relapse rate was generally low. Pts with aggressive relapse showed a very poor long-term outcome while pts with indolent histology at relapse survived long-term. Secondary malignancies occurred; however, they were rare with no excess leukemias/MDS following treatment with very high doses of etoposide and other cytotoxic agents. Supported by Deutsche Krebshilfe. Figure Disclosures Nickelsen: Roche Pharma AG: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Janssen: Membership on an entity's Board of Directors or advisory committees. Hänel:Amgen: Honoraria; Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board; Roche: Honoraria. Truemper:Nordic Nanovector: Consultancy; Roche: Research Funding; Mundipharma: Research Funding; Janssen Oncology: Consultancy; Takeda: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding. Held:Roche: Consultancy, Other: Travel support, Research Funding; Amgen: Research Funding; Acrotech: Research Funding; MSD: Consultancy; Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding. Dreyling:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Novartis: Other: scientific advisory board; Sandoz: Other: scientific advisory board; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Acerta: Other: scientific advisory board. Viardot:Kite/Gilead: 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; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosenwald:MorphoSys: Consultancy. Lenz:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Employment, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy. Schmitz:Novartis: Honoraria; Gilead: Honoraria; Celgene: Equity Ownership; Riemser: Consultancy, Honoraria.

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ABVD Versus Escalated Beacopp in Advanced Stage Hodgkin's Lymphoma: Results from a Retrospective, Multicenter European Study

Blood ◽

10.1182/blood-2019-128198 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1565-1565 ◽

Cited By ~ 1

Author(s):

Patrizia Mondello ◽

Irene Dogliotti ◽

Jan-Paul Bohn ◽

Federica Cavallo ◽

Simone Ferrero ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Advanced Stage ◽

Advisory Committees ◽

Free Survival ◽

High Risk Patients ◽

Risk Patients

Purpose: Hodgkin's lymphoma (HL) is a highly curable disease even in advanced-stage, with >90% of long-term survivors. Currently, the standard of care is ABVD (doxorubicin, etoposide, vinblastine and dacarbazine), as it is less toxic and as effective as other more intensive chemotherapy regimens. Alternatively, BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) has been proposed as front-line intensified regimen with a better initial disease control and prolonged time to relapse when compared to ABVD. However, this advantage is associated with higher rates of severe hematologic toxicity, treatment-related deaths, secondary neoplasms and infertility. To date, the debate regarding which regimen should be preferred as first line for advanced-stage HL is still ongoing. To shed some light on this open question we compared efficacy and safety of both regimens in clinical practice. Patients and Methods: From October 2009 to October 2018, patients with HL stage III-IV treated with either ABVD or BEACOPP escalated (BEACOPPesc) were retrospectively assessed in 7 European cancer centers. Results: A total of 372 consecutive patients were included in the study. One-hundred and ten patients were treated with BEACOPPesc and 262 with ABVD. The baseline characteristics of the two groups did not differ significantly, except for a higher rate of high-risk patients in the BEACOPPesc group in contrast to the ABVD one (47% vs 18%; p= 0.003). Complete response rate (CR) assessed by PET imaging at the end of the second cycle was 67% and 78% for the ABVD and BEACOPPesc group (p= 0.003), respectively. Thirteen patients of the ABVD group achieved stable disease (SD) and 6 had a progression disease (PD). On the other hand, 4 of the patients in the BEACOPPesc group progressed, another 2 interrupted therapy because life-threatening toxicity. At the end of the therapy, CR was 76% in the ABVD group and 85% in the BEACOPPesc group (p= 0.01). A total of 20% patients in the ABVD group and 14% patients in the BEACOPPesc group received consolidation radiotherapy on the mediastinal mass at the dose of 30Gy. After radiotherapy, the number of patients with CR increased to 79% and 87% in the two groups (p= 0.041), respectively. Thirty-nine patients (35%) in the BEACOPPesc group required dose reduction of chemotherapy due to toxicity compared to 12 patients (5%; p= <0.001) in the ABVD group. Overall, the rate of severe toxicities was higher in the BEACOPPesc group in comparison with the ABVD cohort. In particular, there was a significant increased frequency of acute grade 3-4 hematologic adverse events (neutropenia 61% vs 24%; anemia 29% vs 4%; thrombocytopenia 29% vs 3%), febrile neutropenia (29% vs 3%), severe infections (18% vs 3%). Myeloid growth factors were administered to 85% and 59% of patients in the BEACOPPesc group compared to the ABVD group. Blood transfusions were required in 51% and 6% of patients in the BEACOPPesc group compared to the ABVD cohort. Progression during or shortly after treatment occurred in 5 patients in the BEACOPPesc group (4%) and in 16 patients in the ABVD group (6%; p= 0.62). Among the 96 patients who achieved a CR after BEACOPPesc and radiotherapy, 8 relapsed (8%), compared to 29 of 208 patients in the ABVD group (14%; p= 0.04). At a median follow-up period of 5 years, no statistical difference in progression free survival (PFS; p=0.11) and event-free survival (EFS; p=0.22) was observed between the BEACOPPesc and ABVD cohorts. Similarly, overall survival (OS) did not differ between the two groups (p=0.14). The baseline international prognostic score (IPS <3 vs ≥ 3) significantly influenced the EFS with an advantage for the high-risk group treated with BEACOPPesc (Figure 1A; p=0.03), but not the PFS (Figure 1B; p=0.06) and OS (Figure 1C; p=0.14). During the follow-up period, in the BEACOPPesc group one patient developed myelodysplasia and one acute leukemia. Second solid tumors developed in one patient in the ABVD group (lung cancer) and one in BEACOPPesc group (breast cancer). Conclusion: We confirm that the ABVD regimen is an effective and less toxic therapeutic option for advanced-stage HL. Although BEACOPP results in better initial tumor control especially in high-risk patients, the long-term outcome remains similar between the two regimens. Disclosures Ferrero: EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Speakers Bureau. Martinelli:BMS: Consultancy; Pfizer: Consultancy; ARIAD: Consultancy; Roche: Consultancy; Novartis: Consultancy. Willenbacher:European Commission: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Myelom- und Lymphomselbsthilfe Österreich: Consultancy, Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Science: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; IQVIA: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; oncotyrol: Employment, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fujimoto: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: 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, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tirol Program: Research Funding; Abbvie: Consultancy, Honoraria; Sandoz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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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

