Prolonged Follow-up Confirmed a Role for Upfront Tandem Auto-Allo Transplant in Multiple Myeloma Also in the Era of New Drugs

Abstract Introduction: Before the introduction of new drugs, we designed a trial where treatment of newly diagnosed multiple myeloma (MM) patients with double autografts or autograft followed by nonmyeloablative allograft was based on the presence or absence of HLA identical siblings (Bruno B et al. N Engl J Med 2007) We reported an update with special focus on long term outcomes. Methods: From September 1998 to July 2004, 162 consecutive patients with newly diagnosed MM up to the age of 65 years and at least one sibling were enrolled at 5 Italian centers, and divided into 2 groups: donor (N=80) vs no donor (N=82). First-line treatments consisted of a cytoreductive autograft followed by a HLA identical sibling nonmyeloablative allograft or a second melphalan-based autograft (N=58 and N=46, respectively, completed the protocol). Results: Median follow-up was 12.3 years (range, 7.7-15.3) from allograft, and 12.1 years (range, 10.5-15.4) from second autograft. The 5-year cumulative incidence of non-relapse mortality was 17.2% (95%CI: 7.4 to 27.1) in the allograft arm and 4.3% (95%CI:0 to 10.3) in the autograft arm. One of the main concern post allograft is the impact of chronic graft-versus-host disease (cGVHD): in our setting its 2-year cumulative incidence was 67.2% (95%CI: 54.9 to 79.5). We also evaluated the cumulative incidence of immunesuppression discontinuation in patients with cGVHD, considering both death and relapse as competing events: 26.8% of cGVHD patients (95%CI: 13 to 40.6) at 24 months and 39% (95%CI:23.6 to 54.4) at 60 months were alive and without therapy. Median overall survival (OS) and progression-free survival (PFS) from second transplant were 137 and 43 months in the allograft arm and 46 and 18 months in the autograft one (p=0.006 and p=0.001, respectively). In the allograft arm, 33 out of 58 patients relapsed at least once, and first salvage treatments included donor lymphocyte infusion (DLI, N=13), thalidomide (N=10) and bortezomib (N=8). Of note, 2 patients lost complete remission status but did not require further therapy. Nineteen out of 33 patients required a second post-transplant salvage treatment: 1 received chemotherapy, 1 DLI, 1 received debulking treatment with bortezomib followed by a second allograft, and 16 patients were treated with new drugs containing regimens. In the autograft arm, 36/46 patients relapsed and received salvage treatments consisting of: allograft (N=1), 3rd autograft prepared with a new-drugs containing regimen (N=6), thalidomide (N=17), bortezomib (N=7), lenalidomide (N=1), chemotherapy alone (N=4). Among these, 19 required a third-line treatment: 1 received an allograft, and 18 a regimen containing new drugs. Median OS from 1st relapse was 89.8 months (95%CI: 33.3 to n.r.) in the allograft arm vs 23.5 months (95%CI: 12.5 to 50.5) in the autograft (p=0.009). Conclusions: Our update showed that more then a third of patients developing cGVHD were relapse-free and cGVHD-free at 5-years post-transplant and that the advantage in OS in the allograft arm is maintained also after relapse, suggesting a synergism between graft-vs-myeloma effect and new agents. Upfront allograft in MM remains a matter of debate, and it should be performed only within clinical trials. The main limit of the present study was the lack of novel agents as part of the pre-transplant approach, nevertheless our results suggested that allograft may have a role, and it might be considered in young patients with high-risk features such as del [13], t(4;14), del(17p), and t(14;16), who remain at poor prognosis even in the era of new drugs. Disclosures Bringhen: Mundipharma: Other: ADVISORY BOARD; Amgen: Other: ADVISORY BOARD; Janssen-Cilag: Honoraria; Celgene: Honoraria; BMS: Honoraria; Karyopharm: Other: ADVISORY BOARD. Massaia:Janssen: Other: advisory board; Roche: Other: advisory board, research support; Gilead: Other: advisory board. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Boccadoro:CELGENE: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; SANOFI: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Mundipharma: Research Funding; Abbivie: Honoraria; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding.

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Induction with New Drugs and Planned Autologous Followed by Non-Myeloablative Allogeneic Transplantation in Newly Diagnosed Myeloma.

Blood ◽

10.1182/blood.v114.22.4330.4330 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4330-4330

Author(s):

Luisa Giaccone ◽

Moreno Festuccia ◽

Roberto Sorasio ◽

Nicola Mordini ◽

Fabrizio Carnevale Schianca ◽

...

Keyword(s):

Multiple Myeloma ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

New Drugs ◽

Newly Diagnosed ◽

Advisory Committees ◽

Post Transplant ◽

The Impact

Abstract Abstract 4330 Introduction Immunomodulatory drugs have recently changed the treatment options in multiple myeloma. Moreover, thalidomide, bortezomib and lenalidomide have also been used in the setting of allografting as post-transplant salvage therapy or as maintenance. We are currently evaluating the impact of new drugs as induction therapy in newly diagnosed multiple myeloma before a planned standard autograft followed by a non-myeloablative allograft (Tandem auto-allo). Patients and methods Twenty-five newly diagnosed patients (median age 55 years old, range 26-65) entered a recently designed prospective phase II program of tandem auto-allo which included the use of so-called new drugs during induction. Here, we report data on the first 11 evaluable patients with a follow up of at least 1 month after the allograft. Induction consisted of lenalidomide and dexamethasone (n=5), thalidomide and dexamethasone (n=4), or bortemomib-containing regimens (n=2), followed by G-CSF mobilized peripheral blood stem cell harvest. A standard autograft after melphalan 200 mg/m2 was planned 2-4 months before a low-dose (2 Gy) TBI-based allograft from an HLA-identical sibling. GVHD prophylaxis consisted of cyclosporin and mycophenolate mofetil. Disease status at allografting and post-transplant outcomes were compared to those of 22 patients pair-matched for beta2microglobulin and age, who underwent tandem auto-allo after induction with VAD-based regimens without new drugs (Blood, 2009). Results At the time of allografting after induction with new drugs and the autograft overall response rate was 81% (9/11), including a immunofixation-negative complete remission (CR). Following allografting, all patients promptly achieved donor engraftment. After a median follow-up of 11 months (2-26), all patients are alive and the overall response rate was 91% (10/11). Incidence of grade II-IV GVHD was 34% (4/11), including 1 patient with grade III GVHD. Chronic GVHD was observed in 40% (4/10) of patients with at least 3 months of follow-up. The induction with new drugs did not increase allotransplant-related toxicity or incidence of acute GVHD (Table 1). We observed a higher response disease before allografting in patients treated with new drugs. Conclusions Induction with lenalidomide, thalidomide or bortezomib does not impact feasibility and safety of tandem auto-allo. Longer follow up and a larger cohort of patients are necessary to evaluate the impact of new drugs in improving disease control post-tandem auto-allo. Disclosures: Patriarca: Janssen Cilag: Honoraria; Celgene: Honoraria. Boccadoro:Celgene: Consultancy, advisory committees, Research Funding; Pharmion: Consultancy, advisory committees, Research Funding; Janssen Cilag: Consultancy, advisory committees, Research Funding.

