In patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), daratumumab reduced the risk of disease progression or death by 44% in MAIA (daratumumab/lenalidomide/dexamethasone; D-Rd) and 58% in ALCYONE (daratumumab/bortezomib/melphalan/prednisone; D-VMP). Minimal residual disease (MRD) is a sensitive measure of disease and response to therapy. MRD-negativity status and durability were assessed in MAIA and ALCYONE. MRD assessments using next-generation sequencing (10-5) occurred for patients achieving complete response (CR) or better, and after ≥CR at 12, 18, 24, and 30 months from the first dose. Progression-free survival (PFS) by MRD status and sustained MRD negativity lasting ≥6 and ≥12 months were analyzed in the intent-to-treat population and among patients achieving ≥CR. In MAIA, (D-Rd, n=368; Rd, n=369), and ALCYONE (D-VMP, n=350; VMP, n=356), the median duration of follow-up was 36.4 months and 40.1 months, respectively. MRD-negative status and sustained MRD negativity lasting ≥6 and ≥12 months were associated with improved PFS, regardless of treatment group. However, daratumumab-based therapy improved rates of MRD negativity lasting ≥6 months (D-Rd, 14.9% vs Rd, 4.3%; D-VMP, 15.7% vs VMP, 4.5%) and ≥12 months (D-Rd, 10.9% vs Rd, 2.4%; D-VMP, 14.0% vs VMP, 2.8%), both of which translated to improved PFS versus control groups. In a pooled analysis, patients who were MRD negative had improved PFS versus patients who were MRD positive. Patients with NDMM who achieved MRD-negative status or sustained MRD negativity had deep remission and improved clinical outcomes. ClinicalTrials.gov identifier NCT02252172 (MAIA); NCT02195479 (ALCYONE).
Background Multiple myeloma (MM) patients with high cytogenetic risk have poor outcomes. In CASTOR, daratumumab plus bortezomib/dexamethasone (D-Vd) prolonged progression-free survival (PFS) versus bortezomib/dexamethasone (Vd) alone and exhibited tolerability in patients with relapsed or refractory MM (RRMM). Methods This subgroup analysis evaluated D-Vd versus Vd in CASTOR based on cytogenetic risk, determined using fluorescence in situ hybridization and/or karyotype testing performed locally. High-risk patients had t(4;14), t(14;16), and/or del17p abnormalities. Minimal residual disease (MRD; 10−5 sensitivity threshold) was assessed via the clonoSEQ® assay V2.0. Of the 498 patients randomized, 40 (16%) in the D-Vd group and 35 (14%) in the Vd group were categorized as high risk. Results After a median follow-up of 40.0 months, D-Vd prolonged median PFS versus Vd in patients with standard (16.6 vs 6.6 months; HR, 0.26; 95% CI, 0.19-0.37; P < 0.0001) and high (12.6 vs 6.2 months; HR, 0.41; 95% CI, 0.21–0.83; P = 0.0106) cytogenetic risk. D-Vd achieved deep responses, including higher rates of MRD negativity and sustained MRD negativity versus Vd, regardless of cytogenetic risk. The safety profile was consistent with the overall population of CASTOR. Conclusion These updated data reinforce the effectiveness and tolerability of daratumumab-based regimens for RRMM, regardless of cytogenetic risk status. Trial registration ClinicalTrials.gov, NCT02136134. Registered 12 May 2014
A gradient of Ran⅐GTP typically regulates traffic through the nuclear pore by modulating association of receptors with cargo.However, here we demonstrate that the yeast high mobility group box transcription factor Nhp6Ap enters the nucleus via a novel nuclear localization signal recognized by calcium calmodulin in a process that does not require Ran. Calmodulin is strictly required for the nondiffusional nuclear entry of Nhp6Ap. Calmodulin and DNA exhibit mutually exclusive binding to NHP6A, indicating that the directionality of Nhp6Ap nuclear accumulation may be driven by DNA-dependent dissociation of calmodulin. Our findings demonstrate that calmodulin can serve as a molecular switch triggering nuclear entry with subsequent dissociation of calmodulin binding upon interaction of cargo with chromatin. This pathway appears to be evolutionarily conserved; mammalian high mobility group box transcription factors often have two nuclear localization signals: one a classical Ran-dependent signal and a second that binds calmodulin. The finding that Nhp6Ap nuclear entry requires calmodulin but not Ran indicates that Nhp6Ap is a good model for studying this poorly understood but evolutionarily conserved calmodulin-dependent nuclear import pathway.Proteins enter the nucleus through nuclear pore complexes (NPCs).2 Those smaller than ϳ40 -50 kDa can traverse these pores by passive diffusion (1-5). Many larger proteins require soluble receptors, termed importins or karyopherins, which bind cargo in the cytoplasm, accompany it through the NPC, and release it in