Blood ◽

10.1182/blood.v122.21.2090.2090 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2090-2090 ◽

Cited By ~ 4

Author(s):

Michele Cavo ◽

Monica Galli ◽

Annalisa Pezzi ◽

Francesco Di Raimondo ◽

Claudia Crippa ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Low Risk ◽

Standards Of Care ◽

Consolidation Therapy ◽

Phase 3 ◽

Advisory Committees ◽

Cox Regression Analysis

Abstract 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. 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.

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

Blood ◽

10.1182/blood.v124.21.4761.4761 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4761-4761 ◽

Cited By ~ 1

Author(s):

Tomer M Mark ◽

Abbe Schickner ◽

John N. Allan ◽

Adriana C Rossi ◽

Roger Pearse ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Maximum Response ◽

First Line ◽

Advisory Committees ◽

Cell Harvest ◽

Grade Iii

Abstract Background: Carfilzomib (Cfz), lenalidomide, and dexamethasone synergize to provide an impressive overall response rate (ORR) in upfront treatment of multiple myeloma (MM) (Jakubowiak et al 2012). The ORR to Cfz+dexamethasone (Cfz-Dex) as first-line therapy is unknown. We hypothesized that sequential treatment with Cfz-dex and BiRD would improve provide similar ORR and improve tolerability. A protocol of Cfz-Dex, consolidation with BiRd (Clarithromycin(Biaxin¨), Lenalidomide/(Revlimid¨), dexamethasone), and lenalidomide maintenance (Len) was conducted to evaluate ORR and safety as induction therapy for MM. Methods: Forty patients (pts) with symptomatic untreated MM were enrolled in a phase 2 study of Car-BiRd. Car-BiRd therapy is: Cfz IV over 30 min on Days 1, 2, 8, 9, 15, 16 of a 28-day cycle at a dose of 20mg/m2 on days 1, 2 of the 1st cycle only and 45mg/m2 for each dose thereafter and dex 40mg on D1, 8, 15, 22. After the first 26 pts were enrolled, the protocol was amended to increase the Cfz from 45 to 56mg/m2. Echocardiography and spirometry were performed prior to study entry and serum brain natriuretic peptide (BNP) was followed monthly to evaluate for heart or lung toxicity. Cfz-dex was continued until plateau in disease response, defined as unchanged M-protein for 2 cycles. Elective stem cell collection was then performed in transplant eligible pts and consolidation with BiRd initiated. Transplant ineligible pts proceeded directly to BiRd. BiRd is: Clarithromycin 500mg BID, lenalidomide 25mg daily on D1-21, and dex 40mg on D1, 8, 15, 22 of 28-day cycle. BiRd was continued until a 2nd response plateau after which lenalidomide maintenance (Len) at 10mg daily D1-21 of 28 day cycle was continued until disease progression or intolerability. Results: 36 pts completed at least 1 cycle and were evaluable for response. 