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Ixazomib or Lenalidomide Maintenance Following Autologous Stem Cell Transplantation and Ixazomib, Lenalidomide, and Dexamethasone (IRD) Consolidation in Patients with Newly Diagnosed Multiple Myeloma: Results from a Large Multi-Center Randomized Phase II Trial

Blood ◽

10.1182/blood-2019-130644 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 602-602 ◽

Cited By ~ 5

Author(s):

Ravi Vij ◽

Thomas G. Martin ◽

Nitya Nathwani ◽

Mark A. Fiala ◽

Feng Gao ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Interim Analysis ◽

Research Funding ◽

Advisory Board ◽

Hematologic Toxicity ◽

Newly Diagnosed ◽

Advisory Committees ◽

Grade 3

Background: Maintenance therapy with lenalidomide post-autologous stem cell transplantation (ASCT) has shown to improve progression-free survival (PFS) in multiple myeloma (MM), and has largely become the standard of care. However, toxicity leads to early discontinuation in nearly one-third of patients and additional options are needed (McCarthy, et al, JCO, 2017). Ixazomib is another maintenance option that has been shown to improve PFS; however, studies comparing lenalidomide and ixazomib are lacking. In this randomized phase 2 study, we analyzed the safety and efficacy of using lenalidomide and ixazomib as part of consolidation and maintenance therapies after ASCT (NCT02253316). Methods: Eligible patients, age 18-70 with newly diagnosed MM undergoing ASCT during first-line treatment, were consented prior to ASCT. Approximately 4 months following ASCT, patients received 4 cycles of consolidation therapy with IRd [ixazomib 4 mg on days 1, 8 and 15 of a 28-day cycle, lenalidomide 15 mg on days 1 through 21, and dexamethasone 40 mg on days 1, 8 and 15]. Primary data on IRd consolidation were presented at ASH 2018 (Abstract 109920). One month after the last consolidation cycle, patients were randomized (1:1) to maintenance therapy with single-agent ixazomib (4 mg on days 1, 8 and 15 of a 28-day cycle) or lenalidomide (10 mg daily months 1-3 followed by 15 mg for months 4+). The arms were stratified based on MRD-status post-consolidation. In total, 237 patients were enrolled from 10 US centers. This abstract coincides with planned interim analysis 3 which is the first comparison of ixazomib and lenalidomide maintenance. While the study was not powered to compare PFS between the two arms, the sample will provide a reasonable power to estimate non-inferiority. There is a planned stopping rule for non-inferiority set at a hazard ratio of >1.3 in favor of lenalidomide. Secondary end-points include MRD-negativity following 12 cycles and toxicity. Results: At time of abstract submission, 215 patients had completed IRd consolidation and 191 had begun maintenance. 90 were randomized to ixazomib and 94 to lenalidomide. 7 patients were not randomized due to toxicity during consolidation; data from these patients are not included in the analyses. The characteristics of the two arms are summarized in Table 1. Hematologic toxicity has been infrequent with ixazomib with neutropenia and thrombocytopenia occurring in 11% and 23% of patients. In comparison, neutropenia and thrombocytopenia occurred in 45% and 35% of patients on lenalidomide. The most common non-hematologic toxicities in both arms have been GI-related and infections, both expected events. 16% of patients on ixazomib have experienced Grade 3-4 non-hematologic toxicity compared to 34% on lenalidomide. No grade 3 or higher peripheral neuropathy has been reported in either arm. 11% of patients on ixazomib have discontinued due to toxicity and another 9% have required a dose reduction to 3mg. Lenalidomide toxicity has led to discontinuation in 15% of patients and another 12% were dose reduced to 5mg. Only 45% of patients receiving 4+ cycles of lenalidomide were able to titrate to the 15mg dose. After a median follow-up of 11.2 months from randomization (19.7 months post-ASCT), 30% of patients on ixazomib have discontinued treatment due to disease progression. After a median follow-up of 12.3 months from randomization (20.2 months post-ASCT), 18% patients on lenalidomide have discontinued treatment due to disease progression. Conclusion: Ixazomib and lenalidomide maintenance have been well tolerated to date. A comparison of PFS is currently being conducted as part of interim analysis 3 and final results will be presented, representing the first report directly comparing lenalidomide and ixazomib maintenance. Table 1: Disclosures Vij: Genentech: Honoraria; Karyopharm: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria; Sanofi: Honoraria. Martin:Amgen, Sanofi, Seattle Genetics: Research Funding; Roche and Juno: Consultancy. Fiala:Incyte: Research Funding. Deol:Novartis: Other: Advisory board; Kite: Other: Advisory board; Agios: Other: Advisory board. Kaufman:Celgene: Consultancy; Winship Cancer Institute of Emory University: Employment; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Janssen: Honoraria; Incyte: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; Takeda: Consultancy. Hofmeister:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Nektar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Imbrium: Membership on an entity's Board of Directors or advisory committees. Gregory:Poseida: Research Funding; Celgene: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau. Berdeja:AbbVie Inc, Amgen Inc, Acetylon Pharmaceuticals Inc, Bluebird Bio, Bristol-Myers Squibb Company, Celgene Corporation, Constellation Pharma, Curis Inc, Genentech, Glenmark Pharmaceuticals, Janssen Biotech Inc, Kesios Therapeutics, Lilly, Novartis, Poseida: Research Funding; Poseida: Research Funding; Amgen Inc, BioClinica, Celgene Corporation, CRISPR Therapeutics, Bristol-Myers Squibb Company, Janssen Biotech Inc, Karyopharm Therapeutics, Kite Pharma Inc, Prothena, Servier, Takeda Oncology: Consultancy. Chari:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Research Funding; GlaxoSmithKline: Research Funding; Novartis Pharmaceuticals: Research Funding; Oncoceutics: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Rosko:Vyxeos: Other: Travel support.

