Uddevalla sjukhus

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Simple SummaryOutcomes for high-risk myeloma patients are still poor, despite many advances in treatment. In addition, scarce data exist on double maintenance in transplant-eligible high-risk newly diagnosed multiple myeloma (NDMM) patients. We present the results of a prospective study on 120 transplant-eligible NDMM patients with prolonged cytogenetic risk-based all-oral maintenance with lenalidomide + ixazomib (IR) for high-risk patients and lenalidomide (R) alone for non-high-risk patients after ixazomib–lenalidomide–dexamethasone (IRD) induction plus autologous stem cell transplantation followed by IRD consolidation. We found that high-risk cytogenetics had no impact on the proportion of patients achieving sustained undetectable minimal residual disease or on the rate of progression-free survival with IR maintenance. Our data suggest that prolonged use of all-oral double maintenance with IR with reasonable adverse effects would be a potential option for high-risk myeloma patients.Scarce data exist on double maintenance in transplant-eligible high-risk (HR) newly diagnosed multiple myeloma (NDMM) patients. This prospective phase 2 study enrolled 120 transplant-eligible NDMM patients. The treatment consisted of four cycles of ixazomib–lenalidomide–dexamethasone (IRD) induction plus autologous stem cell transplantation followed by IRD consolidation and cytogenetic risk-based maintenance therapy with lenalidomide + ixazomib (IR) for HR patients and lenalidomide (R) alone for NHR patients. The main endpoint of the study was undetectable minimal residual disease (MRD) with sensitivity of <10−5 by flow cytometry at any time, and other endpoints were progression-free survival (PFS) and overall survival (OS). We present the preplanned analysis after the last patient has been two years on maintenance. At any time during protocol treatment, 28% (34/120) had MRD < 10−5 at least once. At two years on maintenance, 66% of the patients in the HR group and 76% in the NHR group were progression-free (p = 0.395) and 36% (43/120) were CR or better, of which 42% (18/43) had undetectable flow MRD <10−5. Altogether 95% of the patients with sustained MRD <10−5, 82% of the patients who turned MRD-positive, and 61% of those with positive MRD had no disease progression at two years on maintenance (p < 0.001). To conclude, prolonged maintenance with all-oral ixazomib plus lenalidomide might improve PFS in HR patients.

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: Autologous stem cell transplantation (ASCT) proceeded by induction with proteasome inhibitor, immunomodulatory agent, +/- CD38 monoclonal antibody and dexamethasone is the standard of care (SOC) for eligible patients with multiple myeloma. Despite novel drugs, the outcome of high-risk patients is poor. This phase 2 Nordic Myeloma Study Group (NMSG) trial, NCT03376672, investigates the response to ixazomib (I), lenalidomide (R) and dexamethasone (D) (IRD) induction followed by IRD consolidation and risk-based maintenance either with R alone in non-high-risk patients (NHR) or IR in high-risk patients (HR). Here we present the preplanned results for all patients after 2 years on maintenance. Aims: The primary endpoint is the minimal residual disease (MRD) <10-4 (positive or negative) by flowcytometry at any time during treatment compared to the historical Finnish Myeloma Group (FMG) trial (RVD+ASCT+R maintenance). The secondary endpoints include flow-MRD negativity <10-5, overall response rate (ORR), safety, progression-free survival (PFS), results between NHR and HR patients and overall survival (OS). MRD was assessed every 6 months in patients achieving CR. Methods: A written informed consent was obtained from all patients. Altogether 120 patients were included in the study which consisted of 4 IRD cycles as induction, ixazomib 4 mg on days (d) 1, 8, 15, lenalidomide 25 mg on d 1-21, dexamethasone 40 mg weekly in 28-day cycles. Mobilization and single ASCT were performed according to the SOC. Three months post-ASCT patients received 2 IRD consolidation cycles followed by risk stratified maintenance. Patients with del17 (cut of 60%), t(4;14), t(14;16), t(14;20) or +1q were included in HR group and they received ixazomib 4 mg on d 1, 8, 15 and lenalidomide 10 mg on d 1-21/28. If well tolerated, lenalidomide was increased to 15 mg after 3 cycles. At inclusion 52.5% of patients belonged to NHR and 47.5% to HR group. Results: The ORR, at least PR, with induction, was 84%. Forty-three percent (51/120) of patients were MRD <10-4 at any time during protocol treatment versus 45% of historical control. At 2 years on maintenance 40/120 (33%) were ≥CR and 18/40 (45%) also flow-MRD neg <10-5. At 2 years on maintenance 82% of NHR and 74% of HR patients were progression-free (p= 0.395). In the high-risk group, patients with +1q with other HR aberration had the shortest median PFS, 24 (6-48) months. Sustained flow-MRD negativity <10-5 in at least two consecutive samples was detected in 12 patients in the HR group (21%) compared to 12 in the non-HR group (19%), p=0.778. Median PFS for patients with sustained flow-MRD negativity was not reached and was 38 (20-48) months for patients who lost the negativity and 29 (0-47) months for flow-MRD positive patients. OS at 3 year was 92% in NHR and 86% in HR group, p=0.573. Treatment related mortality was 1.7% Pneumonia was the most common grade 3 SAE. Two (1.7%) secondary malignancies were diagnosed: one lung and one pancreas cancer. Summary/Conclusion: The ORR was 84% for IRD induction and 43% had MRD <10-4 at any time during treatment. After 2 years of maintenance 33% of patients were in ≥ CR and 45% of those were also flow-MRD negative <10-5. There was no difference in sustained MRD negativity <10-5 or PFS between HR and NHR patients. The 3-year OS was comparable between NHR and HR groups, 92% vs 86%, respectively. Ixazomib plus lenalidomide maintenance seemed to overcome the worse prognosis for HR in regard to PFS and OS. Keywords: Multiple myeloma, Minimal residual disease (MRD), High risk

