Early Versus Late Discontinuation of Maintenance Therapy in Multiple Myeloma

Background: Indefinite maintenance therapy after autologous stem cell transplant (ASCT) is the current standard of care in multiple myeloma (MM). However, in the real world, patients often discontinue treatment due to various reasons. In this study, we sought to analyze the effect of and reasons for early discontinuation of maintenance therapy on survival outcomes, studying patients who received less than 3 years of maintenance therapy (short-term maintenance group) or more than 3 years (continuous maintenance group). Methods: We retrospectively reviewed 340 patients who underwent ASCT from 2005-2016 and received maintenance therapy for at least six months without progression. The patients started maintenance therapy after 100 days of ASCT. Lenalidomide (89%) and bortezomib (10%) were the most commonly used agents for maintenance therapy. The primary endpoints included were progression-free survival (PFS) and overall survival (OS). All the endpoints were measured from the time of ASCT. The discontinuation was defined as permanently stopping the maintenance therapy. Patient, disease, and transplant-related characteristics were compared between the two groups using the Mann-Whitney U test for continuous variables, and chi-squared or Fisher's exact test for categorical variables. The probabilities of PFS and OS were calculated using the Kaplan-Meier (KM) method and compared using log-rank test. Results: One hundred and two (n= 102; 30%) patients discontinued maintenance therapy in the first 3 years (short-term maintenance group), while 238 patients remained on maintenance therapy for ≥ 3 years (continuous maintenance group). The groups had similar baseline characteristics in terms of age, gender, ISS staging, cytogenetics, response before ASCT, and melphalan dosing. About 20% of patients in both groups were older than 65 years. Among those alive at the last contact, the median follow up were 5.4 years and 6.1 years for the short-term and continuous maintenance therapy group, respectively. At the time of the last follow-up, 131/238 (55%) patients in the continuous maintenance group were still on maintenance therapy. The median PFS in the short-term maintenance group was 5.1 years (95% CI: 4.4-7.4) and median OS was 9.8 years (95% CI: 8.2- to NR), whereas in the continuous maintenance group both median PFS (95% CI: 8.5- NR) and OS were not reached. This latter group had significantly longer PFS and OS than the short-term maintenance group with a 5-year estimated PFS of 80% (95%CI: 74-85%) vs. 50% (95% CI: 39-60%) (p<0.001) and OS of 96% (95% CI: 92-98%) vs. 79% (95% CI: 69-86%) (p<0.001) (Figure 1). This remained significant after adjusting for race, post-transplant remission status and ISS staging, with an hazard ratio for risk of relapse or death of 0.31, 95% CI: 0.21-0.45; and HR for risk of death of 0.34, 95% CI: 0.18-0.64. The most common reasons for early discontinuation of maintenance therapy (< 3 years) were adverse events related to maintenance therapy (58%). Four patient (4%) patients developed second primary malignancy (SPM) in this group. The most frequent hematological adverse events (AEs) were pancytopenia and isolated neutropenia. Fatigue and diarrhea were the most common non-hematological AEs. The reasons for stopping maintenance in the continued maintenance group were disease progression (24%) and adverse events (14%), while five patients (2%) developed SPM. Conclusion: In our institutional experience, 30 percent of MM patients discontinued maintenance therapy within 3 years of ASCT due to AEs or patient preference. These patients had inferior PFS and OS after ASCT compared to patients on continuous maintenance. Therefore, continuation of maintenance therapy should be strongly encouraged as safely possible and strategies like dose reduction or switching therapy are recommended. Figure 1 Figure 1. Disclosures Bumma: Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Long-term safety and effectiveness of mycophenolate mofetil in adults with lupus nephritis: a real-world study in Japan

ABSTRACT Objectives To assess the safety and effectiveness of mycophenolate mofetil (MMF) in Japanese adults with lupus nephritis (LN) in real-world clinical practice. Methods This multicentre, prospective, post-marketing surveillance study investigated the effectiveness and safety of MMF, as induction or maintenance therapy, in LN patients. Primary endpoints were adverse drug reactions (ADRs), changes in renal function from baseline, and relapse rate (RR) after 6 months in the maintenance group, estimated using the Kaplan–Meier method. Complete remission (CR) and partial remission (PR) were estimated by renal measurements. Results Overall, 112 patients were enrolled in the induction group and 340 in the maintenance group. Of these 452 patients, 418 were evaluable for safety and 396 for effectiveness. Eighty-three patients (19.85%) experienced ADRs, most commonly herpes zoster (3.34%) and diarrhoea (3.11%). Serious ADRs occurring in more than three patients were cytomegalovirus infections (1.43%), acute pyelonephritis (0.71%), and herpes zoster (0.71%). One patient died from herpes zoster disseminated. CR and PR were 19.54% and 44.82%, respectively, in the induction group, and 40.62% and 66.16%, respectively, in the maintenance group. RR in the maintenance group was 0.70%. Conclusions The tolerability of MMF is in line with that reported in other studies. Since the average dose of MMF was <1.5 g/day, research into the optimal dose for achieving effectiveness is required.