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Hevylite and Freelite Tests in Newly Diagnosed Multiple Myeloma: Clinical Utility and Correlations with Clinical Features

Blood ◽

10.1182/blood.v128.22.5625.5625 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5625-5625

Author(s):

Paola Omedé ◽

Valter Redoglia ◽

Monica Astolfi ◽

Alessandra Larocca ◽

Stefano Spada ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Light Chain ◽

Research Funding ◽

Chromosomal Abnormalities ◽

Advisory Board ◽

Bone Marrow Infiltration ◽

Newly Diagnosed

Abstract Introduction Heavy light chain (HLC) assay is a recently developed method that separately quantifies the k and L-bounded amounts of a given intact immunoglobulin (Ig). It allows an accurate quantification of both the involved/uninvolved Ig and permits to quantify even small monoclonal protein. Free light chain (FLC) and HLC can provide prognostic information for multiple myeloma patients. We evaluated the role of HLC and FLC tests in the assessment and evolution of the disease in newly diagnosed multiple myeloma (MM) patients. Methods From February 2011 to April 2014, 1510 patients aged ≤65 years with symptomatic newly diagnosed MM were enrolled in the EMN02/HO95 study. Details about treatments and preliminary results of the main study were previously reported (Cavo M et al, abs8000, J Clin Oncol 34, 2016). In this analysis, we focused on patients enrolled in Italy (N=718). Serum samples from each enrolled patient were collected at diagnosis, before starting maintenance, and thereafter every 6 months. Samples from 665 patients at diagnosis and 156 at pre-maintenance were analyzed. Involved HLC ratio (iHLCR) was calculated with the involved Ig (either G or A) as numerator. Involved FLC ratio (iFLCR) was calculated as K/L or L/K with the monoclonal chain as numerator. FLC ratio (FLCR) and HLC ratio (HLCR) were calculated as K/L. The analyses were performed using Spearman correlation. Results Median follow-up was 32 months. At baseline the type of paraprotein was IgG in 428 (298 IgG-k, 130 IgG-L), IgΑ in 123 (77 IgΑ-k, 46 IgΑ-L) or light chain in 104 patients (k 73, L 31); 10 patients were IgD or IgM. International Staging System (ISS) stages were well distributed in all the isotypes. The median involved HLC values were IgG-K 28.97, IgG-L 30.6, IgA-K 41.7, IgA-L 35.7 g/L, light chain K 2719.58 mg/L, and light chain L 3369.75 mg/L. HLC IgG was significantly correlated with B2-microglobulin (r=0.31), extensive bone marrow infiltration >60% (r=0.31) and hemoglobin (r=-0.39). HLC IgA was not correlated with any disease parameter. In light chain MM, iFLC was correlated to B2-microglobulin (r=0.41), creatinine (r=0.39), extensive bone marrow infiltration >60% (r=0.39) and hemoglobin (r=-0.36). The increase of iFLCR (≥ median value) was significantly associated with IgG, ISS III, anemia, extensive bone marrow infiltration and higher creatinine (p<0.001), but not with the presence of high risk chromosomal abnormalities. High iFLCR (> third quartile) was significantly associated with inferior TTP (median 43.4 versus NR, HR 1.75 95% CI 1.22-2.53, p 0.003). The increase of iHLCR (≥ median value) was significantly associated with ISS III, anemia, and extensive bone marrow infiltration (p<0.001), whereas the presence of high risk chromosomal abnormalities was not. At pre-maintenance, 17% of patients had an abnormal HLCR, whereas 82% had a normalization of HLCR. The normalization of HLCR before starting maintenance was significantly related with the achievement of complete response (CR) (p=0.02) and a trend towards a longer 3-years TTP was observed (83% versus 74%, Log-rank test 0.05). Before start of maintenance, 27% of patients had a normalization of FLCR. No significant correlation with response or outcome was observed for patients who had a normalization of FLCR. At pre-maintenance, 67% IgG or IgA MM patients were immunofixation (IFX) negative. Among them, 8% had still an abnormal HLCR compared to IFX positive patients (8% versus 36%, p<0.001). Conclusions This preliminary analysis confirms the prognostic role of high iFLCR and iHLCR in newly diagnosed MM patients. HLCR normalization may be a valuable parameter to better define CR and predict outcome. HLC can quantify even small monoclonal protein when immunofixation is negative. Further follow-up is needed to assess the prognostic impact of HLC and FLC on survival outcome. Updated results will be presented at the meeting. Disclosures Larocca: Janssen-Cilag: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Celgene: Honoraria. Cavo:Janssen-Cilag: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Millennium: Consultancy, Honoraria. Petrucci:Bristol-Myers Squibb: Honoraria; Sanofi: Honoraria; Janssen-Cilag: Honoraria; Celgene: Honoraria. Patriarca:Bristol-Myers Squibb: Other: Advisory board; Mundipharma: Other: Advisory board; MSD: Consultancy; Janssen-Cilag: Other: Advisory board; Celgene: Consultancy. Corradini:Takeda: Consultancy, Speakers Bureau; Celgene: Honoraria; Janssen: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau; Servier: Honoraria; Gilead: Honoraria, Speakers Bureau; Gentium: Honoraria, Speakers Bureau. Sonneveld:Celgene: Other: Advisory board, Research Funding; Onyx: Other: Advisory board, Research Funding; Millennium: Other: Advisory board, Research Funding; Janssen-Cilag: Other: Advisory board, Research Funding. Boccadoro:Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding; SANOFI: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Abbivie: Honoraria; Mundipharma: Research Funding. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria.

