Sustained Minimal Residual Disease Negativity in Newly Diagnosed Multiple Myeloma (NDMM) Patients Treated with Carfilzomib (CFZ), Lenalidomide (LEN), and Dexamethasone (DEX) Followed By 2 Years of Lenalidomide Maintenance (CRd-R): Updated Results of a Phase 2 Study

Abstract Background: State of the art treatment for patients with NDMM involves induction with triplet regimens utilizing newer therapies including combinations of immunomodulatory (IMiD) drugs and proteasome inhibitors (PI) which improve progression-free survival (PFS) over doublet regimens. CFZ is a selective PI that inhibits the chymotrypsin-like activity of the 20S proteasome and has been approved in combination with LEN and DEX for the treatment of patients with relapsed or refractory MM who have received 1-3 lines of therapy. Furthermore, it has been associated with decreased neuropathy and increased clinical benefit over bortezomib-based combinations. This phase 2 study of 45 patients demonstrated that deep and durable responses with CRd-R can be achieved in the NDMM setting (Korde et al. JAMA Onc 2015). Here, we expand on our initial results in assessing minimal residual disease negativity (MRDneg) at complete response (CR) and after 1 and 2 years of LEN maintenance. We also characterize depth of response by age and cytogenetic risk profile. Methods: Treatment-na•ve patients with MM were treated for 8 cycles (28-day cycles) with CFZ 20/36 mg/m2 IV days 1, 2, 8, 9, 15, 16; LEN 25 mg PO days 1-21, and DEX 20/10 mg IV/PO days 1, 2, 8, 9, 15, 16, 22, 23. Transplant eligible patients underwent stem cell collection after ≥4 cycles of CRd and then continued CRd treatment (i.e. by-default-delayed high-dose melphalan with autologous stem cell transplant; HDM-ASCT). After 8 cycles of combination therapy, patients with SD or better received 2 years of LEN 10 mg PO maintenance. The primary objective of the study was to estimate the rate of ³ Grade 3 peripheral neuropathy with secondary objectives of response (ORR), MRDneg, PFS, and response duration (DoR) assessed after every cycle during induction and subsequently after every 90 days of maintenance therapy. Assessment of MRDneg by multi-color flow cytometry (bone marrow aspirate; 10-5 sensitivity) was performed after 8 cycles of induction, and 1 and 2 years of LEN maintenance. Results: Forty-five patients meeting eligibility criteria were enrolled (60% male; median age 60, range 40-89; race: 82% White, 13% Black, 4% Asian; isotypes: 51% IgG kappa, 16% IgG lambda, 13% IgA kappa, 9% IgA lambda, 9% free kappa, and 4% free lambda). The proportion of patients who obtained a complete response (CR) with MRDneg after 8 cycles of induction, 1 year of maintenance and 2 years of maintenance was 44%, 54% and 46%, respectively (Table 1). These deep responses of MRDneg CR were observed regardless of age group or cytogenetic-based risk profile (Table 2). ORR was 98% with a DoR at 48 months of 81%. PFS at 48 months was 82% and overall survival at 58 months was 86% with a median duration of follow-up of 31 months. Toxicities, in general, were manageable, with Grade 3-4 events occurring in >1 patient including lymphopenia (69%), neutropenia (27%), thrombocytopenia (20%) anemia (18%), hypophosphatemia (18%), leukopenia (16%), maculo-papular rash (13%), alanine aminotransferase elevation (11%), fatigue (9%), dyspnea (9%), hyponatremia 7%, thromboembolism (7%), lung infection (4%), hypoalbuminemia (4%). Serious adverse events included thromboembolism (13%), dyspnea (9%), anemia (7%), lung infection (4%), thrombocytopenia (4%), hyponatremia (4%), and pleural effusion (4%). Conclusions: Upfront treatment of NDMM with modern, highly efficacious CRd-R therapy with by-default-delayed HDM-ASCT led to high rates of sustained MRDneg CR (as defined by the updated 2016 IMWG response criteria) which is correlated with longer PFS and OS. Clinically important, these deep responses were observed regardless of the age of patients or cytogenetic risk. Our findings stress the importance of utilizing highly efficacious triplet-based regimens for the treatment of patients with NDMM regardless of age or cytogenetic risk. Updated results will be presented at the Annual Meeting. Disclosures Korde: Medscape: Honoraria. Bhutani:Prothena: Research Funding; Takeda Oncology: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Onyx, an Amgen subsidiary: Speakers Bureau. Landgren:Takeda: Honoraria; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Medscape Myeloma Program: Honoraria; Merck: Honoraria; BMS: Honoraria.

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Subcutaneous PAD As Induction Therapy for Patients with Newly Diagnosed Myeloma: A Phase 2 Trial Assessing the Impact of Minimal Residual Disease (MRD) in Patients with Deferred Autologous Stem Cell Transplantation (PADIMAC)

Blood ◽

10.1182/blood.v124.21.4745.4745 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4745-4745

Author(s):

Rakesh Popat ◽

James D Cavenagh ◽

Roger G Owen ◽

Matthew Streetly ◽

Stephen A Schey ◽

...

Keyword(s):