58% of pts were ISS II/III. High-risk cytogenetics and unfavorable MyPRS score were found in 62% and 21% of pts, respectively. Median study follow-up was 66.2 weeks (range 3.7-114.7). Maximum response to the Cfz-dex, BiRd, and Len is shown in Table 1. Median time to PR was 1 cycle. Median time to maximum response with Cfz-dex, BiRD, and Len was 2, 2, and 4 cycles respectively. At last audit, 8 (22%) pts remain on Cfz-Dex; 21 (58%) reached plateau and received BiRd. Of the pts that received BiRd, 9 (43%) improved categorical response and 19 (90.5%) received Len. Two (11%) pts deepened response to CR while on Len. 97.5% of pts are alive and 82.5% without progression at last follow-up. One pt died after coming off study (withdrew consent) from sepsis during elective autologous stem cell transplant. Pts with high risk cytogenetics had a trend towards a shorter progression free survival (PFS), with median 71.7 weeks vs not reached (NR) (P = 0.058). Similar results were seen with unfavorable MyPRS score with a shorter median PFS at 71.7 weeks vs NR (P = 0.094). 17 pts had stem cell harvest following Cfz-dex. All collected stem cells to support at least two transplants, with median 14.5 x 10^6 (range 7.06-27) CD34/kg in a median of 1 (range 1-2) apheresis session. 18 pts (46.2%) have come off study, 6 (15%) for disease progression (2 during CfzDex , 1 during BiRD, 3 during Len) and 5 pts (12.5%) due to toxicity: 3 pts for renal failure [2 Grade 2, I grade 3, all with renal recovery after discontinuation, all attributable to Cfz]; 1 pt due to Grade III CHF [attributable to Cfz with recovery]; 1 pt with Grade III Thromboembolic [attributable Len]. There was no correlation between pre-study cardiac and lung function, or serial BNP, with toxicities. Seven (17.9%) pts came off study for noncompliance, lost to follow up, investigator discretion, or withdrew consent (Cfz-dex: 4, BiRD: 1, Len: 2). Discussion: This is the first prospective study evaluating induction response to Cfz/Dex in MM. Cfz/Dex is safe and active, with ORR of 91.7% and rate of >=VGPR of 55.6%, despite the majority with a high-risk cytogenetics. Cfz-dex did not hinder stem cell harvest. ORR improved with lenalidomide-based consolidation and maintenance, with CR rate > 50%. Baseline heart/lung function or serial BNP change did not predict emerging toxicities. Table 1: Maximum Response For Car-BiRD Phase: Response Category Car-Dex BiRD Lenalidomide N = 36 N = 21 N = 19 PD 0 1 (4.8) 0 SD 3 (8.3) 0 0 PR 13 (36.1) 1 (4.8) 1 (5.3) VGPR 17 (47.2) 12 (57.1) 8 (42.1) CR 1 (2.8) 0 0 SCR 1 (2.8) 5 (23.8) 8 (42.1) ICR 1 (2.8) 2 (9.5) 2 (10.5) >=PR 91.7 95.2 100 >=VGPR 55.6 90.4 94.7 >=CR 8.4 33.3 52.6 Disclosures Mark: Onyx: Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Carfilzomib is not approved for first-line treatment of myeloma. . Rossi:Celgene: Speakers Bureau. Pekle:Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Perry:Celgene: Speakers Bureau. Coleman:Onyx: Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Niesvizky:Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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A Novel Prognostic Model That Is Superior to FLIPI-1 and FLIPI-2 and Integrates Clinical and Treatment Factors to Predict Progression-Free Survival and Early Treatment Failure in Patients with Follicular Lymphoma in the GALLIUM Trial

Blood ◽

10.1182/blood-2018-99-114620 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2872-2872 ◽

Cited By ~ 2

Author(s):

Farheen Mir ◽

Andrew Grigg ◽

Michael Herold ◽

Wolfgang Hiddemann ◽

Robert Marcus ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Prognostic Model ◽