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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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The Impact of Clonal Hematopoiesis of Indeterminate Potential on Survival in Patients with Newly Diagnosed Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2018-99-116240 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4359-4359

Author(s):

Koji Sasaki ◽

Rashmi Kanagal-Shamanna ◽

Guillermo Montalban-Bravo ◽

Rita Assi ◽

Kiran Naqvi ◽

...

Keyword(s):

Next Generation Sequencing ◽

Myeloid Leukemia ◽

Research Funding ◽

Newly Diagnosed ◽

Next Generation ◽

Risk Of Death ◽

Genetics Research ◽

The Impact ◽

Generation Sequencing

Abstract Introduction: Clearance of detected somatic mutations at complete response by next-generation sequencing is a prognostic marker for survival in patients with acute myeloid leukemia (AML). However, the impact of allelic burden and persistence of clonal hematopoiesis of indeterminate potential (CHIP)-associated mutations on survival remains unclear. The aim of this study is to evaluate the prognostic impact of allelic burden of CHIP mutations at diagnosis, and their persistence within 6 months of therapy. Methods: From February 1, 2012 to May 26, 2016, we reviewed 562 patients with newly diagnosed AML. Next-generation sequencing was performed on the bone marrow samples to detect the presence of CHIP-associated mutations defined as DNMT3A, TET2, ASXL1, JAK2 and TP53. Overall survival (OS) was defined as time period from the diagnosis of AML to the date of last follow-up or death. Univariate (UVA) and multivariate Cox proportional hazard regression (MVA) were performed to identify prognostic factors for OS with p value cutoff of 0.020 for the selection of variables for MVA. Landmark analysis at 6 months was performed for the evaluation of the impact of clearance of CHIP, FLT3-ITD, FLT3D835, and NPM1 mutations. Results: We identified 378 patients (74%) with AML with CHIP mutations; 134 patients (26%) with AML without CHIP mutations. The overall median follow-up of 23 months (range, 0.1-49.0). The median age at diagnosis was 70 years (range, 17-92) and 66 years (range, 20-87) in CHIP AML and non-CHIP AML, respectively (p =0.001). Of 371 patients and 127 patients evaluable for cytogenetic in CHIP AML and non-CHIP AML, 124 (33%) and 25 patients (20%) had complex karyotype, respectively (p= 0.004). Of 378 patients with CHIP AML, 183 patients (48%) had TET2 mutations; 113 (30%), TP53; 110 (29%), ASXL1; 109 (29%), DNMT3A; JAK2, 46 (12%). Of 378 patients, single CHIP mutations was observed in 225 patients (60%); double, 33 (9%); triple, 28 (7%); quadruple, 1 (0%). Concurrent FLT3-ITD mutations was detected in 47 patients (13%) and 12 patients (9%) in CHIP AML and non-CHIP AML, respectively (p= 0.287); FLT3-D835, 22 (6%) and 8 (6%), respectively (p= 0.932); NPM1 mutations, 62 (17%) and 13 (10%), respectively (p= 0.057). Of 183 patients with TET2-mutated AML, the median TET2 variant allele frequency (VAF) was 42.9% (range, 2.26-95.32); of 113 with TP53-mutated AML, the median TP53 VAF, 45.9% (range, 1.15-93.74); of 109 with ASXL1-mutated AML, the median ASXL1 VAF was 34.5% (range, 1.17-58.62); of 109 with DNMT3A-mutated AML, the median DNMT3A VAF was 41.8% (range, 1.02-91.66); of 46 with JAK2-mutated AML, the median JAK2 VAF was 54.4% (range, 1.49-98.52). Overall, the median OS was 12 months and 11 months in CHIP AML and non-CHIP AML, respectively (p= 0.564); 16 months and 5 months in TET2-mutated AML and non-TET2-mutated AML, respectively (p <0.001); 4 months and 13 months in TP53-mutated and non-TP53-mutated AML, respectively (p< 0.001); 17 months and 11 months in DNMT3A-mutated and non-DNMT3A-mutated AML, respectively (p= 0.072); 16 months and 11 months in ASXL1-mutated AML and non-ASXL1-mutated AML, respectively (p= 0.067); 11 months and 12 months in JAK2-murated and non-JAK2-mutated AML, respectively (p= 0.123). The presence and number of CHIP mutations were not a prognostic factor for OS by univariate analysis (p=0.565; hazard ratio [HR], 0.929; 95% confidence interval [CI], 0.722-1.194: p= 0.408; hazard ratio, 1.058; 95% confidence interval, 0.926-1.208, respectively). MVA Cox regression identified age (p< 0.001; HR, 1.036; 95% CI, 1.024-1.048), TP53 VAF (p= 0.007; HR, 1.009; 95% CI, 1.002-1.016), NPM1 VAF (p=0.006; HR, 0.980; 95% CI, 0.967-0.994), and complex karyotype (p<0.001; HR, 1.869; 95% CI, 1.332-2.622) as independent prognostic factors for OS. Of 33 patients with CHIP AML who were evaluated for the clearance of VAF by next generation sequencing , landmark analysis at 6 months showed median OS of not reached and 20.3 months in patients with and without CHIP-mutation clearance, respectively (p=0.310). Conclusion: The VAF of TP53 and NPM1 mutations by next generation sequencing can further stratify patients with newly diagnosed AML. Approximately, each increment of TP53 and NPM1 VAF by 1% is independently associated with 1% higher risk of death, and 2% lower risk of death, respectively. The presence of CHIP mutations except TP53 does not affect outcome. Disclosures Sasaki: Otsuka Pharmaceutical: Honoraria. Short:Takeda Oncology: Consultancy. Ravandi:Macrogenix: Honoraria, Research Funding; Seattle Genetics: Research Funding; Sunesis: Honoraria; Xencor: Research Funding; Jazz: Honoraria; Seattle Genetics: Research Funding; Abbvie: Research Funding; Macrogenix: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Orsenix: Honoraria; Abbvie: Research Funding; Jazz: Honoraria; Xencor: Research Funding; Orsenix: Honoraria; Sunesis: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Astellas Pharmaceuticals: Consultancy, Honoraria. Kadia:BMS: Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding; BMS: Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Abbvie: Consultancy; Celgene: Research Funding. DiNardo:Karyopharm: Honoraria; Agios: Consultancy; Celgene: Honoraria; Medimmune: Honoraria; Bayer: Honoraria; Abbvie: Honoraria. Cortes:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding.