Flow Cytometry ◽

Stem Cell ◽

Genetic Risk ◽

Research Funding ◽

Residual Disease ◽

Phase 2 ◽

Newly Diagnosed ◽

Disease Response ◽

Grade 3 ◽

Minimal Residual

Abstract Introduction: The role of autologous stem cell transplantation (ASCT) as first line treatment for newly diagnosed patients with myeloma is currently under evaluation given the high response rates to novel induction treatment. The outcomes for patients that do not proceed to ASCT following induction remain unclear and are likely to be determined by genetic risk and response to therapy. In order to evaluate this further, this single arm phase 2 clinical trial conducted at 13 sites in the UK was designed to determine the 2 year progression free survival for patients that achieved ≥ very good partial response (VGPR) following induction therapy without ASCT. Those achieving partial response (PR) were consolidated with ASCT according to routine practice. In this first analysis we report secondary endpoints: disease response and regimen-related toxicity in patients completing induction, including minimal residual disease (MRD) negativity by multiparameter flow cytometry. Methods: Patients with newly diagnosed myeloma eligible for ASCT received PAD (bortezomib 1.3mg/m2 days 1, 4, 8, 11; doxorubicin 9mg/m2 days 1-4 and dexamethasone 40mg days 1-4 (and days 8-11 and 15-18 for the first cycle only)) for up to 6 cycles (minimum of 4). Bortezomib was initially given intravenously (IV), but once approved this was switched to sub-cutaneous (SC). Those failing to achieve PR were offered salvage therapy off protocol. All others had peripheral blood stem cell (PBSC) mobilisation using cyclophosphamide + GCSF, followed by MRD assessment on bone marrow aspirates using multi-parameter flow cytometry. Depending on disease response, patients were then stratified to ASCT (PR) or no further treatment (≥VGPR). Responses were assessed using International uniform response criteria (Durie 2006) by intent-to-treat and toxicity scored according to CTCAE version 4.0. High risk disease was defined by the presence of one or more adverse FISH lesions (t(4;14), t(14;16), t(14;20), del(17p13), +1q21) as described in the MRC Myeloma IX trial. Results: Between March 2011 and January 2014, 153 patients were enrolled (median age of 55, range 28-71 years). 139 (91%) received between 4-6 cycles of PAD. The majority (135, 88%) received SC only bortezomib and 18 (12%) received at least 1 cycle IV. The overall response rate to PAD was 81% with 46% achieving ≥VGPR (sCR: 6 (4%), CR: 13 (8%), VGPR: 51 (33%), PR: 54 (35%)). FISH data was available for 122 patients, 91 (75%) patients were standard risk and 31 (25%) were adverse. Responses were similar irrespective of ISS or genetic risk (standard, ≥VGPR 44%, PR 34%; adverse, ≥VGPR 55%, PR 29%). MRD results are currently available in 70 of the 124 patients achieving PR post PBSC harvest. Of this group 41 achieved ≥VGPR post-harvest (22 MRD+ and 19 MRD-) and hence did not proceed to ASCT, 13 patients achieved CR of which 8 were MRD negative. Toxicity was as expected for PAD and predominantly haematological. Notably the incidence of neuropathy was lower than that previously reported with IV bortezomib. Grade 3-4 events were: neutropenia: 18%; thrombocytopenia 7%. Grade 2-4 peripheral neuropathy was reported in 27% compared to 40% in the HOVON-65/ GMMG-HD4 Trial using IV bortezomib. Grade 1-2 neuropathy was similar for patients who received IV (55.6%) or SC (60%) bortezomib; however only 7% of patients receiving SC bortezomib developed grade 3 neuropathy compared to 28% with the IV route. Conclusions: SC PAD is a highly effective induction regimen for patients with newly diagnosed myeloma achieving a ≥VGPR of 46%. Of the 41 patients achieving ≥VGPR post-harvest with MRD result available, 46% were MRD negative. Response rates were similar across ISS and with adverse FISH. The use of SC bortezomib improved tolerability and substantially reduced neurotoxicity. ISRCTN no: 03381785. Disclosures Popat: Janssen: Honoraria. Cavenagh:Janssen: Honoraria. Schey:Janssen: Consultancy, Honoraria. Cook:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cook:Janssen: Honoraria, Research Funding. Yong:Janssen: Honoraria.

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A Pilot Study of Acalabrutinib with Bendamustine/Rituximab Followed By Cytarabine/Rituximab (R-ABC) for Untreated Mantle Cell Lymphoma

Blood ◽

10.1182/blood-2020-143095 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 8-9

Author(s):

Daniel Guy ◽

Marcus Watkins ◽

Fei Wan ◽

Nancy L. Bartlett ◽

Amanda F Cashen ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Residual Disease ◽

Complete Response ◽

High Dose ◽

Advisory Committees ◽

Mantle Cell ◽

Grade 3 ◽

Stem Cell Collection

Introduction The management of younger fit patients with mantle cell lymphoma (MCL) varies widely with no consensus on an optimal induction therapy. To date, the treatments with the longest progression-free survival incorporate a chemotherapy backbone that includes high dose cytarabine, followed by consolidation with an autologous stem-cell transplantation (ASCT) (Hermine et al. Lancet 2016, Eskelund et al. Br J Haematol 2016). Recent data showed that a regimen of bendamustine/rituximab followed by cytarabine/rituximab achieved high complete response rates with high minimal residual disease (MRD) negativity (Merryman RW et al. Blood Adv 2020). We hypothesized that adding the Bruton tyrosine kinase inhibitor acalabrutinib to the same chemotherapeutic backbone would be safe and increase complete response rates as well as minimal residual disease (MRD) negativity pre-transplant, and potentially improve clinical outcomes. Methods We conducted a single arm, single institution pilot study registered at clinicaltrials.gov (NCT03623373). Patients with untreated MCL, who were between ages 18-70 and were candidates for ASCT, were eligible. Patients received six 28-day cycles of treatment. Cycles 1-3 consisted of bendamustine 90 mg/m2 on days 1 and 2, rituximab 375 mg/m2 on day 1 and acalabrutinib 100mg BID on days 1 through 28. Cycles 4-6 consisted of rituximab 375 mg/m2 on day 1, cytarabine 2 g/m2 (1.5 g/m2 if age>60) q12 hours on days 1 and 2, and acalabrutinib 100mg BID on days 1 through 7 and 22 through 28. Restaging PET/CT and response assessment based on the Lugano classification were obtained following cycles 3 and 6. After cycle 6 patients underwent leukapheresis and stem-cell collection as preparation for ASCT. Blood for MRD status was collected after cycles 2, 4 and 6 and will be evaluated using the ClonoSeq assay (Adaptive Biotechnologies). The primary objective was to determine the stem cell mobilization success rate. Secondary objectives included safety and tolerability, overall response rate (ORR), pre-transplant complete response rate (CR), and the MRD negativity rate during and after completion of therapy. Results The trial enrolled 14 patients from December 2018 to February 2020. One patient withdrew consent prior to start of treatment and another was found to have an undiagnosed adenocarcinoma shortly after starting MCL treatment. Both are excluded from the analysis. The median age was 57 years (range 52-66). 11 patients were males (92%), all patients had an ECOG performance status of 0-1. 11 patients (92%) presented with stage IV disease. The mean MCL International Prognostic Index (MIPI) score was 6.3 (25% high-risk, 42% intermediate-risk and 33% low-risk). Of the 12 patients who began treatment, 9 completed all 6 cycles. Three patients did not complete therapy due to: insurance issues (n = 1), and thrombocytopenia (n = 2) following cycle 5 and 4. The side effect profile showed expected hematologic toxicities with grade 3-4 cytopenias in all patients, mostly during cytarabine cycles. In total, 100% of patients developed grade 3-4 thrombocytopenia and 83% of patients developed grade 3-4 neutropenia. Three episodes of febrile neutropenia were observed. One patient had a grade 3 transaminase increase, and one patient had grade 3 diarrhea. No bleeding events or treatment related deaths occurred. The remainder of the side effects were low grade and the treatment was generally well tolerated. Of the 12 evaluable patients, 10 responded (ORR 83%) with 9 achieving CR (75%). One patient achieved PR prior to being removed from the study due to thrombocytopenia and then achieved CR off study. Two patients experienced PD during induction. With a median follow up of 9 months, no responding patients have relapsed. The median CD34+ stem cell collection was 3.84x106 cells/kg (range 2.77 - 5.9). MRD results will be presented at the meeting. Conclusions This is the first study attempting to combine BTK inhibition with a high dose cytarabine containing regimen. The addition of acalabrutinib to a regimen of bendamustine/rituximab followed by cytarabine/rituximab appears to be safe. The R-ABC combination will be further tested in the recently activated intergroup trial EA4181. Disclosures Bartlett: Autolus: Research Funding; BMS/Celgene: Research Funding; Forty Seven: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; BTG: Consultancy; Acerta: Consultancy; Affimed Therapeutics: Research Funding; ADC Therapeutics: Consultancy. Fehniger:ImmunityBio: Research Funding; HCW Biologics: Research Funding; Kiadis: Consultancy; Nkarta: Consultancy; Indapta: Consultancy; Wugen: Consultancy; Orca Biosystems: Consultancy; Compass Therapeutics: Research Funding. Ghobadi:Amgen: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; EUSA: Consultancy; WuGen: Consultancy. Mehta-Shah:Bristol Myers-Squibb: Research Funding; C4 Therapeutics: Consultancy; Celgene: Research Funding; Genetech/Roche: Research Funding; Innate Pharmaceuticals: Research Funding; Kyowa Hakko Kirin: Consultancy; Verastem: Research Funding; Karyopharm Therapeutics: Consultancy; Corvus: Research Funding. Kahl:Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Pharmacyclics LLC: Consultancy; Roche Laboratories Inc: Consultancy; BeiGene: 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; Acerta: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy.