the nucleus. Most cargo proteins contain short nuclear localization signals (NLS), motifs recognized by the various receptor proteins.The small GTPase Ran drives the accumulation of cargo proteins in the nucleus by regulating the association and dissociation of NLS-containing proteins with importin/karyopherins.In the nucleus, most Ran is GTP-bound, whereas it is largely GDP-bound in the cytoplasm. Cargo proteins bind importins in the presence of Ran-GDP in the cytoplasm, and when an importin bound to cargo arrives in the nucleus, Ran-GTP induces cargo release (6). Thus, the Ran⅐GTP gradient across the NPC drives the accumulation of most NLS-containing cargo in the nucleus.Some Ran-independent nuclear import pathways have been described, although most remain poorly understood (for review see Ref. 7). One of the most intriguing of these involves the movement of calmodulin across the nuclear pore (8 -10). Calmodulin nuclear import was argued to be a facilitated mechanism that was blocked by the calmodulin antagonist peptide M13 and did not require cytosolic factors or an ATP-regenerating system (8, 10). In the presence of calcium, calmodulin was also shown to be able to facilitate movement of large molecules into the nucleus. This latter property suggested a Ca 2ϩ -inducible nuclear import function for calmodulin that might operate during cellular activation. The calmodulin-mediated pathway was proposed to be redundant with the canonic Ran⅐GTP-driven nuclear entry pathway...
Introduction: Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action, and has been approved across lines of therapy for the treatment of multiple myeloma. The addition of DARA to standard-of-care (SoC) regimens, lenalidomide and dexamethasone (D-Rd) and bortezomib, melphalan, and prednisone (D-VMP), in the phase 3 MAIA and ALCYONE clinical studies reduced the risk of disease progression or death by ≥44%, nearly doubled the rate of complete response (CR) or better, and induced a >3-fold increase in MRD-negativity rates (10-5 sensitivity threshold) vs SoC alone in pts with TIE NDMM. In both MAIA and ALCYONE, MRD negativity was associated with longer progression-free survival (PFS), irrespective of trial treatments. MRD negativity provides an index of deep clinical response and may be a more robust evaluation of disease control if sustained over time. Here, we evaluate MRD negativity, including sustained MRD negativity, in pts with TIE NDMM from MAIA and ALCYONE and its association with PFS with longer follow-up. Methods: Pts with NDMM ineligible for high-dose chemotherapy with stem cell transplantation due to age (≥65 years) or unacceptable coexisting conditions in MAIA and ALCYONE were randomized (1:1) to SoC ± DARA. Pts in MAIA received 28-day cycles of Rd (R: 25 mg PO on Days 1-21; d: 40 mg PO QW) ± DARA (16 mg/kg IV QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W thereafter). ALCYONE pts received up to nine 6-week cycles of VMP (V: 1.3 mg/m2 SC twice weekly during Weeks 1, 2, 4, and 5 of Cycle 1 and QW during Weeks 1, 2, 4, and 5 of Cycles 2-9; M: 9 mg/m2 PO on Days 1-4 of Cycles 1-9; and P: 60 mg/m2 PO on Days 1-4 of Cycles 1-9) ± DARA (16 mg/kg IV QW for Cycle 1, Q3W for Cycles 2-9, and Q4W for Cycles 10+). Study treatments continued until progressive disease or unacceptable toxicity. MRD was assessed in MAIA and ALCYONE in all pts who achieved a CR or stringent CR. For ≥CR pts, additional MRD assessments occurred at 12, 18, 24, and 30 months after the first dose in ALCYONE and at 12, 18, 24, 30, 36, 48, and 60 months in MAIA. MRD was assessed via next-generation sequencing using the clonoSEQ® assay (v.2.0; Adaptive Biotechnologies, Seattle, WA) at the 10-5 sensitivity threshold. Sustained MRD negativity was defined as the maintenance of MRD negativity confirmed ≥6 or ≥12 months apart with no MRD positive test in between and was evaluated in the intention-to-treat (ITT) population. Results: A total of 737 (D-Rd, n=368; Rd, n=369) pts in MAIA and 706 (D-VMP, n=350; VMP, n=356) pts in ALCYONE were randomized; median duration of follow-up was 36.4 months in MAIA and 40.1 months in ALCYONE. In both studies, DARA-based therapy improved MRD negativity vs SoC in the ITT population (D-Rd, 28.8% vs Rd, 9.2%, P<0.0001; D-VMP, 28.3% vs VMP, 7.0%, P<0.0001). MRD-negative pts had improved PFS vs MRD-positive pts in the ITT population, regardless of treatment arm. In a pooled analysis of pts from DARA (D-Rd/D-VMP) and SoC (Rd/VMP) treatment groups, MRD-negative pts had improved PFS vs pts who were MRD positive, irrespective of treatment arm. In general, baseline characteristics were comparable among pts in DARA and control treatment groups with sustained MRD negativity. A higher