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Newly Diagnosed Multiple Myeloma (MM) Patients Treated With Lenalidomide Induction and Maintenance Show a Low Incidence Of Second Primary Malignancies (SPMs)

Blood ◽

10.1182/blood.v122.21.2074.2074 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2074-2074

Author(s):

Annamaria Brioli ◽

Charlotte Pawlyn ◽

Walter Gregory ◽

Samantha Hinsley ◽

Samantha Marshall ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Incidence Rate ◽

Maintenance Treatment ◽

New Drugs ◽

Newly Diagnosed ◽

Advisory Committees ◽

Non Invasive ◽

To Receive

Abstract Introduction New drugs have significantly improved the outcome of MM patients (pts) increasing both progression free survival (PFS) and overall survival (OS). Among new drugs lenalidomide (LEN) due to its oral availability and favourable toxicity profile is an attractive option both as an induction and as a maintenance treatment, with different studies demonstrating its effectiveness. Long term therapy with LEN, however, has been associated with an increased risk of developing SPMs. Aims We are conducting a large phase III study to evaluate the use of LEN as induction and/or as maintenance therapy. The primary end points of the study are OS and PFS. Secondary end points are response and toxicity. Methods Pts are treated following an intensive or a non intensive pathway based on their eligibility for high dose Melphalan (HDM) and stem cell transplantation (ASCT) and are randomised to receive induction therapy with cyclophosphamide and dexamethasone combined with either LEN (CRD) or thalidomide (CTD). Pts failing to achieve an optimal response are randomised to receive additional therapy with cyclophosphamide, dexamethasone and bortezomib (CVD) or no extra therapy. Pts with minimal or no response will automatically receive further therapy with CVD. A randomisation between LEN maintenance and no maintenance is also performed. Data on the occurrence of SPMs are being routinely collected as part of safety assessment during all protocol phases and follow up. Analyses were performed on treatment actually received. Results As per cut off of the 23rd July, 2371 pts have undergone the induction randomisation, of which 2368 are eligible for the safety analysis; 794 pts entered maintenance randomisation. The median follow up is 1.36 years from initiation of the study and 1.06 years from maintenance randomisation. Localised skin cancer other than melanoma were considered as non-invasive SPMs. At the time of the present analysis 17 SPMs have been reported with a cumulative incidence rate of 0.7% (cumulative rate of 0.6% for invasive SPMs and 0.1% for non-invasive SPMs); four additional patients, reported as having a SPM, were excluded, after central review of the data, either due to a previous history of malignancy or because of the evidence of a pre-existing tumour other than MM at the time of study entry. The median age at the time of SPMs development is 72 years (range 61-92), and the median time from trial entry to development of SPMs is 11 months (range 2.1-27.0). The most common SPMs reported were squamous cell carcinoma (4 pts, 2 invasive and 2 non invasive), breast cancer (3 pts), colon cancer (2 pts) and prostate cancer (2 pts). No haematological SPM has so far been reported. One patient, treated according to the intensive arm with LEN both as induction and maintenance, was reported as having a suspect myelodysplasia (MDS) due to anaemia and thrombocytopenia 2.7 months after entering the maintenance randomisation. No clear histological sign of MDS was found and the values improved after stopping maintenance treatment; these data fit with treatment related toxicity and not with the development of a MDS, and the patient was excluded from this analysis. Ten out of 17 SPMs developed during maintenance treatment or follow up phase, with 7 patients having received LEN maintenance. Median time from maintenance randomisation to SPMs development is 7 months (range 2-20.6 months). The remaining 7 were diagnosed during or immediately after induction. About half of the patients (8/17) were randomised to receive LEN induction; 3 patients received LEN both as induction and as maintenance. Interestingly only one of those 3 pts had been treated according to the intensive arm. With a median follow up of 1.36 years the estimated incidence rate at 1 and 2 years are 0.70% (95% CI .40-1.22)and 1.17% (95% CI .70-1.96) respectively (Figure 1). Conclusions Our data do not confirm previous findings of an excess risk of SPMs in association with the use of LEN and HDM in presenting patients, with 12/17 pts developing SPMs treated on the non intensive pathway that does not contain HDM. Most importantly only 0.4% of the patients enrolled within the intensive pathway developed a SPM, with only 2 of them receiving LEN maintenance. Longer follow up will help to further elucidate the risk of LEN associated SPMs. On behalf of the NCRI Haemato-Oncology subgroup Disclosures: Brioli: Celgene: Honoraria. Off Label Use: The presentation include the use of Lenalidomide as induction and as maintenance treatment for newly diagnosed multiple myeloma patients. Cook:Janssen: Honoraria, Research Funding, Speakers Bureau. Cavo:Celgene: 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; Millenium: 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; Bristol-Meyer Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Morgan:Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millenium: 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; Merck: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Johnson and Johnson: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees.

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Meta-Analytic Summary of the Burden of Pain and Fatigue in Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.5967.5967 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5967-5967

Author(s):

Peter C. Trask ◽

Mark Atkinson ◽

Bhumi Trivedi ◽

Andrew Palsgrove ◽

William Benton Jones ◽

...