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Sustained High Rates of Complete Response and Minimal Residual Disease Negativity after 8 Cycles of Carfilzomib (CFZ), Lenalidomide (LEN), and Dexamethasone (DEX) Followed By 2 Years of Lenalidomide Maintenance (CRd-R) in Patients with High-Risk Smoldering Multiple Myeloma: Updated Results of Clinical and Correlative Phase 2 Study

Blood ◽

10.1182/blood.v128.22.3339.3339 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3339-3339 ◽

Cited By ~ 1

Author(s):

Dickran Kazandjian ◽

Neha S Korde ◽

Mark Roschewski ◽

Sham Mailankody ◽

Candis Morrison ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Combination Therapy ◽

Minimal Residual Disease ◽

Research Funding ◽

Residual Disease ◽

Complete Response ◽

Risk Of Progression ◽

Minimal Residual

Abstract Background: High-risk smoldering multiple myeloma (HR-SMM) is a plasma cell dyscrasia which has a 5-year risk of progression to symptomatic multiple myeloma (MM) of approximately 75% based on current risk models. With the availability of novel therapies, early treatment may decrease the risk of progression and prolong survival as evidenced by the recent QuiRedex study results. More recently, studies have demonstrated that triplet regimens are superior to doublet in MM and whole exome sequencing in HR-SMM is indicative of treatment susceptible biology in early disease; supporting the use of effective combination therapy as early intervention. Expanding on our initial results using modern CRd-R therapy in HR-SMM patients (Korde et al. JAMA Onc 2015) we show unprecedented high rates of obtained and sustained complete response (CR) and minimal residual disease negativity (MRDneg CR) in an expanded cohort of patients with a median follow-up of ~3 years. Methods: Treatment-na•ve patients with HR-SMM (IMWG 2010 criteria; Mayo or PETHEMA models) were treated for 8 cycles (28-day cycles) with CFZ 20/36 mg/m2 IV days 1, 2, 8, 9, 15, 16; LEN 25 mg PO days 1-21, and DEX 20/10 mg IV/PO days 1, 2, 8, 9, 15, 16, 22, 23. Transplant eligible patients underwent stem cell collection after ≥4 cycles of CRd and then continued CRd treatment (i.e. by-default-delayed high-dose melphalan with autologous stem cell transplant; HDM-ASCT). After 8 cycles of combination therapy, patients with SD or better received 2 years of LEN 10 mg PO maintenance. The primary objective was best response (ORR), followed by secondary objectives of progression free survival (PFS) and response duration (DoR) which were assessed after every cycle of induction and every 90 days during maintenance. Correlative studies including assessment of minimal residual disease (MRD) by multi-color flow cytometry (bone marrow aspirate; 10-5 sensitivity) as defined by updated 2016 IMWG response criteria were performed after 8 cycles of induction and 1 and 2 years of maintenance LEN. Results: Eighteen patients meeting eligibility criteria were enrolled (data-lock 7/20/2016). Demographics and disease characteristics are shown in Table 1. Best ORR and >= VGPR rate (n=18) with CRd-R was 100% (Table 2). The proportion of patients who obtained stringent CR/CR after 8 cycles of induction, 1 year of maintenance and 2 years of maintenance was 61%, 89%, and 89%, respectively. Of evaluable patients who achieved at least a CR, the proportion of patients who obtained MRD negativity (MRDneg CR) at the same time-points was 91%, 71%, and 75%, respectively. DoR and PFS at 36 months was 94% and overall survival with a median follow-up duration of 31 months was 100%. Toxicities Grade 3-4 occurring in >1 patient included lymphopenia (39%), neutropenia (28%), anemia (22%), diarrhea (17%), lung infection (17%), hypophosphatemia (11%), and thromboembolic event (11%). Significant serious adverse events included CHF which occurred in one patient. Conclusions: Early treatment of HR-SMM with modern CRd-R combination therapy with by-default-delayed HDM-ASCT resulted in unprecedented high rates of CR and MRDneg CR after 8 cycles of CRd. Following 2 years of additional LEN maintenance therapy, the CR and sustained MRDneg CR rates were 89% and 69%, respectively. Given the significant risk of progression to symptomatic MM and associated life limiting end-organ damage, early intervention for patients with HR-SMM with effective triplet-based therapies may be warranted. This first proof-of-principle study has thus far demonstrated exceptional clinical benefit. Therefore, this study will be re-opened to enrollment and long-term follow up results collected to expand on these promising results. Updated results will be presented at the Annual Meeting. Disclosures Korde: Medscape: Honoraria. Bhutani:Prothena: Research Funding; Takeda Oncology: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Onyx, an Amgen subsidiary: Speakers Bureau. Landgren:BMS: Honoraria; Amgen: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Takeda: Honoraria.

