Patients with multiple myeloma (MM) who achieve minimal residual disease (MRD) negativity after upfront treatment have superior outcomes compared with those who remain MRD+. Recently, associations have been shown between specific commensal microbes and development of plasma cell disorders. Here, we report the association between intestinal microbiota composition and treatment outcome in MM. Microbiota composition of fecal samples collected from 34 MM patients after induction therapy and at the time of flow cytometry–based bone marrow MRD testing was determined by 16S ribosomal RNA sequencing. We observed a higher relative abundance of Eubacterium hallii in the 16 MRD− patients relative to the 18 MRD+ patients. No association was observed between microbial relative abundance and autologous stem cell transplantation history or MM paraprotein isotype. No differences in microbiota α diversity were observed between MRD− and MRD+ patients. The potential association of microbiota composition with treatment response in MM patients is an important parameter for additional correlative and clinical investigation.
INTRODUCTION. Bortezomib, lenalidomide and dexamethasone (VRd) is considered a standard of care combination therapy for newly diagnosed multiple myeloma patients. Prior studies show that ~25% of patients treated with 8 cycles of VRd achieve minimal residual disease (MRD) negativity. Recently, 42% stringent complete response (sCR) rates were reported with the use of VRd combined with the CD38-targeted monoclonal antibody daratumumab (VRd-D). Prior studies using 8 cycles of bi-weekly carfilzomib 36 mg/m2 with lenalidomide and dexamethasone (bKRd) combination therapy in newly diagnosed multiple myeloma show ~40% MRD negativity rates. We were motivated to develop a phase 2 study (total N=82) using weekly dosing of carfilzomib 56 mg/m2 with lenalidomide and dexamethasone (wKRd) in combination with daratumumab (wKRd-D). Our study also included a parallel cohort of bi-weekly dosing of carfilzomib 36 mg/m2 with lenalidomide and dexamethasone (bKRd) in combination with daratumumab (bKRd-D). Primary end-point of our study was to rule out 60% and to target up to 80% MRD negativity rate. METHODS. This is a two-arm, Phase II clinical trial based on Simon's optimal two-stage design. The once-a-week carfilzomib (wKRd) (N=41) has the following treatment schedule: 8 cycles of treatment; 28-day cycles with carfilzomib 20/56 mg/m2 days 1, 8, and 15; lenalidomide 25 mg days 1-21; dexamethasone 40 mg weekly cycles 1-4, 20 mg after cycle 4; and daratumumab 16 mg/kg days 1, 8, 15, and 22 cycles 1-2, days 1 and 15 cycles 3-6, and day 1 cycles 7-8. The bi-weekly carfilzomib (bKRd) (N=41): 8 cycles of treatment; 28-day cycles with carfilzomib 20/36 mg/m2 days 1, 2, 8, 9, 15 and 16; lenalidomide, dexamethasone, and daratumumab are given at the same doses/schedules as the weekly cohort. For fit patients, stem cell collection is recommended after 4 to 6 cycles of therapy; DKRd therapy is resumed after collection to a total of 8 cycles DKRd. Treatment response is being assessed with parallel bone marrow-based MRD assays (10-color single tube flowcytometry and invivoscribe IGHV sequencing); per IMWG guidelines both MRD assays allow detection of 1 myeloma cell in 100,000 bone marrow cells (10^-5). Baseline bone marrow samples are evaluated with targeted DNA sequencing for FISH-Seq and somatic mutational characteristics (myTYPE). RESULTS. The first stage of the weekly cohort (wKRd-D) is fully enrolled (N=28) and the second stage of the cohort (N=13) is anticipated to complete enrollment shortly (total N=41). Currently, 29 patients meeting eligibility criteria were enrolled (14 males, 15 females) between October 2018 and August 2019. Baseline characteristics include; median age 59 years (range 36-70 years); 12 (41%) patients had high-risk FISH/SNP signature defined as one or more of the following: 1q+, t(4;14), t(14;16), t(14;20), and 17p-. At the submission of this abstract, 28 patients