Keyword(s):

Multiple Myeloma ◽

Sensitivity Analysis ◽

Research Funding ◽

Meta Analysis ◽

Clinical Group ◽

Common Symptom ◽

Newly Diagnosed ◽

Eortc Qlq C30 ◽

Eortc Qlq ◽

The Impact

Abstract Aims: Multiple myeloma (MM) is a hematologic malignancy of plasma cells. Bone disease is a characteristic symptom of MM, and pain is one of its most distressing features. Anemia is also a common symptom and is manifested as fatigue and tiredness among MM patients. We conducted a systematic review and meta-analysis of the EORTC QLQ-C30 pain and fatigue scales in two clinical MM populations (one with newly-diagnosed MM and a second undergoing medical management with re-emergent or advanced myeloma) to more precisely quantify the burden of pain and fatigue in MM. Methods: Studies assessing pain and fatigue in MM were identified through a search of specific terms in the medical-subject headings and keywords in PubMed. Inclusion criteria were English-language studies published between January 1, 1996, and July 1, 2014; diagnosis of MM; and availability of data on pain and/or fatigue as measured by the EORTC QLQ-C30. Full-text articles from germane abstracts were retrieved for eligibility assessment, and 27 articles were selected for inclusion in the analysis. Two groups of peer-reviewed articles were created: one consisting of publications that focused on newly-diagnosed MM and the other consisting of articles involving MM patients with advanced conditions, including those who had a disease recurrence or were receiving autologous bone marrow transplantation. The mean values and standard deviations (SDs) were recorded across all publications irrespective of sex, age, and stage of illness. Of the 27 studies, 17 did not report standard error (SE) or SD values associated with EORTC QLQ-C30 pain and fatigue scales. These missing values were estimated using the overall average of SDs for that scale observed across all studies within the publication group (either newly-diagnosed or recurrent/advanced disease). A sensitivity analysis was conducted to compare the pooled mean and SEs associated with results obtained with and without the SD imputation procedure. The means and SDs from the two sets of publications were entered into Comprehensive Meta-analysis™ with both scales (pain or fatigue) and existing or imputed SDs as grouping variables. The summary means and confidence intervals for each scale by clinical group were computed by weighting the individual studies by sample size and were statistically summarized based on a fixed-effect model. Results: The EORTC QLQ-C30 fatigue and pain scales range from 0-100 with higher scores indicating greater symptoms (i.e., more fatigue and pain). The overall mean across the 27 publications was 47.1 for fatigue and 48.2 for pain for MM patients compared to scores of 25.0 and 16.9 for a general population. The results of the sensitivity analysis indicated that estimation of the SDs for those studies missing the statistic did not have a significant effect on the summary mean estimate. In most cases, the inclusion of additional means with estimated SDs reduced the summary SE estimate associated with the summary mean. Overall, the scores for fatigue and pain across research articles involving newly-diagnosed patients (fatigue=48.5 and pain=49.1) were statistically higher (indicating worse pain and fatigue) than among patients who were recurrent or receiving more aggressive treatments (fatigue=39.9 and pain=38.7). Conclusions: The burden of pain and fatigue in MM is substantial and is different between newly-diagnosed and more advanced MM patients. Pain and fatigue can be easily quantified using standardized health-related quality of life instruments. Pivotal clinical trials in MM need to assess the impact of novel treatments on pain and fatigue. Disclosures Trask: Sanofi: Employment. Atkinson:Sanofi: Research Funding. Trivedi:Sanofi: Research Funding. Palsgrove:Sanofi: Research Funding. Jones:Sanofi: Employment. McHorney:Sanofi: Research Funding.

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Clinical Outcomes of Patients with Newly Diagnosed Multiple Myeloma Receiving Triplet Therapy in the Connect MM® Disease Registry

Blood ◽

10.1182/blood.v126.23.4229.4229 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4229-4229

Author(s):

Jatin J. Shah ◽

Rafat Abonour ◽

Mohit Narang ◽

Jayesh Mehta ◽

Howard R. Terebelo ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Risk Of Death ◽

Equity Ownership ◽

Triplet Regimen

Abstract Introduction: Triplet therapies are used for treatment (Tx) of both transplant-eligible and -ineligible patients (pts) with newly diagnosed multiple myeloma (NDMM). Actual patterns and outcomes of Tx are not fully understood. Connect MM® is the first and largest multicenter, US-based, prospective observational cohort study designed to characterize Tx patterns and outcomes for pts with NDMM. This analysis describes demographic and disease characteristics of pts who received triplet Tx as an induction regimen and for whom transplant was or was not intended. The analysis explores the relationship of these factors with overall survival (OS) and other efficacy endpoints. Patients and Methods: Pts aged ≥ 18 y with NDMM within 60 days of diagnosis were eligible for enrollment regardless of disease severity, medical history, or comorbidities. Data including transplant intent (yes/no) was collected at baseline; follow-up data was collected quarterly thereafter. Based on the initial intent, 2 groups were identified: patients with intent to transplant who received transplant (TT) and pts with no intent to transplant who did not receive a transplant (NT). Triplet Tx was defined as the combination of ≥ 3 concurrent therapeutic agents in the first course of Tx (within 56 days of study entry). KM analysis adjusted for age was conducted for OS. Because decisions on use of transplant and triplet therapy are influenced by multiple factors, a multivariable Cox regression analysis was performed to evaluate the contribution of the triplet therapy (yes/no) to OS and was adjusted for other variables, including age, comorbidities, and ISS staging. Results: Between September 2009 and December 2011, 1493 pts were enrolled. This analysis was on 1436 pts: 650 pts with transplant intent and 786 pts without transplant intent. The data cutoff date was November 30, 2014, and the median follow-up for overall survival (OS) was 33.8 mos. Of pts with transplant intent, 451 (69%) received transplant (TT) and 199 (31%) did not. Of pts without transplant intent, 62 (8%) received transplant and 724 (92%) did not (NT). The abstract focuses on TT and NT groups only. NT pts tended to be older and have more advanced ISS staging and higher β2-microglobulin levels than TT pts (Table). The most common triplet regimen given during the first course treatment (within 56 days) was lenalidomide, bortezomib, and dexamethasone (RVd). RVd was administered to 34% of the NT pts (76/225) and 59% of the TT pts (152/257). The most common non-triplet regimen was bortezomib and dexamethasone (Vd), which was given to 31% of NT pts (156/499) and 38% of TT pts (73/194). Within the NT group, pts given triplet Tx had a lower risk of death than those who did not receive triplet Tx (P = .0013). The multivariable analysis found triplet Tx to be associated with a 36% reduced risk of death (hazard ratio [HR] = 0.64 [95% CI, 0.50-0.82]; P = .001). ISS disease stage (HR = 1.43 [95% CI, 1.21-1.69]; P < .001) and history of diabetes (HR = 1.38 [95% CI, 1.08-1.78]; P = .012) were negative prognostic factors for OS. Within the TT group, pts who received triplet Tx did not attain an OS benefit (P = .8993), and no baseline characteristics were significantly associated with OS. These results may be limited by other factors not considered that may have influenced physicians' choice of treatment, including the use of maintenance therapy and a short follow-up period of 33.8 months. Conclusions: Triplet Tx as a first regimen is associated with longer OS in pts without transplant intent who did not receive a transplant. RVd and Vd were the most common first Tx regimens, respectively. Continued follow-up of these pts and enrollment of an additional cohort will provide additional data with mature follow-up. Table 1. Table 1. Disclosures Shah: Bristol-Myers Squibb: Research Funding; Array: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees. Abonour:Celgene: Research Funding, Speakers Bureau. Narang:Celgene: Speakers Bureau. Mehta:Celgene Corporation: Speakers Bureau. Terebelo:Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacylics: 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. Gasparetto:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Honoraria, Other: Export Board Committee, Speakers Bureau. Toomey:Celgene: Consultancy. Hardin:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Srinivasan:Celgene Corporation: Employment, Equity Ownership. Larkins:Celgene Corporation: Employment, Equity Ownership. Nagarwala:Celgene Corporation: Employment, Equity Ownership. Rifkin:Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Treatment Patterns Among Adults with Newly Diagnosed Primary Immune Thrombocytopenia in the United States