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A Phase 2 Study of Carfilzomib, Lenalidomide, and Dexamethasone with Lenalidomide Maintenance (KRd-r) in Newly Diagnosed Multiple Myeloma (NDMM): Sustained Long Term Deep Remissions and Prolonged Progression-Free Duration Regardless of Age or Cytogenetic Risk after 5 Years of Follow up

Blood ◽

10.1182/blood-2018-99-111712 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1957-1957

Author(s):

Dickran Kazandjian ◽

Neha Korde ◽

Sham Mailankody ◽

Yong Zhang ◽

Jennifer Hsu ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Risk Profile ◽

Phase 2 ◽

Time To Progression ◽

Advisory Committees ◽

Phase 2 Study ◽

Grade 3

Abstract Background: State of the art treatment for patients with NDMM involves induction with triplet-based regimens utilizing combinations of immunomodulatory drugs and proteasome inhibitors (PI) which improve time to progression (TTP), progression-free survival, and overall survival (OS) over doublet regimens. Carfilzomib is a selective PI with FDA approval in the KRd combination regimen for the treatment of patients with relapsed or refractory MM. Carfilzomib-based combinations are associated with increased clinical benefit over bortezomib-based combinations and carfilzomib does not cause neuropathy. This phase 2 study of 45 patients demonstrated that deep responses with KRd-r is achieved in the NDMM setting (Korde et al. JAMA Onc 2015). Here, we expand on our initial results in assessing response to present the long-term durability of minimal residual disease negativity (MRDneg) complete response (CR) and time to progression. We also characterize TTP by depth of response, age, and cytogenetic risk profile. Methods:Treatment-naïve patients with MM were treated for 8 cycles (28-day cycles) with carfilzomib 20/36 mg/m2 IV days 1, 2, 8, 9, 15, 16; lenalidomide 25 mg PO days 1-21, and dexamethasone 20/10 mg IV/PO days 1, 2, 8, 9, 15, 16, 22, 23. Transplant eligible patients underwent stem cell collection after ≥4 cycles and then continued KRd treatment (i.e. without default autologous stem cell transplant (ASCT)). After 8 cycles of KRd, patients received 2 years of lenalidomide 10 mg PO maintenance on days 1-21. The primary objective of the study was to estimate the rate of ≥ Grade 3 peripheral neuropathy with secondary objectives of International Myeloma Working Group criteria for overall response rate (ORR), MRDneg CR, TTP, and response duration (DoR) assessed after every cycle during induction and subsequently after every 90 days of maintenance therapy. Assessment of MRDneg CR by multi-color flow cytometry (bone marrow aspirate; 10-5 sensitivity) was performed after 8 cycles of induction, 1 and 2 years of lenalidomide maintenance, and then annually. Results: Forty-five patients meeting eligibility criteria were enrolled (60% male; 42% ≥ age 65, range 40-89; race: 82% White, 13% Black, 4% Asian; isotypes: 51% IgG kappa, 16% IgG lambda, 13% IgA kappa, 9% IgA lambda, 9% free kappa, and 4% free lambda; 33% high risk cytogenetics, del(17p), t(4;14), t(14;16)or t(14;20)). The median potential follow up was 5.7 years (68.3 months). The ORR was 97.8% (95% Confidence Interval (CI): 88.2-99.9%) with a median DoR of 65.7 months (95% CI: 55.6-not reached (NR) months). Strikingly, 28 of the 45 patients, 62.2%, (95% CI: 46.5-76.2%) attained deep responses of MRDneg CR; durability of MRDneg CR was observed up to at least 70 months with a median duration of over 4 years (52.4 months; 95% CI: 35.3-61.6 months). Moreover, the median TTP was over five and a half years (67.3 months; 95% CI: 51.0-NR months) and the median OS was NR, however, at 80 months, 84.3% of patients were still alive. As expected, patients who attained MRDneg CR, by cycle 8, had a 78% reduction in the risk of progression (Hazard Ratio (HR): 0.22 (95% CI: 0.07-0.69); p=0.005) (Figure 1). Importantly, these deep responses of MRDneg CR and long progression free durations were observed regardless of age group or cytogenetic-based risk profile (Table 1). Toxicities have been previously reported and were generally manageable with no Grade ≥ 3 neuropathy or death due to toxicity. Conclusions: Upfront treatment of NDMM with the modern and highly efficacious KRd-r regimen incorporating a "by-default-delayed" ASCT strategy led to high rates of MRDneg CR (10-5 sensitivity) which even more importantly were sustained with a median duration of over 4 years. Moreover, attaining MRDneg CR, was strongly associated with a delay in progression. Clinically important, we observed that these deep responses and long progression-free durations are observed regardless of age or cytogenetic risk and stress the importance of utilizing highly efficacious triplet-based regimens for these sub-categories of NDMM. Lastly, our results with KRd-r in NDMM compare favorably to ASCT-based regimens and question the use of upfront ASCT for all patients. Our observed median TTP of 67 months is approximately 17 months longer than published data using the regimen of bortezomib, lenalidomide, and dexamethasone with ASCT (Attal et al. NEJM 2017). Updated results will be presented at the Annual Meeting. Disclosures Korde: Amgen: Research Funding. Mailankody:Janssen: Research Funding; Juno: Research Funding; Takeda: Research Funding; Physician Education Resource: Honoraria. Landgren:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Pfizer: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Leopard: A Phase II Study of Maintenance Lenalidomide and Prednisolone Post Autologous Stem Cell Transplantation (ASCT) for Myeloma, Incorporating Minimal Residual Disease Assessments

Blood ◽

10.1182/blood.v124.21.2103.2103 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2103-2103

Author(s):

Anna Kalff ◽

Nola Kennedy ◽

Patricia A. Walker ◽

Tiffany T. Khong ◽

Anthony Schwarer ◽

...

Keyword(s):