Paraspinal Muscle Degeneration as an Independent Risk for Loss of Local Alignment in Degenerative Lumbar Scoliosis Patients After Corrective Surgery

Study Design: Retrospective study. Objectives: To investigate the effect of paraspinal muscle degeneration on the maintenance of local and global alignment among degenerative lumbar scoliosis (DLS) patients after corrective surgery. Methods: 98 DLS patients with a mean follow-up period of 38.3 months after corrective surgery were included. The T1 pelvic angle (TPA), lumbar lordosis (LL), pelvic incidence were measured preoperatively, immediate postoperatively and at last follow-up. All patients were divided into LL maintenance group (n = 21) and LL loss group (n = 77). For patients with well-aligned correction (immediate postoperative TPA ≤ 20°, n = 73), they were divided into TPA maintenance group (last follow-up TPA ≤ 20°) and TPA loss group (last follow-up TPA > 20°). The relative gross cross-sectional area (rGCSA) and fat infiltration (FI) of multifidus (MF) and erector spinae (ES), and the relative functional CSA (rFCSA) of psoas major (PS) were measured at L3, L4 and L5 on preoperative magnetic resonance imaging. Results: MF rGCSA were significantly smaller in LL loss group than in LL maintenance group. Both MF rGCSA and PS rFCSA were significantly smaller and MF FI was significantly higher in TPA loss group than in TPA maintenance group. Binary logistic regression revealed that the MF rGCSA was an independent factor of LL loss; Large immediate postoperative TPA was an independent risk factor of TPA loss, but not the parameters of paraspinal muscles. Conclusion: The effect of paraspinal muscles in lower lumbar segments might be mainly focused on the maintenance of local alignment rather than the global alignment.

Effects of short-term dietary restriction on plasma metabolites and the subcutaneous fat area according to metabolic status in obese individuals: a case–control study

Background Research elucidating the metabolic mechanisms that differentiate subtypes of obesity has been increasing. We aimed to investigate the effects of a 12-week dietary intervention on the metabolomic profiles of obese subjects. Methods Subjects followed a 12-week dietary restriction protocol consisting of a 300 kcal/day reduction in their usual caloric intake. Twenty-nine obese subjects were included and divided into two groups: the metabolic status maintenance group (n = 17, controls) and the metabolic status improvement group (n = 12, tests). We analyzed the somatometric and biochemical parameters and performed ultra-performance liquid chromatography-mass spectrometry analysis of the plasma metabolites. Results At 12 weeks, the fat percentage, whole fat area (WFA), subcutaneous fat area (SFA) at the L1 vertebra, and the levels of triglycerides, gamma-glutamyltransferase (gamma-GT), and leptin were markedly decreased in the metabolic status improvement group, while the level of high-density lipoprotein cholesterol increased compared with that in the metabolic status maintenance group. Metabolomic profiling at 12 weeks showed substantial differences in 4-aminobutyraldehyde (p = 0.005) and 4’-apo-β-carotenal (p = 0.024) between the two groups. Furthermore, an AUC value of 0.89 was obtained for the following seven featured biomarkers: triglycerides, gamma-GT, leptin, fat percentage, WFA, and SFA at the L1 vertebra, and 4-aminobutyraldehyde. Conclusions We demonstrated that 4-aminobutyraldehyde and related regional fat distribution parameters were strongly associated with obesity according to metabolic status. Thus, these biomarkers are potentially valuable in confirming the efficacy of short-term interventions and predicting metabolic status in obese individuals. Trials registration: This study was registered at ClinicalTrials.gov under NCT03135132 (registered 1 May 2017—retrospectively registered).

Improved outcomes with maintenance therapy after salvage autologous hematopoietic cell transplantation (AHCT) in multiple myeloma: A CIBMTR study.