Blood ◽

10.1182/blood-2018-99-117252 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 497-497

Author(s):

Karynsa Cetin ◽

Leah J McGrath ◽

Robert Overman ◽

Diane Reams ◽

Anjali Sharma ◽

...

Keyword(s):

Cumulative Incidence ◽

Research Funding ◽

Rescue Therapy ◽

The United States ◽

Advisory Board ◽

Oral Steroid ◽

Newly Diagnosed ◽

Employment Equity ◽

The Us ◽

Equity Ownership

Abstract Introduction: Immune thrombocytopenia (ITP) is a rare platelet disorder that can lead to an increased tendency to bleed. Recommended first-line therapies include corticosteroids, intravenous immunoglobulin (IVIg) and intravenous (IV) anti-D. An estimated two-thirds of adult patients with ITP will develop persistent or chronic disease (ITP lasting 3-12 months or >12 months, respectively). Several evidence-based options for second-line treatment exist, but no randomized trials have directly compared one therapy to another. Patterns of treatment in routine clinical practice therefore vary. There is a paucity of data on current real-world treatment dynamics in ITP, and such data could help identify gaps in care and inform future studies of real-world comparative effectiveness and safety. We described the types of treatments administered following an ITP diagnosis, as well as the subsequent occurrence of bleeding and requirement for rescue therapy among adults being managed in routine practice in the United States (US). Methods: We used electronic health record data from hematology clinics across the US (Flatiron Health, Inc.) linked to MarketScan® employer-based and Medicare Supplemental administrative health insurance claims databases (Truven Health Analytics, Inc.). We included patients aged 18 years or older with a new ITP diagnosis from January 1, 2011 through June 30, 2016, continuous enrollment in MarketScan prior to diagnosis, and no previous diagnosis of a secondary cause of thrombocytopenia. The cumulative incidence of each ITP treatment after diagnosis was estimated using competing risk models to account for deaths occurring before initiation. Estimates were provided specifically for 90 days and 1 year following diagnosis to describe treatment uptake in the newly diagnosed and persistent phases, respectively. The incidence of bleeding events and rescue therapy was quantified after the start of the more prevalent second-line therapies: rituximab, splenectomy, and thrombopoietin receptor agonists (TPO RAs) - eltrombopag and romiplostim. Rescue therapies (those that rapidly increase platelet counts in the setting of severe thrombocytopenia or active bleeding) included IV anti-D, IVIg, IV steroids, and platelet transfusions. Results: Among the cohort of 447 adults diagnosed with primary ITP, 47% were male, 61% were white, 32% were 65 years or older, and the median lowest platelet count in the 60 days prior to diagnosis was 85x109/L (IQR: 39, 125). Use of each ITP therapy by 90 days and 12 months post-diagnosis are provided in the Table. Oral corticosteroids were the most commonly used; the cumulative incidence of initiation was 41% by 90 days and 50% by 1 year following ITP diagnosis. IV steroids and rituximab were the next most frequently used medications (16% and 11% at 90 days; and 26% and 16% by 1 year, respectively). The cumulative incidence of the TPO RAs, eltrombopag and romiplostim, by 90 days was 3% and 7%, respectively, and by 1 year was 5% and 9%, respectively. Splenectomy was relatively rare (<4% by 1 year) as was use of all other non-rescue ITP medications (≤1% by 1 year). At 180 days post-ITP treatment initiation, rituximab initiators (N = 84) had a slightly lower incidence of bleeding overall (12% [6, 20]) than the other treatment groups (17% [6, 33] among 31 eltrombopag initiators; 19% [9, 31] among 49 romiplostim initiators; and 19% [6, 38] among 21 splenectomized patients). However, rituximab initiators had the highest cumulative incidence of rescue therapy use (48% [36, 58] compared with 29% [14, 46] for eltrombopag, 26% [14, 39] for romiplostim, and 19% [6, 39] for splenectomized patients). Subsequent oral steroid use was less frequent among TPO RA initiators than rituximab initiators or patients who underwent splenectomy. Conclusions: In this descriptive study of patients with primary ITP receiving care in the US, oral steroids were the most commonly used medication after diagnosis, reflecting their continued role as a frontline therapy. By 1 year after diagnosis, approximately 15% received rituximab, nearly 10% received romiplostim, and 5% received eltrombopag. Splenectomy was less common. Among the medical treatments, although bleeding risk overall appeared lowest in rituximab patients, oral steroid and rescue therapy use were lowest among the patients who initiated TPO RAs. Table. Table. Disclosures Cetin: Amgen Inc: Employment, Equity Ownership. Sharma:Amgen: Employment, Equity Ownership. Brookhart:Amgen Inc: Consultancy, Research Funding; NoviSci: Equity Ownership; Union Chimique Belge: Consultancy; GlaxoSmithKline: Consultancy; Merck: Consultancy; Genentech: Consultancy; TargetPharma: Consultancy; RxAnte: Consultancy; AstraZeneca: Research Funding. Altomare:Genentech: Consultancy; Ipsen: Other: Advisory Board Member; Amgen: Consultancy; Celgene: Other: Advisory Board Member; Novartis: Consultancy; Bayer: Consultancy; Incyte: Consultancy. Wasser:Amgen Inc: Consultancy; Novartis: Consultancy; Becton Dickinson: Equity Ownership; Abbott Labs: Equity Ownership; Biogen: Equity Ownership; Allergan: Equity Ownership; Eli Lilly: Equity Ownership; Incyte: Research Funding; Merck: Equity Ownership, Research Funding; Pfizer: Equity Ownership, Research Funding; Guardant: Research Funding.