Low Risk ◽

Prognostic Variables ◽

Advisory Committees ◽

High Risk Disease ◽

Risk Patients ◽

Equity Ownership

Abstract Introduction: Progression of disease within 24 months of initial therapy (POD24) is associated with poor survival in patients with follicular lymphoma (FL). Existing prognostic models, such as FLIPI-1 and FLIPI-2, show poor sensitivity for POD24, and are derived from cohorts lacking bendamustine-treated patients. More accurate predictive models based on current standard therapies are needed to identify patients with high-risk disease. The Phase III GALLIUM trial (NCT01332968) compared the safety and efficacy of standard chemotherapy regimens plus rituximab (R) or obinutuzumab (G) in patients with previously untreated FL. Using GALLIUM data, we developed a novel risk stratification model to predict both PFS and POD24 in FL patients after first-line immunochemotherapy. Methods: Enrolled patients were aged ≥18 years with previously untreated FL (grades 1-3a), Stage III/IV disease (or Stage II with bulk), and ECOG PS ≤2, and required treatment by GELF criteria. Patients were randomized to receive either G- or R-based immunochemotherapy, followed by maintenance with the same antibody in responders. The chemotherapy arm (CHOP, CVP, or bendamustine) was selected by each study center. POD24 was defined as progressive disease or death due to disease within 24 months of randomization (noPOD24 = no progression or lymphoma-related death in that period). The most strongly prognostic variables, based on PFS hazard ratios, were estimated using penalized multivariate Cox regression methodology via an Elastic Net model. Selected variables were given equal weights, and a clinical score was formed by summating the number of risk factors for each patient. Low- and high-risk categories were determined using a cut-off that provided the best balance between true- and false-positives for PFS. PFS correlation and sensitivity to predict POD24 were assessed. The data used are from an updated GALLIUM efficacy analysis (data cut-off: April 2018; median follow-up: 57 months). Results: 1202 FL patients were enrolled. Based on data availability and biological plausibility (i.e. could reasonably be linked with high-risk disease), 25 potential clinical and treatment-related prognostic variables were entered into the Elastic Net model (Table). A model containing 11 factors was retained by the methodology and chosen as the best model (Table). Patients were categorized as 'low risk' if they scored between 0 and 3 (n=521/1000 patients with complete data) and as 'high risk' if they scored between 4 and 11 (n=479/1000 patients). At 2 years, the PFS rate was 84.5% in the whole FL population. Using our model, 2-year PFS for high-risk patients was 77% compared with 79.9% for FLIPI-1 and FLIPI-2. In low-risk patients, 2-year PFS was 92% compared with 87.9% for FLIPI-1 and 87.6% for FLIPI-2 (low-intermediate-risk patients). Our model increased the inter-group difference in 2-year PFS rate from 8% (FLIPI-1) and 7.7% (FLIPI-2) to 15%. At 3 years, the inter-group difference increased from 6.9% (FLIPI-1) and 9% (FLIPI-2) to 17% (Figure). Sensitivity for a high-risk score to predict POD24 was 73% using our model compared with 55% for FLIPI-1 and 52% for FLIPI-2 (based on 127 POD24 and 873 noPOD24 patients with complete data). Excluding patients who received CVP, which is now rarely used, resulted in an inter-group difference in PFS of 15% at 2 years and 16.8% at 3 years. A sensitivity analysis showed that inclusion of the 9 clinical factors only (i.e. removal of CVP and R treatment as variables) formed a more basic scoring system (low-risk patients, 1-3; high-risk patients, 4-9); the inter-group difference in PFS was 16.5% at 2 years and 17.6% at 3 years. However, sensitivity for POD24 decreased to 56%. Conclusion: Our clinical prognostic model was more accurate at discriminating patients likely to have poor PFS than either FLIPI-1 or FLIPI-2, and its prognostic value was sustained over time. Our model also identified the FL population at risk of POD24 with greater sensitivity. Variables such as age and bone marrow involvement were not retained by our model, and thus may not have a major impact in the current era of therapy. Factors such as sum of the products of lesion diameters were included, as this captures tumor burden more accurately than presence of bulk disease. Future studies will aim to improve the accuracy of the model by considering gene expression-based prognostic markers and DNA sequencing to form a combined clinico-genomic model. Disclosures Mir: F. Hoffmann-La Roche: Employment. Hiddemann:F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding. Marcus:F. Hoffman-La Roche: Other: Travel support and lecture fees; Roche: Consultancy, Other: Travel support and lecture fees ; Gilead: Consultancy. Seymour:Genentech Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Bolen:Roche: Other: Ownership interests PLC*. Knapp:Roche: Employment. Launonen:Launonen: Other: Ownership interests none PLC; Travel, accommodation, expenses; Novartis: Consultancy, Equity Ownership, Other: Ownership interests none PLC; Travel. accommodation, expenses; Roche: Employment, Other: Travel, accommodation, expenses. Mattiello:Roche: Employment. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Oestergaard:Roche: Employment, Other: Ownership interests PLC. Wenger:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership, Other: Ownership interests PLC. Casulo:Gilead: Honoraria; Celgene: Research Funding.

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EARLY Results of TOTAL Therapy 7 (TT7): High Response Rates of NEWLY Diagnosed High Risk Myeloma to Daratumumab

Blood ◽

10.1182/blood-2019-131887 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4569-4569 ◽

Cited By ~ 1

Author(s):

Frits van Rhee ◽

Sharmilan Thanendrarajan ◽

Carolina D. Schinke ◽

Jeffery R. Sawyer ◽

Adam Rosenthal ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Response Rates ◽