Minimal Residual Disease ◽

Phase Ii ◽

Research Funding ◽

Residual Disease ◽

Complete Response ◽

Multi Centre Study ◽

Poor Risk ◽

Depth Of Response ◽

Grade 3 ◽

Minimal Residual

Abstract Background Despite improved outcomes achieved with high dose melphalan conditioned ASCT for Myeloma (MM) patients, relapse is inevitable. Maintenance therapy following ASCT improves the depth of response achieved by induction therapy and prolongs both progression free (PFS) and overall survival (OS). Achievement of stringent (s) complete response (CR) is predictive of improved outcome, as is minimal residual disease (MRD) negativity (-neg) assessed by sensitive techniques such as multiparameter flow cytometry (MFC) of bone marrow (BM). Aim To document disease response changes, PFS/OS in MM patients receiving maintenance lenalidomide and alternate-day prednisolone (RAP) after ASCT. To sequentially quantify MRD in patients achieving a complete response (CR) utilising freeLite chain (FLC) and MFC. To assess safety and tolerability. Methods Phase II, open label, single arm, multi-centre study. Newly diagnosed patients with MM commenced RAP maintenance (lenalidomide 10mg/continuous daily increasing to 15mg after 8/52 and alternate day prednisolone 50mg) 6-8 weeks after a single MEL200 ASCT as part of first-line therapy. RAP continued until toxicity or relapse/progression. Serum for FLC was collected every 2/12, patients achieving CR had serial BM MFC. Statistical analysis: Prism v5.0a. Results 60 patients (M=37, F=23), with a median age of 61 years (range 41-71) commenced RAP maintenance. ISS stage at diagnosis: I: 20, II/III: 37 (3 unknown). 51/60 patients had diagnostic cytogenetics ± FISH performed – 15 had poor risk features (t(4;14), t(14;16), del17p, del13, +1q21), 11/15 had +1q21. After a median 23 months (range 12-36) following initiation of RAP, 33 patients remain on therapy. One patient has been lost to follow-up. Discontinuation was due to relapse/progressive disease (10), AEs (13), physician choice (2), poor compliance (1) and death (1). 15 patients have relapsed/progressed, 11 patients have died; 7 due to MM, 2 due to therapy related AML (tAML) and 2 other. Both the median PFS and OS have not been reached. When looking at the association between survival and poor risk cytogenetics ± FISH, those with +1q21 had both inferior PFS and OS: median PFS was 646 days vs not reached (NR) for those without +1q21 (P=0.04), median OS was 701 days vs NR for those without +1q21(P=0.013). 34 patients improved their post ASCT response on RAP. Best response was CR in 36 (60% - 25 sCR), 21 VGPR (35%) and 2 PR (3%), achieved in a median of 77 days (range, 0-447). 30 of 36 patients in CR went on to have sequential MRD studies: 21/30 were multiply MRD-neg and 9/30 were multiply MRD-pos. There was no difference in PFS between MRD-pos and MRD-neg patients (p=0.3). Of the MRD-neg patients, 16/21 had predominantly normal FLC ratios (sCR), 4/21 MRD-neg patients relapsed, 3 had normal FLC ratios. Of the MRD-pos patients, 6/9 had normal FLC ratios (sCR), 3/9 MRD-pos relapsed. Correlation between MRD neg and sCR was poor (r2=0.05) and there was no difference in relapse rate between patients achieving MRD-neg versus those who achieved sCR. All grade haematologic AEs comprised thrombocytopenia 15/60 (25%)(grade 3/4: 6 [10%]), neutropenia 10/60 (grade 3: 5), and anaemia 5/60 (%)(grade 3: 1). All grade non-haematologic AEs regardless of relatedness to study treatment (>10%) were: infections (URTI: 35%, LRTI: 25%, VZV reactivation: 13%), diarrhoea (38%), insomnia (32%), fatigue (26%), peripheral neuropathy (20%), cramps (18%), hyperglycemia (12%). There have been six second primary malignancies (SPMs) – 2 tAML (onset post C1D1: 15m, 21m), 1 adenocarcinoma of bowel (onset post C1D1: 30m) and 3 skin cancers (SCCs). AEs leading to discontinuation were myelosuppression (9), SPM (2), retinal vein thrombosis (1) and fatigue (1). 24 patients (40%) tolerated lenalidomide dosing as per protocol, 13 were not increased from 10mg/d to 15mg day, and 23 required dose modifications for AEs. Conclusion RAP maintenance improved depth of response post-ASCT (including conversion to deeper response categories > 14months), with high rates of CR/sCR (60%). Neither MFC or FLC demonstrated superiority over the other for prediction of outcome and correlation between the two was poor. Recapitulating earlier findings of an interim analysis, patients with +1q21 had inferior PFS/OS, suggesting that this group may benefit less from RAP maintenance. Only 21% of patients discontinued RAP due to toxicity, comparable to IFM 2005-02 and CALGB 100104 studies. Disclosures Off Label Use: Lenalidomide used as maintenance post-ASCT. Spencer:Takeda: Consultancy, Honoraria; janssen-Cilag: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Honoraria, Research Funding; celgene: Consultancy, Honoraria, Research Funding.

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A Prospective Phase 2 Study to Assess Minimal Residual Disease after Ixazomib, Lenalidomide and Dexamethasone Treatment for Newly Diagnosed Transplant Eligible Multiple Myeloma Patients

Blood ◽

10.1182/blood-2020-138643 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 40-41

Author(s):

Raija Helena Silvennoinen ◽

Anders Waage ◽

Valdas Peceliunas ◽

Fredrik Schjesvold ◽

Pekka Anttila ◽

...

Keyword(s):

Research Funding ◽

Residual Disease ◽

Median Number ◽

Tumor Burden ◽

Advisory Board ◽

Phase 2 ◽

Board Meeting ◽

Cd34 Cells ◽

Grade 3 ◽

Minimal Residual

Introduction Autologous stem cell transplantation (ASCT) combined with novel agents is considered as the standard treatment for eligible patients < 70(-75) years of age with multiple myeloma (MM). The number of induction cycles is usually 4-6 followed by ASCT, consolidation and maintenance. The role of consolidation is still under debate especially if complete response has been achieved and maintenance will follow. To improve the quality of life and avoid the frequent visits at hospital an all-oral treatment would be a preferred choice. Despite novel drugs, the outcome of high-risk (HR) patients is poor. We designed a phase 2 Nordic Myeloma Study Group (NMSG) trial (NCT03376672) to explore the response of ixazomib, lenalidomide and dexamethasone (IRd) induction, followed by single ASCT, IRd consolidation and risk-based maintenance either with IR or R. Here we present the response rates and safety after IRd x 4 induction in all patients and in 87% of patients before consolidation. Patients and methods This study included 120 patients in 22 NMSG sites. Patients received 4 IRd cycles as induction, ixazomib 4 mg on days 1, 8, 15, lenalidomide 25 mg on days 1-21, dexamethasone 40 mg weekly in 28-day cycles. Mobilization and ASCT were performed according to standard practice. Three months post-ASCT all patients will receive 2 IRd as consolidation followed by maintenance. Thereafter patients will be stratified to HR if any of the following FISH aberrations were found at inclusion: del17p at least 60%, t(4;14), t(14;16), t(14;20) or +1q and they receive ixazomib 4 mg on days 1, 8, 15 and lenalidomide 10 mg on days 1-21. Non-HR patients receive lenalidomide 10 mg on days 1-21. Maintenance will continue until progression (PD). Lenalidomide dose will increase to 15 mg after 3 cycles. The primary endpoint of the study is minimal residual disease (MRD) by 8-color Euroflow < 0.01%. The secondary endpoints include flow-MRD negativity by 10-5, overall response, safety and progression-free survival. Serological responses were assessed before cycles and if sCR or CR is achieved flow-MRD sampling will be performed and repeated every 6 months. Samples were taken concomitantly for later comparison with BM- molecular-MRD, blood cell-free DNA, blood heavy-light chain assay and blood mass spectrometry. Results Within 21 months 120 patients were included, 46 % of them belong to the HR group. Mobilization is by July 2020 performed for 101 (84%) patients with cyclophosphamide (Cy) + G-CSF in 74% and G-CSF alone in 26%. Plerixafor was needed in 32 (32%) patients. The median number of harvesting days was 2 (0-4) and the median number of collected CD34+ cells was 6.4 (0-19.2) x 106/kg. Four patients (4%) failed to mobilize during 1st attempt. Eighty-six (72%) patients have so far received ASCT with the median number of 3.4 x 106/kg CD34+ cells in graft. Overall response rate is 93%. The responses after IRD x 4 induction and before consolidation are presented in Table 1. Before consolidation 10 patients (8%) are out of study due to PD and 4 (3%) have been withdrawn due to toxicity. Toxicity events included hypersensitivity with hepatorenal failure, grade 3 cytopenia with liver toxicity and one unexplained encephalitis. One patient was withdrawn due to Cy toxicity. Eight additional patients are withdrawn from study, 7 by physician´s decision and 1 by patient´s decision. All these 7 patients had high tumor burden based on paraprotein level either in serum (53 - 102 g/L) or in 24h urine (7.8 - 23.2 g/24h) and achieved only stable disease (SD) during induction. Fifty-eight grade 3-4 SAE reports from 39 (33%) patients have been received and 57% of these were infections. Three patients had grade 3 liver problems and 2 patients grade 3 peripheral neuropathy. Seventeen (14%) patients have reported skin reactions, only 4 of them grade 3 events. Conclusion We present here data on response and safety after observation of all patients until post-induction phase and of 87 % of the patients until start of the consolidation phase. The ORR is 93% when all patients have received induction treatment. Nine patients achieved only SD and seven of them with high tumor burden were withdrawn before mobilization. At least VGPR after ASCT was achieved in 37%. Toxicity caused the withdrawal of 4 (3%) patients and 39 (33%) patients have reported grade 3-4 non-hematological SAEs. In all, 98/120 (82%) patients continue in the study including 80% of the HR patients. Disclosures Silvennoinen: BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Cancer patients Finland: Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Waage:Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy; Shire: Honoraria. Schjesvold:Celgene, Amgen, Janssen, Oncopeptides: Research Funding; Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, SkyliteDX, Takeda: Honoraria; Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, Takeda: Consultancy. Anttila:Sanofi: Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Research Funding; Janssen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Research Funding. Säily:Amgen: Honoraria; Abbvie: Honoraria; Celgene: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria; Takeda: Honoraria; Janssen Cilag: Honoraria; Boehringer Ingelheim: Honoraria. Sankelo:Celgene, Amgen, Sanofi: Other: Congress travel support. Partanen:Abbvie: Honoraria, Other: Scientific Advisory Board Meeting; Behring: Honoraria; Takeda: Other: Scientific Advisory Board Meeting.

