Lenalidomide, bortezomib, and dexamethasone (RVd) followed by autologous stem cell transplantation (ASCT) is standard frontline therapy for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). This study evaluated addition of daratumumab (D) to RVd in ASCT-eligible NDMM patients. Patients (N=207) were randomized 1:1 to receive RVd ±D induction (4 cycles), ASCT, RVd ±D consolidation (2 cycles), and lenalidomide ±D maintenance (26 cycles). At the primary endpoint analysis, the stringent complete response (sCR) rate by the end of post-ASCT consolidation favored D-RVd over RVd (42.4% vs 32.0%; odds ratio, 1.57; 95% confidence interval [CI], 0.87-2.82; 1-sided P=0.068) and met the prespecified 1-sided alpha of 0.10. With longer follow-up (median, 22.1 months), responses continued to deepen; rates of sCR improved for D-RVd versus RVd (62.6% vs 45.4%; P=0.0177), as did rates of minimal residual disease negativity (10−5 threshold) in the intent-to-treat population (51.0% vs 20.4%; P<0.0001). Four (3.8%) and 7 (6.8%) patients in the D-RVd and RVd groups progressed, respectively, and 24-month progression-free survival rates were 95.8% (D-RVd) and 89.8% (RVd). Grade 3/4 hematologic adverse events were more common with D-RVd. More infections occurred with D-RVd, but rates of grade 3/4 infections were similar. Median CD34+ cell yield was 8.2´106/kg for D-RVd and 9.4´106/kg for RVd, although plerixafor use was more common in the D-RVd arm. There was no difference in median times to neutrophil or platelet engraftment. In summary, daratumumab with RVd induction and consolidation improved depth of response in patients with transplant-eligible NDMM, with no new safety concerns. Clinicaltrials.gov NCT02874742.

BackgroundCALGB 100104 (Alliance) studied lenalidomide vs. placebo following autologous stem cell transplant (ASCT) for newly diagnosed myeloma patients, demonstrating improved time to progression (TTP) and overall survival (OS), and an increase in second primary malignancies (SPM) for lenalidomide at 34-months median follow-up. Here we report an updated intent-to-treat analysis at 91-months median follow-up.MethodsPatients were eligible if they had active myeloma, had received at most two induction regimens and had achieved stable disease or better in the first 100 days after ASCT. In this phase 3 study, 460 patients were randomised in a double-blind manner to either lenalidomide (n=231) or placebo (n=229) utilizing a permutated-block randomisation with fixed block size. Randomisation was stratified by three factors: normal or elevated β2-microglobulin level at registration (≤2·5 mg/L vs > 2·5 mg/L), prior use or nonuse of thalidomide during induction therapy, and prior use or nonuse of lenalidomide during induction therapy. The starting dose was 10 mg daily, escalated to 15 mg daily after three months. The primary endpoint was TTP (time of progressive disease or death from any cause) using intent-to-treat analysis. After three interim analyses, the study was unblinded at median follow-up of 18 months and 86/128 placebo patients without progressive disease chose to cross over to lenalidomide. This study is registered with ClinicalTrials.gov identifier NCT00114101; new patients are no longer being recruited, but some patients remain on treatment and in follow-up.FindingsThe median TTP for lenalidomide is 57·3 months (95% CI 44·2–73·3) and 28·9 months (95% CI 23·0–36·3) for placebo (hazard ratio (HR): 0·57, 95% CI 0·46–0·71, p<0·0001). The TTP benefit with lenalidomide was observed regardless of whether patients were in a complete response at time of randomisation or whether they had received thalidomide or lenalidomide induction therapy. The most common grade 3–4 adverse events were neutropenia (116 (50%) of 231 patients in the lenalidomide arm and 37 (16%) of 229 patients in the placebo arm) and thrombocytopenia (34 patients (15%) in the lenalidomide arm and 11 patients (4·8%) in the placebo arm. Eighteen haematological (7·8%) and 14 solid tumour (6·1%) SPMs have been diagnosed following randomisation and prior to disease progression in the lenalidomide arm vs. three haematological (1·3%) and nine solid tumour (3·9%) SPMs in the placebo arm. Of the placebo SPMs, three haematological and five of nine solid tumour SPMs were in the crossover subgroup.InterpretationDespite an increase in haematological adverse events and SPMs, lenalidomide maintenance therapy following ASCT significantly improves TTP and can be considered a standard of care.