have completed one or more cycles wKRd-D; among these, 10 patients have completed therapy. The median number of cycles delivered is currently 6 (range 1-8). Seven of the 10 patients who have completed study treatment are MRD negative. So far, additional 8 patients have become MRD negative while on therapy. Thus, among patients treated on the weekly cohort (wKRd-D) and who were evaluable for the MRD primary end-point at this analysis, we found 15/18 (83%) to be MRD negative. We further show no added major clinical toxicities with wKRd-D compared to our institution standard of care bKRd. The bi-weekly carfilzomib cohort (bKRd-D) shows similar results to the weekly cohort (wKRd-D). With a comparable efficacy and safety profile coupled with a substantial reduction of the number of infusions (total of 51 vs 27 infusions with bKRd-D vs wKRd-D, respectively), we conclude that the weekly dosing (wKRd-D) may offer an attractive treatment modality for newly diagnosed multiple myeloma patients. CONCLUSIONS. Among patients evaluable for the MRD primary end-point, in the absence of an autologous bone marrow transplant, we show an unprecedented 15/18 (83%) MRD negativity rate among newly diagnosed multiple myeloma patients treated on the weekly cohort (wKRd-D) using carfilzomib 56 mg/m2 dosing. Our promising results have prompted the development of a large randomized multi-center study ("ADVANCE") evaluating wKRd-D in relation to established standard of care, which is anticipated to start enrollment in Q3/Q4 of 2019. Disclosures Landgren: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Theradex: Other: IDMC; Abbvie: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Lesokhin:GenMab: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Honoraria; Janssen: Research Funding; Genentech: Research Funding; Takeda: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Hassoun:Novartis: Consultancy; Celgene: Research Funding; Janssen: Research Funding. Smith:Fate Therapeutics and Precision Biosciences: Consultancy; Celgene: Consultancy, Patents & Royalties, Research Funding. Shah:Physicians' Education Resource: Honoraria. Landau:Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Karyopharm: Consultancy, Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Arcila:Invivoscribe, Inc.: Consultancy, Honoraria. Ho:Invivoscribe, Inc.: Honoraria. Roshal:Auron Therapeutics: Equity Ownership, Other: Provision of services; Physicians' Education Resource: Other: Provision of services; Celgene: Other: Provision of Services. Dogan:Corvus Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Roche: Consultancy, Research Funding. OffLabel Disclosure: Dara-KRd is not an FDA approved combination therapy for newly diagnosed multiple myeloma.
Introduction Newly diagnosed multiple myeloma (NDMM) patients who achieve and maintain minimal residual disease (MRD) negativity demonstrate clinical benefit with prolonged progression-free survival and overall survival. Based on available data showing MRD negativity with standard dose KRD (36 mg/m2) approximating 40% (Korde JamaOnc 2015), we designed a MRD response-adapted treatment study for NDMM, where the number of treatment cycles is determined based on MRD status, instead of the traditional paradigm of fixed number of cycles followed by autologous hematopoietic cell transplantation (AHCT). We integrated a flow-based MRD driven platform in this phase I/II study evaluating higher doses of twice-weekly carfilzomib (Car) (45 and 56 mg/m2) in combination with lenalidomide (Len) and dexamethasone (Dex). Methods Eligible NDMM patients were given escalating doses of Car (45 and 56 mg/m2), Len, and Dex in a single arm, phase I standard 3+3 schema design, based on dose-limiting toxicities (DLTs) occurring in cycle 1. Treatment consisted of 28-day cycles with Car 20/45 mg/m2 or 20/56 mg/m2 - days 1, 2, 8, 9 15 and 16; Len 25 mg - days 1-21; and Dex 40 mg weekly cycles 1-4, 20 mg after cycle 4. AHCT eligible patients underwent stem cell collection after 