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Phase 2 Study of the Combination of Daratumumab, Ixazomib, Pomalidomide, and Dexamethasone As Salvage Therapy in Relapsed/Refractory Multiple Myeloma: Stage I Results

Blood ◽

10.1182/blood-2020-143147 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 5-6

Author(s):

Caitlin L. Costello ◽

Benjamin Brookhart ◽

Matthew J. Wieduwilt ◽

Nina Shah ◽

Carolyn Mulroney ◽

...

Keyword(s):

Research Funding ◽

Residual Disease ◽

Stage I ◽

Phase 2 ◽

Upper Respiratory Infection ◽

Efficacy Analysis ◽

Phase 2 Study ◽

Upper Respiratory ◽

Grade 3 ◽

Stage 1

Background: Triplet combination regimens have been widely accepted as the standard of care for the management of multiple myeloma (MM) due to improved outcomes as compared to doublet regimens. The combination of daratumumab, pomalidomide, and dexamethasone (DPd) has previously demonstrated deep and durable responses including high rates of minimal residual disease (MRD) negativity in patients with relapsed/refractory (R/R) MM. Quadruplet regimens may further improve these outcomes. We report preliminary findings from an ongoing phase 2 multi-center trial of the addition of ixazomib to DPd (DIPd) in patients with R/R MM. Methods: We are conducting a prospective, multi-center, open-label, single-arm phase 2 study to determine the efficacy and safety of DIPd as salvage therapy in R/R MM. A Simon's optimal 2-stage design includes a safety run-in period at the beginning of Stage 1 where the first 6 patients are enrolled for toxicity assessment. If ≤1 patient experiences any DLT, the study continues to accrue more Stage 1 patients. Key secondary endpoints include progression-free survival (PFS), overall survival (OS) and MRD-negativity rates. Eligible patients may have received ≥1 and ≤3 prior lines of therapy, have had no prior exposure to daratumumab or ixazomib, are lenalidomide refractory, and may have not progressed on prior pomalidomide. The first six patients were treated in a safety run-in with daratumumab 16mg/kg IV weekly x 8 doses, biweekly x 8 doses, then monthly, pomalidomide 4mg orally daily on days 1-21 of a 28-day cycle, ixazomib 4mg orally daily on days 1,8,15 every 28 days, and dexamethasone 20-40mg weekly. Patients continued therapy until disease progression, intolerability or preference. Dose-limiting toxicities (DLT) were defined as grade 3-4 hematologic adverse events (AE) or any AE that required a dose modification of pomalidomide or ixazomib at the lowest dose levels on a dose de-escalation plan. An interim safety review is being performed after the enrollment and completion of the DLT observation period for the 14 planned patients in stage I. An interim efficacy analysis was also planned after all patients had completed 3 months of therapy. Minimal residual disease assessments are being performed by EuroFlow for patients in VGPR or suspected CR. Pharmacodynamic changes in patients' tumor microenvironments were established by custom panel mass cytometry to include T-cell memory and activated subpopulations, B-cell content, NK-cell subpopulations as well as MDSCs, Tregs and T-exhaustive markers, monocytes and dendritic cells. Results: At the time of this analysis, all 14 patients have enrolled and started treatment as part of stage I of the trial. Patients had a median age of 61 (range 52-65) and median number of 1 prior line of therapy (range 1-3). All patients were refractory to lenalidomide and all were pomalidomide naïve. In the safety run-in, all 6 patients experienced ≥ grade 3 neutropenia, and per DSMB recommendation, the starting doses of pomalidomide and ixazomib were both reduced to 3mg for the subsequent 8 patients in stage 1. Common AEs included neutropenia, thrombocytopenia, and upper respiratory infection. Grade 3-4 AEs were predominantly hematologic, including neutropenia and thrombocytopenia. One patient had a grade 3 infusion-related reaction (IRR) with daratumumab administration. No DLTs have occurred. After median follow up of 4.1 months (range 1-22), all 14 patients were evaluable for efficacy. At the time of data analysis, the overall response rate to date is 85%, and the best responses include: 5 (36%) stringent complete response; 1 (7%) very good partial response; 5 (36%) partial responses; and 3 (21%) patients with stable disease. Six (42%) patients are off study treatment: 3 due to disease progression, 1 to undergo salvage autologous SCT, and 2 due to toxicity related to treatment (IRR and upper respiratory infection). MRD and pharmacodynamic data will be presented at ASH. Conclusion: The quadruplet regimen DIPd in patients with R/R MM is a well-tolerated combination and has shown early safety and promising efficacy in the first 14 patients enrolled to stage 1 of the trial. A pre-planned interim efficacy analysis is ongoing prior to future enrollment in stage 2 at multiple sites within the University of California Hematologic Malignancies Consortium. Disclosures Costello: Celgene: Honoraria, Research Funding; Janssen: Research Funding; Poseida Therapeutics: Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Wieduwilt:Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Shire: Research Funding; Macrogeneics: Research Funding; Amgen: Research Funding; Leadiant: Research Funding; Merck: Research Funding; Reata Pharmaceuticals: Current equity holder in publicly-traded company. Shah:GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy; BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding.