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A Multicenter, Open Label Phase I/II Study of Carfilzomib, Pomalidomide and Dexamethasone in Relapsed and/or Refractory Multiple Myeloma (MM) Patients

Blood ◽

10.1182/blood.v128.22.1145.1145 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1145-1145 ◽

Cited By ~ 5

Author(s):

Sara Bringhen ◽

Valeria Magarotto ◽

Anna Marina Liberati ◽

Angelo Belotti ◽

Alessandra Larocca ◽

...

Keyword(s):

Multiple Myeloma ◽

Phase I ◽

Dose Level ◽

Research Funding ◽

Low Dose ◽

Response Rate ◽

Primary Objective ◽

Advisory Board ◽

Level 1

Abstract Background: Survival rates of multiple myeloma (MM) patients (pts) has improved over the past few years, but patients inevitably relapse and become more resistant to subsequent treatments. Carfilzomib and Pomalidomide were both approved for the treatment of relapsed/refractory MM (RRMM). Combinations including a proteasome inhibitor (PI) plus an immunomodulator (IMiD), such as Bortezomib-Lenalidomide-Dexamethasone (VRD) or Carfilzomib-Lenalidomide-Dexamethasone (CRD), showed a very high response rate with an acceptable toxicity. Moreover, in the CHAMPION1 study (Berenson et al Blood 2016), the weekly infusion of Carfilzomib showed to be as effective as the twice schedule. In this phase I/II study we assessed for the first time weekly Carfilzomib plus Pomalidomide and low dose Dexamethasone (wKPd) for the treatment of RRMM. Here we report preliminary results. Methods: the primary objective of the phase I part of the trial was to determine the maximum tolerated dose (MTD) of wKPd combination. The primary objective of the phase II was to determine the rate of partial response (PR). Patients with RRMM, who received 1-3 prior lines of treatments and were refractory to Lenalidomide were eligible. Treatment consisted of 28-day cycles of oral Pomalidomide at fixed dose of 4 mg on days 1-21 (1 week off), oral or intravenous (iv) Dexamethasone 40 mg on days 1,8,15,22 and iv Carfilzomib at escalating doses on days 1,8,15. Escalation started at the dose of 36 mg/m2 (0 level) and used a standard 3+3 schema based on dose-limiting toxicities (DLTs) occurring in cycle 1. Treatment was continued until relapse or intolerance. Results: A total of 57 patients were enrolled in 6 Italian centers. Fifty-two patients could be evaluated for this analysis (5 patients did not complete the first cycle yet). The median age was 62 years with a median time from diagnosis of 4 years. 17/39 (44%) of patients were considered high risk according to cytogenetic abnormalities [at least one among t (4;14) t (14;16) and deletion chromosome 17 (del17) detected by FISH]. In the phase I of the trial 15 patients were enrolled. The first 3 patients at the dose level 0 of Carfilzomib did not experience any DLT. In the next cohort with Carfilzomib 20/45 mg/m2 a G3 hypertension and a sudden death occurred. According to the protocol, 3 more patients were enrolled at dose level 0: 1 patient experienced G3 atrial fibrillation, 2 patients ≥ G3 hypertension. Considering the serious adverse events (SAEs) occurred, the trial was temporary stopped to evaluate the benefit of continuing the study. All the DLTs were cardiologic and occurred in patients with a prior history of cardiac disease. As per protocol, they were evaluated with ECG and echocardiogram before the enrolment and were considered eligible for the study. The safety committee established new procedures for the evaluation of cardiac function of potentially eligible patients, including 24 h continuing pressure monitoring before the enrolment and serial measurement of blood pressure during and after Carfilzomib infusions. Six more patients were enrolled at dose level -1 (Carfilzomib 20/27 mg/m2) and none experienced a DLT. The MTD was established at dose level -1 with Carfilzomib 20/27 mg/m2, Pomalidomide 4 mg and Dexamethasone 40 mg. In the phase II portion of the trial, 42 patients were enrolled. Considering both phase I and II portions of the study, the most frequent drug related, grade ≥ 3 AEs were hematologic (65% of neutropenia and 13% of thrombocytopenia) and cardiologic (17%, mainly hypertension). We recorded only 4% of infection and ≥ G3 peripheral neuropathy. The overall response rate (ORR) of phase I/II portions was 58% (30/52) including 25% (13/52) of ≥ very good partial remission (VGPR). The ORR of high risk patients was 44% (7/16) including 19% (3/16) of ≥ VGPR. With a median follow-up of 10 months, median progression free survival (PFS) was 9.5 months and the median overall survival was not reached. Conclusions: This is the first phase I/II trial that combined weekly Carfilzomib with Pomalidomide and Dexamethasone. This combination was highly effective in RRMM. After a median follow-up of 10 months, wKRd showed a double median PFS in comparison with Pomalidomide-low dose dexamethasone (Sanmiguel et al Lancet Oncology 2013): 9.5 vs 4 months respectively, confirming the efficacy of combining a PI with an IMiD. An updated analysis will be presented at the meeting. Disclosures Bringhen: BMS: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Amgen: Other: ADVISORY BOARD; Mundipharma: Other: ADVISORY BOARD; Karyopharm: Other: ADVISORY BOARD. Larocca:Celgene: Honoraria; Janssen-Cilag: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria. Gaidano:Karyopharm: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Oliva:Amgen: Honoraria; Celgene: Honoraria; Takeda: Honoraria. Sonneveld:Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Boccadoro:Janssen: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Abbivie: Honoraria; Mundipharma: Research Funding; SANOFI: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding.

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