6 cycles, and then continue with protocol therapy. Patients achieving MRD negative status (serum, urine, and bone marrow with 10-color flow) received 2 additional cycles from the time of conversion and then stop therapy. Patients with less than an MRD negative response after any cycle continued therapy until treatment completion (max 12 cycles), disease progression, or unacceptable toxicity. The primary endpoint of the phase II study was to determine the MRD negative rate at the MTD dose, using a Simon's optimal two-stage design. Herein, we have updated results on phase I and phase II portions of the study with a median follow-up of 20.7 months (1.4-31.1). For available data, we present MFC and NGS MRD platforms. Results Twenty-nine patients have enrolled onto study between October 2016 - June 2018, with 18 in phase 1 and stage I of phase II and 11 in stage II of phase II, thus completing target accrual. There were 16 males, 13 females, median age 61 (43-75) years. Baseline characteristics included 18(62%) ISS-I, 9(31%) ISS-II, and 2(7%) ISS-III, and 7(24%) patients high risk FISH (t(4,14), t(14,16), p53 deletion). There were no DLTs within the first cycle that met protocol criteria (0/3 patients in 20/45 mg/m2 cohort and 0/6 patients in 20/56 mg/m2). The MTD chosen was 20/56 mg/m2, and an additional 20 patients were enrolled. Three patients came off study (56 mg/m2 cohort): one due to MI (during C2); one due to intolerable rash (during C2); and one due to personal preference (during C2). Among all 29 patients, grade 3/4 non-hematologic toxicities included 6(21%) rash, 5(17%) electrolyte disturbances, 4(14%) infections, 3(10%) GI, 2(7%) cardiopulmonary, 2(7%) VTE, 2(7%) mood, 2(7%) cataract, and 1(3%) hyperglycemia, and grade 3/4 hematologic toxicities included 12(41%) lymphopenia, 2(7%) leukopenia, 1(3%) neutropenia, and 1(3%) thrombocytopenia. Ten patients had 13 SAEs. For the 15 patients completing protocol therapy, a median number of 11 (7-12) cycles were delivered, and best responses include 9(60%) sCR/CR MRD neg and 6(40%) obtaining VGPR. Among patients reaching sCR/CR MRD neg status, the median time to reach was 8 (5-9) cycles. Among the eleven patients currently remaining on study, 7 have received at least 1 cycle of therapy (response eligible) and best responses thus far, included 1(14%) sCR/CR MRD pending, 4(57%) VGPR, and 2(29%) PR with a median number of 4 (1-8) cycles delivered. Table comparison of MRD platforms shown in sCR/CR patients. Among patients that remain on study, median 20.7 months, no patients have progressed and all remain alive. One patient that came off study due to personal preference during cycle 2 achieved a PR, and has progressed since. Conclusion In this phase I/II clinical trial assessing higher doses of twice-weekly Car dosing in combination with Len and Dex, we established MTD 56 mg/m2 and demonstrated a MRD platform using multi-parametric flow cytometry can be successfully used to tailor individualized treatment plans. Higher doses of twice weekly Car (45 and 56 mg/m2) in combination with Len and Dex, resulted in rapid and deep responses with approximately 60% MRD negative rate, and a safety profile similar to KRD standard dose (Car 36 mg/m2). Table. Table. Disclosures Korde: Amgen: Research Funding. Mailankody:Janssen: Research Funding; Physician Education Resource: Honoraria; Takeda: Research Funding; Juno: Research Funding. Hassoun:Oncopeptides AB: Research Funding. Lesokhin:Janssen: Research Funding; Squibb: Consultancy, Honoraria; Genentech: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Serametrix, inc.: Patents & Royalties: Royalties; Takeda: Consultancy, Honoraria. Smith:Celgene: Consultancy, Patents & Royalties: CAR T cell therapies for MM, Research Funding. Arcila:Invivoscribe, Inc.: Consultancy, Honoraria. Ho:Invivoscribe, Inc.: Honoraria. Landgren:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Karyopharm: Consultancy; Pfizer: Consultancy.
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