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BLAST: A Confirmatory, Single-Arm, Phase 2 Study of Blinatumomab, a Bispecific T-Cell Engager (BiTE®) Antibody Construct, in Patients with Minimal Residual Disease B-Precursor Acute Lymphoblastic Leukemia (ALL)

Blood ◽

10.1182/blood.v124.21.379.379 ◽

2014 ◽

Vol 124 (21) ◽

pp. 379-379 ◽

Cited By ~ 31

Author(s):

Nicola Goekbuget ◽

Hervé Dombret ◽

Massimiliano Bonifacio ◽

Albrecht Reichle ◽

Carlos Graux ◽

...

Keyword(s):

Clinical Studies ◽

Research Funding ◽

Response Rate ◽

Residual Disease ◽

Primary Objective ◽

Phase 2 ◽

Off Label Use ◽

Phase 2 Study ◽

Equity Ownership ◽

Minimal Residual

Abstract Introduction: In ALL, minimal residual disease (MRD) is defined as the detection of leukemic cells in bone marrow by PCR or flow cytometry in the presence of hematological complete remission (CR). Patients with persistent/recurrent MRD after induction therapy have a higher risk of relapse than those with no detectable MRD. Effective treatment of patients with MRD aims to avoid hematologic relapse, reduce MRD load, and provide a bridge to subsequent HSCT. Blinatumomab, an investigational BiTE® antibody construct, redirects CD3+ T cells to CD19+ target cells, resulting in serial lysis of CD19+ B cells. In a phase 2 study of blinatumomab in 21 patients with MRD+ ALL in first-line treatment, 80% of evaluable patients achieved a complete MRD response. BLAST, a confirmatory single-arm, phase 2 study evaluated efficacy, safety, and tolerability of blinatumomab in patients with MRD+ ALL in a larger population. Methods: Adults (≥18 years) with B-precursor ALL in hematologic CR (<5% blasts in bone marrow) after ≥3 intensive chemotherapy treatments and with MRD ≥10-3 were eligible. Patients with current CNS pathology or extramedullary disease, previous allogeneic HSCT, or Ph+ ALL eligible for treatment with tyrosine kinase inhibitors were excluded. Blinatumomab 15 µg/m²/day was given by continuous IV infusion for 4 weeks, followed by a 2-week treatment-free period (1 cycle). Responders could receive ≤4 cycles of treatment or undergo HSCT after ≥1 cycle. Patients with hematologic relapse discontinued treatment. Rate of complete MRD response (absence of MRD confirmed with a sensitivity of at least 10-4 after 1 cycle) was the primary endpoint. MRD was assessed by allele-specific quantitative real-time PCR for clonal rearrangements of immunoglobulin or T-cell receptor genes by a central laboratory. Overall survival (OS), relapse-free survival (RFS), duration of complete MRD response, and incidence and severity of adverse events (AEs) were secondary endpoints. Per protocol, OS and RFS will be analyzed after 18 months minimum follow-up. Results: 116 patients enrolled and received blinatumomab. Median (range) age was 45 (18–76) years; 15 (13%) patients were ≥65 years of age. 35% of the patients were treated in second or later remission (Table). As of February 2014, 106 patients had ended treatment: 74 had completed treatment (4 cycles or 1 cycle followed by HSCT) and 32 had discontinued treatment due to AEs, disease relapse, or investigators' decision; 79 patients were still alive and being followed. Three patients were excluded from the efficacy analysis: one had no central lab assay and two had assays with a sensitivity of 5×10-4. Eighty-eight patients (78% [95% CI, 69%–85%]) had a complete MRD response after 1 cycle of treatment. The lower CI bound exceeded 44% (the null hypothesis response rate), confirming that the study met its primary objective. Two additional patients had a complete MRD response after >1 cycle of blinatumomab; across all cycles the complete MRD response rate was 80%. The rate of complete MRD response did not differ significantly across baseline age, sex, line of treatment, and MRD burden categories (Table). All patients experienced ≥1 AE. AEs occurring in ≥20% of patients included pyrexia (88%), headache (38%), tremor (29%), chills (25%), fatigue (24%), nausea (22%) and vomiting (22%). Serious AEs (SAEs) occurred in 60% of patients; 59% and 27% of patients had grade ≥3 and grade ≥4 AEs, respectively. SAEs occurring in ≥5% of patients were pyrexia (15%), tremor (7%), aphasia (5%), encephalopathy (5%) and overdose (5%). Two fatal AEs occurred on treatment: subdural hemorrhage and atypical pneumonia (the latter was deemed treatment-related). Conclusion: This is the largest prospective trial with an experimental compound in MRD+ ALL.Blinatumomab treatment resulted in complete MRD response across multiple patient demographics including patients in second-line treatment and those with high MRD burden. With a complete MRD response rate of 78%, the study met its primary objective. Among patients with a complete MRD response, 98% had a response within the first treatment cycle. In patients with MRD+ ALL following intensive therapy, rapid MRD response induced by blinatumomab has the potential to improve patient outcomes. Figure 1 Figure 1. Disclosures Goekbuget: Amgen Inc.: Consultancy, Honoraria, Research Funding. Off Label Use: This presentation will discuss the off-label use of blinatumomab, as this agent is not approved for use by the FDA, EMA or any other regulatory authorities.. Dombret:Amgen Inc.: Honoraria, Research Funding. Bonifacio:Amgen Inc.: Consultancy. Graux:Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Buss:Amgen Inc.: Reimbursement for participation in clinical studies, Reimbursement for participation in clinical studies Other; BMS: Travel support, Travel support Other; Novartis: Travel support Other; Pfizer: Reimbursements for participation in clinical studies, Reimbursements for participation in clinical studies Other. Bruggemann:Amgen Inc.: Consultancy, Research Funding. Stieglmaier:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Wessels:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Haddad:Amgen Ltd.: Employment. Zugmaier:Amgen Research (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Nagorsen:Amgen Inc.: Employment, Equity Ownership, Related to blinatumomab Patents & Royalties. Bargou:Amgen Inc.: Consultancy, Honoraria.

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Phase 3 Study of Pomalidomide with Cyclophosphamide and Dexamethasone Versus Pomalidomide and Dexamethasone in Asian Patients with Relapsed/Refractory Myeloma (RRMM) - Interim Analysis of a Trial By the Asian Myeloma Network (AMN)

Blood ◽

10.1182/blood-2020-139019 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 1-1

Author(s):

Wee-Joo Chng ◽

Xinhua Li ◽

Cindy Lin ◽

Jin Seok Kim ◽

Hiroshi Handa ◽

...