Newly Diagnosed ◽

Advisory Committees ◽

Early Results ◽

Research Grant

Background. The TT approach has significantly improved the outcome of multiple myeloma (MM) by combining new drugs with a regimen that comprises induction, tandem autologous stem cell transplantation (ASCT), consolidation and maintenance. However, a group of 15% of patients with high risk multiple myeloma (HRMM) have derived little benefit despite similar response rates to induction chemotherapy and ASCT when compared to low risk MM. The poor outcome of HRMM is explained by early relapse post ASCT resulting in a short progression free survival (PFS) with only 15-20% of patients surviving long-term. Daratumumab (Dara) is a human IgG1k anti-CD38 monoclonal antibody that has shown favorable results in early single-arm studies and more recently in phase III studies for relapsed/refractory and newly diagnosed MM. In TT7, we introduced Dara during all phases of therapy, including immune consolidation early post ASCT, to improve responses rate and PFS in HRMM. Methods. Patients had newly diagnosed HRMM as defined by high risk cytogenetic abnormalities, presence of extramedullary disease, >3 focal lesions on CT-PET, elevated LDH due to MM, or ISS II/III with cytogenetic abnormality. Dara (16mg/kgx1) was added to induction with KTD-PACE (carfilzomib, thalidomide, dexamethasone; and four-day continuous infusions of cisplatin, doxorubicin, cyclophosphamide, etoposide). Conditioning for tandem autologous stem cell transplantation (ASCT) was with fractionated melphalan (50mg/m2x4) (fMEL) based on prior observations that patients with adverse cytogenetics fare better with fMEL rather than single high dose MEL200mg/m2.In the inter tandem ASCT period immunological consolidation with Dara (16mg/kg) alone for 2 doses was followed by Dara (16mg/kg) on day 1 combined with K (36mg/m2) and D (20mg) weekly for 2 cycles. DaraKD was administered to avoid treatment free periods allowing for myeloma regrowth. The 2nd ASCT was followed by further immunological consolidation with Dara (16mg/k) for 2 doses, and maintenance therapy for 3 yrs with 3-months block of alternating Dara-KD (dara 16mg/kg day 1; K 36mg/m2 and dex 20mg weekly) and Dara-lenalidomide (R)D (dara 16mg/kg day 1; R 15mg day 1-21 q28 and D 20mg weekly). Results. TT7 enrolled 43 patients thus far. The median follow-up was 11 months (range: 1-22). The median age was 61 yrs (range 44-73). Sixteen patients were ≥65 yrs (37.2%). A mean of 29.4x106 CD34+ cells/kg (range: 4.6-86.4) were collected. 36 patients completed ASCT #1 (83.7%) and 18 (41.9%) ASCT #2, whilst 14 patients have proceeded to the maintenance phase. R-ISS II/III or metaphase cytogenetic abnormalities were present in 85.1 and 58.1% of patients, respectively. Elevated LDH or >3FL on CT-PET were noted in 30 and 41.8%. The 1-yr cumulative incidence estimates for reaching VGPR and PR were 87 and 83%, respectively. A CR or sCR was achieved in 68 and 46%. The 1-yr estimates of PFS and OS were 91.6 and 87.2%. 40 subjects are alive, whilst 5 progressed on study therapy and 3 subsequently died. 38 patients are progression free at the time of reporting. Dara was well-tolerated and no subjects discontinued therapy due to dara-related side effects. The CR and sCR rates compared favorably to the predecessor HRMM TT5 protocol where CR and sCR rates were 59 and 27%. Conclusion. The early results of TT7 point to increased response rates of HRMM to a dara-based TT regimen with especially higher rates of CR and sCR. Longer follow-up is required to determine if these early results translate into superior PFS and OS. Figure Disclosures van Rhee: Karyopharm Therapeutics: Consultancy; Kite Pharma: Consultancy; Adicet Bio: Consultancy; Takeda: Consultancy; Sanofi Genzyme: Consultancy; Castleman Disease Collaborative Network: Consultancy; EUSA: Consultancy. Walker:Celgene: Research Funding. Morgan:Amgen, Roche, Abbvie, Takeda, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: research grant, Research Funding. Davies:Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor; Janssen, Celgene: Other: Research Grant, Research Funding.

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A Randomized Placebo-Controlled Phase 2 Study of Metformin for the Prevention of Progression of Monoclonal Gammopathy of Undetermined Significance and Low Risk Smoldering Multiple Myeloma

Blood ◽

10.1182/blood-2021-151878 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1659-1659

Author(s):

Catherine R. Marinac ◽

Robert A. Redd ◽

Julia Prescott ◽

Alexandra Savell ◽

Courtney Igne ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Monoclonal Gammopathy ◽