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Although antioxidants promote melanoma metastasis, the role of reactive oxygen species (ROS) in other stages of melanoma progression is controversial. Moreover, genes regulating ROS have not been functionally characterized throughout the entire tumor progression in mouse models of cancer. To address this question, we crossed mice-bearing knock-out of Klf9, an ubiquitous transcriptional regulator of oxidative stress, with two conditional melanocytic mouse models: BrafCA mice, where BrafV600E causes premalignant melanocytic hyperplasia, and BrafCA/Pten−/− mice, where BrafV600E and loss of Pten induce primary melanomas and metastases. Klf9 deficiency inhibited premalignant melanocytic hyperplasia in BrafCA mice but did not affect formation and growth of BrafCA/Pten−/− primary melanomas. It also, as expected, promoted BrafCA/Pten−/− metastasis. Treatment with antioxidant N-acetyl cysteine phenocopied loss of Klf9 including suppression of melanocytic hyperplasia. We were interested in a different role of Klf9 in regulation of cell proliferation in BrafCA and BrafCA/Pten−/− melanocytic cells. Mechanistically, we demonstrated that BRAFV600E signaling transcriptionally upregulated KLF9 and that KLF9-dependent ROS were required for full-scale activation of ERK1/2 and induction of cell proliferation by BRAFV600E. PTEN depletion in BRAFV600E-melanocytes did not further activate ERK1/2 and cell proliferation, but rendered these phenotypes insensitive to KLF9 and ROS. Our data identified an essential role of KLF9-dependent ROS in BRAFV600E signaling in premalignant melanocytes, offered an explanation to variable role of ROS in premalignant and transformed melanocytic cells and suggested a novel mechanism for suppression of premalignant growth by topical antioxidants.

Background: BCMA targeted immunotherapy has yielded promising results for relapsed/refractory multiple myeloma (RRMM). TNB-383B is a BCMA x CD3 bispecific T-cell redirecting antibody incorporating a unique anti-CD3 moiety that preferentially activates effector over regulatory T-cells and uncouples cytokine release from anti-tumor activity, as well as 2 heavy-chain-only anti-BCMA moieties for a 2:1 tumor associated antigen to CD3 stoichiometry. Results from the ongoing phase 1 dose escalation and expansion First-in-Human (FIH) study of TNB-383B are presented (NCT03933735). Methods: Eligible patients have RRMM and have been exposed to at least 3 prior lines of therapy including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody. Patients have been treated with escalating doses of TNB-383B infused IV over 1-2 hours Q3W (without step-up dosing). The primary objectives are to determine the safety/tolerability and clinical pharmacology of TNB-383B and to identify the MTD/RP2D. The study used a 3+3 design for dose escalation, with additional patients enrolled on cleared dose levels. Patients on earlier dose cohorts were allowed to increase to the highest cleared dose with investigator consensus. Responses were assessed by IMWG criteria and Adverse Events (AEs) were graded according to CTCAE v5.0. Minimal residual disease (MRD) assessment was performed via NGS on bone marrow samples in patients achieving a complete response (CR). Results: As of 13 July 2020, 38 subjects have been dosed with TNB-383B (0.025 - 40 mg). Demographics and disease characteristics at study entry are summarized in Table 1. The most common Gr 3/4 AEs were anemia (6/38; 16%) and thrombocytopenia (5/38; 13%). The most common drug-related AEs were CRS (8/38; 21%) and headache (5/38; 13%). One case of Gr 2 CRS was observed at 0.075 mg; all other CRS events were seen at 5.4 mg and above. Cases of CRS were grade 1 (5/8) or 2 (3/8) and occurred only after the first dose of TNB-383B. All but 3 subjects were managed with fluids and acetaminophen (the other 3 received 1 dose each of tocilizumab). One DLT, Gr3 confusion that resolved within 6 hours without sequelae was seen at the 20 mg dose in an additional patient enrolled on this cohort. No IRRs were observed. Dose modification was necessary in 1 subject for Gr 3 neutropenia associated with CRS; the subject escalated to their full dose after tolerating subsequent doses without incident. 5 subjects died from their underlying disease during follow-up. 15 subjects discontinued treatment, all of them for progressive disease. Preliminary PK data support Q3W dosing of TNB-383B. Activity was observed in one patient each at 0.2 mg and 1.8 mg; at doses of 5.4 - 40 mg an ORR of 52% (12/23) was observed. Depth and duration of response are summarized in Table 2. Conclusions: TNB-383B is well tolerated at doses up to 40 mg, without the need for step/split dosing. A preliminary ORR of 52% (12/23) was observed at doses ≥ 5.4 mg, including deep (6 PR / 3 VGPR / 3 CR) and durable (up to 24 weeks) responses despite dosing only every 3 weeks. Enrollment into the dose escalation arm is ongoing; updated data will be presented at the meeting. Disclosures Rodriguez: BMS, Takeda, Amgen: Consultancy, Speakers Bureau. D'Souza:Amgen: Research Funding; Akcea: Consultancy; Pfizer: Consultancy; Teneobio: Research Funding; Imbrium: Consultancy; Merck: Research Funding; Janssen: Consultancy. Shah:GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy; BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding. Voorhees:Bristol-Myers Squibb: Other: Personal fees; Adaptive Biotechnologies: Other: Personal fees; Novartis: Other: Personal fees; Celgene: Other: Personal fees; Janssen: Other: Personal fees; Oncopeptides: Other: Personal fees; TeneoBio: Other: Personal fees; Levine Cancer Institute, Atrium Health: Current Employment. Buelow:Teneobio, Inc.: Current Employment, Current equity holder in private company. Kumar:Karyopharm: Consultancy; Tenebio: Other, Research Funding; Sanofi: Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genecentrix: Consultancy; Dr. Reddy's Laboratories: Honoraria; Adaptive Biotechnologies: Consultancy; Merck: Consultancy, Research Funding; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Cellectar: Other; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Carsgen: Other, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding; MedImmune: Research Funding; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Kite Pharma: Consultancy, Research Funding.