Keyword(s):

Interim Analysis ◽

Research Funding ◽

Response Rate ◽

Prior Exposure ◽

Phase 2 ◽

Asian Patients ◽

Phase 2 Study ◽

Grade 3 ◽

Experienced Grade

Background Pomalidomide is an immunomodulatory drug that has been approved for the treatment of relapse refractory myeloma. A previous small randomized phase 2 study in the United States showed that combination of Pomalidomide, cyclophosphamide and dexamethasone induce a greater response rate than pomalidomide and dexamethasone1. In our prior study, AMN0012, we should that in patients with sub-optimal response to pomalidomide and dexamethasone, the addition of cyclophosphamide can increase response resulting in improvement of progression free survival. In the current study, we seek to randomize Asian patients with RRMM between PCD and PD to confirm the benefit of PCD. Method We conducted a prospective randomized trial of pomalidomide (4mg daily for 21 days followed by 7 days rest) plus dexamethasone 40mg once weekly for 4 weeks with or without cyclophosphamide (400mg once a week) in patients with relapse and refractory myeloma that has to be refractory to lenalidomide and has prior exposure to proteasome inhibitors. Each cycle is 4 weeks. Patients from Singapore, Japan and Korea (NCT03143049) were included in this Asian Myeloma Network trial. The trial was started in Sep 2017 and is still ongoing. To date, 53 patients have been recruited so far. This interim report presents data available up till the data cut-off date of 24 June 2020. Results Forty-six patients have available base line information and safety data and is included in this interim analysis. 50% of patients are male and median age of the cohort is 68 years old. 39% and 28% of patients are International Stage System (ISS) stage 2 and 3 respectively. 20% of patients have abnormal creatinine clearance. Median prior line of treatment is 3. All patients are refractory to lenalidomide and 96% have prior exposure to bortezomib. In addition, 12 patients (26%) and 5 (11%) have been treated with Carfilzomib and Ixazomib respectively. 15 (33%) patients had prior high dose melphalan and autologous stem cell transplant. 20 (44%) patients required dose reduction of pomalidomide, cyclophosphamide or dexamethasone. 89% of patients experience adverse events (AEs) of any grade. Of the 297 episodes of AEs, 43% are grade 3 or higher, with 50% of these episodes related to the study drugs. 57% of patients experienced serious AEs (SAEs) of any grade. Of the 74 episodes of SAE, 89% are grade 3 or higher, with 49% of these episodes related to the study drugs. Almost all of these events are related to cytopenias and infections. 20 (44%) of the patients develop grade 3 neutropenic fever and 9 (20%) patients have grade 3 or higher pneumonia. Only 1 patient experienced grade 3 peripheral neuropathy, 1 patient develop grade 3 pulmonary embolism, 1 patient developed grade 3 venous thromboembolism, and 1 patient experienced grade 3 renal impairment. At a median follow-up of 10.9 months, 9 of the 46 patients have died, and 21 have progressed. Three patients withdrew due to toxicity. While the overall response of the study population is not part of this interim analysis, we assessed the response of patients from the National University Cancer Institute, Singapore which has the highest number of patients recruited to get an idea of the therapeutic efficacy. Of the 14 patients recruited at NCIS, 1 patient achieved CR, 3 VGPR, 7 PR, producing a response rate of 79%. Conclusion In this interim analysis of a prospective randomized study of pomalidomide and dexamethasone with or without cyclophosphamide in Asian patients, we demonstrated the feasibility and efficacy of this combination. Longer follow-up and final analysis of the study will be needed to ascertain the therapeutic advantage of PCD over PD in relapse and refractory myeloma that is refractory to lenalidomide. References 1. Baz RC, Martin TG 3rd, Lin HY, Zhao X, Shain KH, Cho HJ, Wolf JL, Mahindra A, Chari A, Sullivan DM, Nardelli LA, Lau K, Alsina M, Jagannath S. Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood. 2016 May 26;127(21):2561-8. 2. Soekojo CY, Kim K, Huang SY, Chim CS, Takezako N, Asaoku H, Kimura H, Kosugi H, Sakamoto J, Gopalakrishnan SK, Nagarajan C, Wei Y, Moorakonda R, Lee SL, Lee JJ, Yoon SS, Kim JS, Min CK, Lee JH, Durie B,Chng WJ. 3. Pomalidomide and dexamethasone combination with additional cyclophosphamide in relapsed/refractory multiple myeloma (AMN001)-a trial by the Asian Myeloma Network. Blood Cancer J. 2019 Oct 8;9(10):83. Disclosures Chng: Novartis: Honoraria; Abbvie: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

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Autologous Transplantation for Aggressive Non-Hodgkin’s Lymphoma: Results of a Randomized Trial Evaluating Graft Source and Minimal Residual Disease

Journal of Clinical Oncology ◽

10.1200/jco.2002.09.138 ◽

2002 ◽

Vol 20 (9) ◽

pp. 2344-2352 ◽

Cited By ~ 68

Author(s):

Julie M. Vose ◽

Graham Sharp ◽

Wing C. Chan ◽

Craig Nichols ◽

Kevin Loh ◽

...

Keyword(s):

Stem Cell ◽

Median Time ◽

Response Rate ◽

Complete Response Rate ◽

Residual Disease ◽

Complete Response ◽

Hematopoietic Stem ◽

Transfusion Independence ◽

Rbc Transfusion ◽

Minimal Residual

PURPOSE: To determine whether the source of autologous hematopoietic stem cells altered the clinical outcomes of patients undergoing high-dose chemotherapy and hematopoietic stem-cell transplantation (HSCT) for aggressive non-Hodgkin’s lymphoma (NHL). PATIENTS AND METHODS: Of 105 high-risk, persistent, or relapsed NHL patients slated for an autologous HSCT entered onto this trial, 93 eligible patients were randomized to receive cytokine-naive autologous bone marrow transplantation (ABMT) (n = 46) or mobilized peripheral-blood stem-cell transplantation (PBSCT) (n = 47). All patients received carmustine, etoposide, cytarabine, and cyclophosphamide as the conditioning regimen. PBSCT patients also received identical mobilization with granulocyte colony-stimulating factor (G-CSF) 10 μg/kg/d, and both groups received G-CSF 5 μg/kg/d after the infusion of the stem-cell product until neutrophil engraftment. RESULTS: PBSCT patients had significantly faster engraftment of all cell lineages: median time to absolute neutrophil count ≥ 500/μL, 10 days versus 13 days on the ABMT arm; median time to platelet count greater than 20,000/μL untransfused, 11 days versus 15 days on the ABMT arm; and median time to RBC transfusion independence, 8 days versus 16 days on the ABMT arm. The complete response rate was 72% for PBSCT and 54% for ABMT. The death rate before posttransplant day 100 was 2% on the ABMT arm and 6% on PBSCT arm. Event-free survival was 37% for PBSCT and 37% for ABMT. However, overall survival for PBSCT was 61% compared with 43% for ABMT. CONCLUSION: Patients with aggressive NHL receiving HSCT randomized to PBSCT demonstrated improved neutrophil engraftment and platelet and RBC transfusion independence. The complete response rate and EFS were not statistically different by randomization arm. Patients whose harvests were positive for minimal residual disease by molecular analysis had poorer EFS.

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