Research Funding ◽

Controlled Trial ◽

Low Risk ◽

M Protein ◽

Advisory Committees ◽

Randomized Controlled ◽

Bone Marrow Plasma

Abstract Background: Multiple Myeloma (MM) is thought to evolve from the precursor conditions monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM), which are common premalignant disorders that progress to overt MM in a subset of individuals for reasons that are poorly understood. Despite increasing interest in preventing disease progression in this patient population, the standard of care still consists of close surveillance until progression to MM; however, once MM develops it cannot be cured. Therefore, the identification of prevention and interception strategies for patients with MGUS and SMM is of considerable importance. A promising pharmacologic intervention to reduce the risk of progression of MGUS/SMM to MM is metformin, a drug commonly used to treat type 2 diabetes but that is also considered safe for use in non-diabetic populations. In vivo and in vitro studies have revealed that metformin has direct antitumor effects across a variety of cancers including MM, and recent epidemiological data suggests it may reduce the risk of MM in diabetic patients with MGUS. Here, we describe the first randomized controlled trial testing the efficacy of metformin in reducing clinical signs of disease progression in patients with MGUS and SMM (NCT04850846). Study Design and Methods: This is a phase II single center, randomized controlled trial of metformin vs. placebo in patients with high-risk MGUS and low-risk SMM. The primary objective of the study is to determine whether metformin can reduce or stabilize serum monoclonal (M-)protein concentrations from baseline to 6-months. Exploratory objectives include mass spectrometry quantification of M-protein, examination of molecular evolution of tumor cells in response to metformin, as well as changes in other clinical laboratory parameters in response to metformin. To be eligible, patients must have high-risk MGUS or low-risk SMM. High-risk MGUS is defined as bone marrow plasma cell concentration <10% with one or more of the following higher-risk features: serum M-protein level ≥1.5 g/dL to <3 g/dL or abnormal free light-chain (FLC) ratio (<0.26 or>1.65); a forthcoming amendment will include non-IgG subtype as an additional high-risk feature. Low-risk SMM is defined as bone marrow plasma cells ≥10%with the absence of any features of high-risk SMM. Metformin and its corresponding placebo are the pharmacological treatments. The metformin dose is 1500 milligrams/day, provided in 500 milligram pills. To minimize gastrointestinal symptoms, metformin is started at a low dose of 500 milligram (1 pill) per day and participants gradually increase the dosage over the course of the first month of treatment until the full 1500 milligram (3 pill) per day regimen is achieved. The study treatment period is 6 months, with primary outcomes assessed at the end of the 6-month treatment period. Conclusions and Future Directions: While the cornerstone of clinical management in MGUS and SMM is to delay therapy until progression to symptomatic MM, patients and oncologists continually seek new ways to prevent end organ damage and incurable malignancy. This trial is positioned to provide preliminary but robust mechanistic data to support the development of novel prevention strategies for MGUS and SMM patients. Disclosures Marinac: GRAIL Inc: Research Funding; JBF Legal: Consultancy. Sperling: Adaptive: Consultancy. Parnes: Sigilon: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; UniQure: Membership on an entity's Board of Directors or advisory committees; Sunovion: Consultancy; I-mAb: Consultancy; Aspa: Consultancy; Genentech/Hoffman LaRoche: Research Funding; Shire/Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Richardson: Protocol Intelligence: Consultancy; Regeneron: Consultancy; Sanofi: Consultancy; Secura Bio: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; GlaxoSmithKline: Consultancy; AstraZeneca: Consultancy; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy. Nadeem: Karyopharm: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: metformin, which is an anti-diabetic medication

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Safety and Efficacy Data for Combined Checkpoint Inhibition with Ipilimumab (Ipi) and Nivolumab (Nivo) As Consolidation Following Autologous Stem Cell Transplantation (ASCT) for High-Risk Hematological Malignancies — CPIT-001 Trial

Blood ◽

10.1182/blood-2018-99-113586 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 256-256 ◽

Cited By ~ 5

Author(s):

Alan P Skarbnik ◽

Michele L. Donato ◽

Robert Korngold ◽

Rena Feinman ◽

Scott D. Rowley ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Median Time ◽