proportion of pts in the ITT populations of MAIA (D-Rd, n=368; Rd, n=369) and ALCYONE (D-VMP, n=350; VMP, n=356) achieved sustained MRD negativity with DARA-based therapy vs SoC for ≥6-months (D-Rd, 14.9% vs Rd, 4.3%, P<0.0001; D-VMP, 15.7% vs VMP, 4.5%, P<0.0001) and ≥12-months (D-Rd, 10.9% vs Rd, 2.4%; P<0.0001; D-VMP, 14.0% vs VMP, 2.8%, P<0.0001). PFS was prolonged in pts with sustained MRD negativity for ≥6-months and ≥12-months vs pts without sustained MRD negativity in the pooled ITT populations, regardless of treatment arm (Figure). Conclusions: DARA-based combination regimens induce higher rates of MRD-negativity and sustained MRD negativity in pts with TIE NDMM, which are associated with deep responses and improved PFS. Disclosures San-Miguel: Amgen, BMS, Celgene, Janssen, MSD, Novartis, Takeda, Sanofi, Roche, Abbvie, GlaxoSmithKline and Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees. Avet-Loiseau:Celgene and Janssen: Research Funding; Celgene, Amgen, Bristol-Myers Squibb, Sanofi, and Janssen;: Honoraria, Speakers Bureau. Paiva:Takeda: Consultancy, Honoraria, Research Funding; SkylineDx: Consultancy; Kite: Consultancy; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Honoraria; Adaptive: Honoraria; Roche: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding. Kumar:Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Cellectar: Other; Merck: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Kite Pharma: Consultancy, Research Funding; MedImmune: Research Funding; Sanofi: Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding; Karyopharm: Consultancy; BMS: Consultancy, Research Funding; Carsgen: Other, Research Funding; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genecentrix: Consultancy; Tenebio: Other, Research Funding; Dr. Reddy's Laboratories: Honoraria. Dimopoulos:Beigene: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Takeda: Honoraria. Facon:Celgene, Janssen, Takeda, Amgen, Roche, Karyopharm, Oncopeptides, BMS, Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mateos:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Pharmamar: Consultancy; Adaptive: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; EDOMundipharma: Consultancy; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Touzeau:Sanofi: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; GlaxoSmithKline: Honoraria, Research Funding. Jakubowiak:AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive, Juno: Consultancy, Honoraria. Usmani:Sanofi: Consultancy, Honoraria, Research Funding; Celgene: Other; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Abbvie: Consultancy; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; GSK: Consultancy, Research Funding; Array Biopharma: Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Incyte: Research Funding; SkylineDX: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding; Merck: Consultancy, Research Funding. Cook:Karyopharm: Honoraria; Celgene, Janssen, Takeda: Research Funding; Amgen, Bristol-Myers Squibb, Celgene, Janssen, Takeda, Roche, Sanofi: Honoraria. Cavo:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Karyopharm: Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Quach:GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Consultancy; GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Honoraria; Amgen, Celgene, karyopharm, GSK, Janssen Cilag, Sanofi.: Membership on an entity's Board of Directors or advisory committees; Amgen, sanofi, celgene, Karyopharm, GSK: Research Funding. Ukropec:Janssen: Current Employment, Current equity holder in publicly-traded company. Ramaswami:Janssen: Current equity holder in publicly-traded company. Pei:Janssen: Current Employment, Current equity holder in publicly-traded company. Sun:Janssen: Current Employment, Current equity holder in publicly-traded company. Wang:Janssen: Current Employment. Krevvata:Janssen: Current Employment. DeAngelis:Janssen: Current Employment, Current equity holder in publicly-traded company. Heuck:Christoph Heuck: Current Employment, Current equity holder in publicly-traded company. Van Rampelbergh:Janssen: Current Employment. Kudva:Janssen: Current Employment, Current equity holder in publicly-traded company; Memorial Sloan Kettering Cancer Center: Other: non-paid consultancy. Kobos:Janssen: Current Employment, Current equity holder in publicly-traded company. Qi:Janssen: Current Employment, Current equity holder in publicly-traded company; Johnson and Johnson: Current equity holder in publicly-traded company. Bahlis:Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; Sanofi: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; GSK: Consultancy, Honoraria.
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