Abstract Background and objective: Receptor activator of nuclear factor-kappa ligand (RANKL) and Osteoprotegerin (OPG) perform functions in orthodontic tooth movement (OTM) by regulation of osteoblast and osteoclast activation. This novel approach aims to monitor continuous changes in OPG and RANKL levels in the saliva during two years of OTM. Material and methods: Nine healthy females (15-20 years of age) were included in this prospective longitudinal pilot study. All patients had crowding requiring four premolar extractions and fixed appliances in both jaws. In total, 134 stimulated and 134 unstimulated saliva samples were collected: before tooth extractions (baseline), and then every 6-8 weeks at follow-up appointments during the whole treatment period of two years. All saliva samples were analysed by enzyme-linked immunosorbent assay. The mean levels of OPG and RANKL were calculated according to the different orthodontic treatment stages: alignment, space closure and finishing. A mixed model analysis was used to compare the means of treatment stages. Results: RANKL was not detectable either in stimulated or unstimulated saliva. OPG levels were measured in stimulated saliva due to low levels in unstimulated saliva. A significant increase in OPG was observed at all treatment stages: alignment, space closure and finishing compared with baseline (p = 0.002, p = 0.039, p = &lt; 0.001, respectively). A small non-significant decrease was seen in space closure compared with alignment. OPG reached peak levels during the finishing stage. Conclusions: The salivary levels of OPG increased gradually, except during space closure, reaching peak levels at the finishing stage. This novel approach shows the changes in the levels of OPG in OTM and indicates how and when to sample saliva during orthodontic treatment to analyse bone remodelling.

Lenalidomide (Len) plus dexamethasone (Dex) is approved for the treatment of relapsed or refractory multiple myeloma (RRMM). It is possible that single‐agent Len may be effective as prolonged treatment regimen in RRMM once patients demonstrate an initial response to Len+Dex induction. Patients with RRMM who responded to first‐line Len+Dex in an observational study (NCT01430546) received up to 24 cycles of either Len (25 mg/day) or Len+Dex (25 mg/day and 40 mg/week) as prolonged treatment in a subsequent phase 2 clinical trial (NCT01450215). In the observational study (N = 133), median time to response was 1.7 (range 0.6–9.6) months. A complete response to all treatments received in both studies was observed in 11% of patients; very good partial response and partial response rates were 31% and 38%, respectively. Corresponding response rates in the subgroup of patients who did not enter the phase 2 trial (n = 71) were 3%, 18%, and 39%, respectively. Rates of disease progression at 2 years in the phase 2 trial were 47% versus 31% for Len versus Len+Dex (P = 0.14). After 36 months median follow‐up in surviving patients, median time to progression was not reached with Len+Dex and was 24.9 months (95% confidence interval 12.5–not calculable, P < 0.001) with Len. Three‐year OS among the total observational study population was 61% (95% CI, 52–69%). The corresponding rate among patients who entered the phase 2 clinical trial was 73% (95% CI, 60–83%) and was significantly lower among those patients who achieved ≥PR but did not proceed into the phase 2 trial (55%; P = 0.01). In the phase 2 trial, OS was 73% in both treatment arms (P = 0.70). Neutropenia and thrombocytopenia were more common with prolonged (phase 2 trial) versus short‐term (observational study) Len administration but remained manageable. Prolonged treatment with Len with or without Dex provides sustained, clinically relevant responses and demonstrates an acceptable safety profile.

PurposeDespite therapeutic advances, patients with multiple myeloma (MM) continue to experience disease relapse and treatment resistance. The gene ABCB1 encodes the drug transporter P-glycoprotein, which confers resistance through drug extrusion across the cell membrane. Lenalidomide (Len) is excreted mainly via the kidneys, and, given the expression of P-gp in the renal tubuli, single-nucleotide polymorphisms (SNPs) in the ABCB1 gene may influence Len plasma concentrations and, subsequently, the outcome of treatment. We, therefore, investigated the influence of ABCB1 genetic variants on Len treatment outcomes and adverse events (AEs).MethodsNinety patients with relapsed or refractory MM, who received the second-line Len plus dexamethasone in the Rev II trial, were genotyped for the ABCB1 SNPs 1199G>A (Ser400Asn, rs2229109), 1236C>T (silent, rs1128503), 2677G>T/A (Ala893Ser, rs2032582), and 3435C>T (silent, rs1045642) using pyrosequencing, and correlations to response parameters, outcomes, and AEs were investigated.ResultsNo significant associations were found between genotype and either best response rates or hematological AEs, and 1236C>T, 2677G>T or 3435C>T genotypes had no impact on survival. There was a trend towards increased time to progression (TTP) in patients carrying the 1199A variant, and a significant difference in TTP between genotypes in patients with standard-risk cytogenetics.ConclusionsOur findings show a limited influence of ABCB1 genotype on lenalidomide treatment efficacy and safety. The results suggest that 1199G>A may be a marker of TTP following Len treatment in standard-risk patients; however, larger studies are needed to validate and clarify the relationship.