Patient Population ◽

Research Funding ◽

Hematological Malignancies ◽

Checkpoint Inhibition ◽

Advisory Committees ◽

Safety And Efficacy

Abstract Rationale: ASCT remains a standard-of-care as consolidation or salvage for multiple myeloma (MM), post-salvage consolidation for Diffuse Large B-Cell Lymphoma (DLBCL) and upfront consolidation or salvage for Peripheral T-Cell Lymphomas (PTCL) Pts with high-risk disease still show poor outcome and frequent progression within the first 18 months. Maintenance strategies post ASCT, particularly in lymphomas, have failed to show benefit, underlining the need for novel approaches to help disease control following ASCT. We have previously reported on the preliminary safety and efficacy of checkpoint inhibitor consolidation with Ipi and Nivo following ASCT trying to take advantage of the immunological milieu during post-ASCT recovery (Skarbnik et al., ASH 2017). Here we present updated data from our Phase I CPIT-001 trial. Methods: Pts with high-risk DLBCL, PTCL or MM (as defined in Table 1, divided in cohorts) were eligible if they experienced at least stable disease after most recent salvage therapy (NHL, PTCL or relapsed MM) or after induction therapy for high-risk MM. Pts were enrolled prior to ASCT, starting in July 2016. All pts with DLBCL/PTCL received BEAM (carmustine 300 mg/m2 day -6, etoposide 200 mg/m2 and cytarabine 200 mg/m2 days -5 to -2, melphalan 140 mg/m2 day -1) as conditioning regimen for ASCT, all pts with MM received melphalan 200 mg/m2 on day -1 For pts who achieved appropriate hematologic recovery (ANC >800/mm3 and platelets > 20,000/mm3), Ipi/Nivo were started between days 14 and 28 post ASCT. The infusion schedule was: Ipi: 1 mg/kg; 6 doses Weeks 1, 4, 7, 10, 16, 22Nivo: 3 mg/kg; 12 doses Weeks 1, 4, 7, 10, 12, 14, 16, 18, 20, 22, 24, 26 Primary objectives were: Safety profile evaluation; PFS and OS at 18 months (PFS18 and OS18). Cox proportional hazards regression was utilized to determine predictors of outcome. Results: 31 pts received at least one dose of Ipi/Nivo following ASCT and were included in the intent-to-treat population. Median follow up for the whole cohort is 16 months. As of February 2018, the FDA has halted all studies including checkpoint inhibitors for pts with MM. At that time, only one pt with MM was actively receiving Ipi/Nivo, which was then discontinued. At 18 months post ASCT, estimated PFS for the entire cohort was 67% and OS was 84% (Figures 1 and 2). Disease-specific PFS18 and OS18 are described in Table 2. At study entry, 48% of pts were in CR (NHLs) or stringent CR (sCR, MMs). At most recent follow-up (range 2-25 months) 71% of pts were in CR (NHL) or sCR (MM). Disease status at study entry (i.e. CR vs <CR) didn't correlate with PFS nor OS. 65% of pts developed immune-related adverse events (irAEs) grade 2 or higher, requiring treatment with systemic steroids. Most common irAEs of any grade were: colitis (58%), rash (48%), thrombocytopenia (45%), anemia (45%) and transaminitis (32%). One pt (3%) died from complications of pneumonitis related to study drugs. All other irAEs resolved. Median time from 1st Ipi/Nivo to development of irAEs was 4 weeks. Median time to improvement to Grade 1 or baseline was 1 week after high-dose steroids were initiated. Treatment-related AEs of any grade that led to discontinuation of Ipi/Nivo occurred in 6 pts (19%). Development of irAEs, use of steroids or length of steroid-exposure did not correlate with PFS or OS. Conclusion: At 18 months post-ASCT, PFS for pts with high-risk hematological malignancies is 67%. This number underscores the potential for longer remissions by associating checkpoint inhibition with ASCT. For patients in the transplant-naïve MM with high-risk cytogenetics cohort, the 71% PFS18 (fig 3) is particularly striking, when compared to median PFS of 13-15 months in previous reports of ASCT alone in this patient population (Sonneveld et al, Blood 2016). In addition, the primary-refractory DLBCL population (43% of which were not in CR at time of ASCT) presented with a PFS18 of 83% (fig 4), while the reported PFS18 for this patient population with ASCT alone is 50% (Crump et al, Blood 2017). The cohort of pts with DLBCL relapsed within 1 year of induction had the poorest outcomes, possibly related to these pts being the most heavily pretreated in the whole cohort (median of 3 prior lines of therapy), with 57% of pts in this cohort refractory to most recent line of therapy. The manageable toxicity profile, coupled with the encouraging efficacy outcomes warrant further evaluation of this approach in a Phase II trial, which is currently planned. Disclosures Skarbnik: Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Speakers Bureau. Munshi:Kite: Speakers Bureau. Siegel:BMS: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau. Feldman:Pharmacyclics: Speakers Bureau; KITE: Speakers Bureau; Portola: Research Funding; Celgene: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau; Johnson and Johnson: Speakers Bureau; Janssen: Speakers Bureau. Biran:BMS: Research Funding; Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Merck: Research Funding. Atkins:BMS: Consultancy; Merck: Consultancy.

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Evaluation of the International Prognostic Index for Chronic Lymphocytic Leukemia (CLL-IPI) and Validation of a Proposed Novel Risk Model (BALL Score) in Real-World Relapsed/Refractory (R/R) CLL Patients Receiving Idelalisib and Rituximab

Blood ◽

10.1182/blood-2019-126717 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5485-5485

Author(s):

Massimo Gentile ◽

Gianluigi Reda ◽

Francesca Romana Mauro ◽

Paolo Sportoletti ◽

Luca Laurenti ◽

...

Keyword(s):

High Risk ◽

Risk Stratification ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Low Risk ◽

Intermediate Risk ◽

Advisory Committees ◽

Scientific Advisory Board ◽

Scientific Advisory

The CLL-IPI score, which combines genetic, biochemical, and clinical parameters, represents a simple worldwide model able to refine risk stratification for CLL patients. This score, developed in the era of chemo-immunotherapy, has not been gauged extensively in R/R-CLL patients treated with novel targeted agents, such as BCR and BCL2 inhibitors. Soumerai et al (Lancet Hematol 2019) assembled a novel risk model for OS in the setting of R/R-CLL receiving targeted therapies in clinical trials. This model, consisting of four accessible markers (β2M, LDH, Hb, and time from initiation of last therapy; BALL score), is able to cluster 3 groups of CLL patients with significantly different OS. This multicenter, observational retrospective study aimed to validate the proposed Soumerai (BALL) and/or CLL-IPI scores for R/R-CLL real-world patients treated with idelalisib and rituximab (IDELA-R). The primary objectives were to determine whether: i) the CLL-IPI retains its prognostic power also in R/R patients treated with IDELA-R; ii) the BALL score is of prognostic value for IDELA-treated R/R-CLL patients, and iii) the BALL score is predictive of PFS. This study, sponsored by Gilead (ISR#IN-IT-312-5339), included CLL patients collected from 12 Italian centers, who received IDELA-R (idelalisib 150 mg b.i.d. and a total of 8 rituximab infusions intravenously) outside clinical trials as salvage therapy with available data for the calculation of the CLL-IPI and BALL scores at the time of treatment start. OS was estimated for all subgroups of both scores. Additionally, risk-specific PFS was assessed. Kaplan-Meier curve, log-rank test, and Cox regression analyses were performed. The prognostic accuracy of the predictive model was assessed by Harrell's C-index. Overall, 120 CLL patients were included in this analysis. The majority of patients were Binet stage B and C (94.2%). The median age was 75 years and 83 cases (69.2%) were male. The median number of previous therapies was 3 (range 1-9) Baseline patient features are listed in Table 1. After a median follow-up of 1.6 years (1 month to 5.8 years), 33 patients had died and 39 experienced an event (death or progression). CLL-IPI scoring (115/120 evaluable cases) indicated that 6 patients (5.2%) were classified as low-risk, 24 (20.9%) as intermediate-risk, 58 (50.4%) as high-risk, and 27 (23.5%) as very high-risk. Stratification of patients according to the CLL-IPI score did not allow prediction of significant differences in OS. Thus, low-risk patients had a 2-year OS probability of 75% (HR=1), with an intermediate-risk of 68% (HR=2.9, 95%CI 0.37-23.3, P=0.3), high-risk of 83% (HR=1.58, 95%CI 0.2-12.5, P=0.66), and very high-risk of 63% (HR=5.9, 95%CI 0.78-45.2, P=0.86). Next, we tested a modified CLL-IPI by assigning a more balanced score to the original CLL-IPI variables (Soumerai et al, Leukemia Lymphoma 2019), partially overlapping previous results. Specifically, modified CLL-IPI high-risk group showed a significantly different OS as compared with intermediate- and low-risk groups. However, differently from the original report no difference was observed between low- and intermediate-risk). According to the BALL score (120/120 evaluable cases), 33 patients (27.5%) were classified as low-risk, 68 (56.7%) as intermediate-risk, and 19 (15.8%) as high-risk. Stratification of patients according to the BALL score predicted significant differences in terms of OS. Thus, low-risk patients had a 2-year OS probability of 92% (HR=1), intermediate-risk of 76% (HR=5.47, 95%CI 1.3-23.7, P=0.023), and high-risk of 54% (HR=15.1, 95%CI 3.4-67, P<0.0001) (Figure 1). Harrell's C-statistic was 0.68 (P<0.001) for predicting OS. To note, BALL score failed to significantly stratify patients in terms of PFS. As for Soumerai et al (Leukemia Lymphoma 2019), the original CLL-IPI score did not retain discriminative power in term of OS in R/R-CLL patients receiving IDELA-R. The modified CLL-IPI failed to stratify low- and intermediate-risk groups, likely due to the number of cases analysed in the current cohort and the heterogeneous IDELA-containing regimens included in the Soumerai study (Soumerai et al, Leukemia Lymphoma 2019). The CLL-IPI was designed for CLL patients treated with first-line chemo-immunotherapy. Herein, we confirm the prognostic power of the BALL score in this real-world series for OS, while losing the predictive impact of patient outcomes in terms of PFS. Disclosures Mauro: Gilead: Consultancy, Research Funding; Jannsen: Consultancy, Research Funding; Shire: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Roche: Consultancy, Research Funding. Coscia:Abbvie: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Varettoni:ABBVIE: Other: travel expenses; Roche: Consultancy; Janssen: Consultancy; Gilead: Other: travel expenses. Rossi:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Other: Scientific advisory board; Janseen: Honoraria, Other: Scientific advisory board; Roche: Honoraria, Other: Scientific advisory board; Astra Zeneca: Honoraria, Other: Scientific advisory board. Gaidano:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesys: Consultancy, Honoraria; Astra-Zeneca: Consultancy, Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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