8022 Background: Maintenance therapy in multiple myeloma (MM) after first autologous hematopoietic cell transplantation (AHCT1) is considered standard of care. Data regarding maintenance therapy after a salvage AHCT (AHCT2) in the setting of relapsed MM are scarce. Therefore, we used data from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry to examine the use of maintenance therapy after AHCT2 in MM patients and its effect on post-transplant patient outcomes. Methods: We included US adult MM patients who underwent AHCT2 after melphalan conditioning regimen from 2010-2018, and excluded patients who underwent tandem transplants. Outcomes of interest included non-relapse mortality (NRM), relapse/progression (REL), progression-free and overall survival (PFS, OS). Cox proportional hazards models were developed to study the main effect (maintenance use) with other covariates of interest including age, sex, race, performance status, HCT-comorbidity index, MM subtype, stage, creatinine, cytogenetic, conditioning melphalan dose, disease status at transplant, and time from AHCT1 to AHCT2. Results: Of 522 patients, 342 received maintenance therapy and 180 did not after AHCT2. Baseline characteristics were similar between the two groups. Median follow up was 58 months in the maintenance group and 61.5 months in the no-maintenance group. Common maintenance regimens included immunomodulatory drugs (IMID)-lenalidomide (N = 145, 42%) or pomalidomide (N = 46, 13%) and proteasome inhibitor, bortezomib (N = 45, 13%). Univariate analysis showed superior outcomes at 5 years in maintenance compared to the no-maintenance group: NRM 2 (0.7-3.9)% vs 9.9 (5.9-14.9)%, p < 0.001, REL 70.2 (64.4-75.8)% vs 80.3 (73.6-86.3)%, p 0.003, PFS 27.8% (22.4-33.5) vs. 9.8% (5.5-15.2), p < 0.001, and OS 54% (47.5-60.5) vs 30.9% (23.2-39.2) p < 0.001, respectively. IMID-containing maintenance regimens were associated with an improved 5-year PFS and OS compared to other maintenance regimens. Use of maintenance therapy retained its association with improved outcomes in multivariate analysis, including NRM: hazard ratio (HR) 0.19 (0.08-0.44), p 0.0001, REL: HR 0.58 (0.47-0.72), p < 0.0001, PFS HR 0.52 (0.43-0.64), p < 0.0001, and OS HR 0.46 (0.36-0.60), p < 0.0001. We conducted additional analyses to investigate a possible selection bias in the maintenance group including landmark analysis at 100-days and 6-months post-AHCT2 as well as a subgroup analysis of patients who received melphalan 200mg/m2 as conditioning for AHCT2 (as a surrogate for fitness)- all these analyses also showed improved outcomes in the maintenance group. Second cancers were reported in 17 (5%) patients in the maintenance group and 6 (3%) patients and no-maintenance group (p 0.39). Conclusions: Maintenance therapy after AHCT2 is associated with superior outcomes in MM patients.

Capecitabine maintenance therapy after induction chemotherapy in newly diagnosed metastatic nasopharyngeal carcinoma: An open-label, randomized, controlled, phase trial.

6044 Background: Capecitabine maintenance therapy improves outcomes in various tumor types, but minimal data are available on the effect of capecitabine maintenance therapy in metastatic nasopharyngeal carcinoma (NPC). We aimed to investigate whether capecitabine maintenance therapy would prolong the progression-free survival (PFS) of newly diagnosed metastatic NPC, in comparison to best supportive care (BSC). Methods: This was an open-label, randomized, controlled, phase trial. Eligible patients for maintenance randomisation were aged 18-65 years old with newly diagnosed metastatic NPC at the Sun Yat-Sun University Cancer Center (SYSUCC), had completed 4 to 6 cycles of induction chemotherapy as per protocol and had achieved disease control to protocol treatment, including capecitabine. Patients were randomly assigned 1:1 to capecitabine maintenance (oral 1,250 mg/m2/day on days 1-14 every 21 days) for up to 24 months with BSC or BSC alone. The primary endpoint was PFS. The secondary endpoints included overall survival, duration of response, objective response rate and adverse effects. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02460419 and is ongoing and no longer recruiting new patients. Results: Between May 16th, 2015, and January 9th, 2020, 140 metastatic NPC patients were screened, and 104 eligible patients were randomly assigned to capecitabine maintenance plus BSC (n = 52) or BSC alone (n = 52). After a median follow-up of 33.1 months (IQR, 21.5-50.7 months), median PFS was 35.2 months in the capecitabine maintenance group and 9.1 months in the BSC group (HR: 0.426; 95%CI: 0.248-0.731, P = 0.001). The most commongrade 3 or 4 adverse events during maintenance therapy were hand-foot syndrome (10.0%), nausea/vomiting (6.0%), fatigue (4.0%), and mucositis (4.0%). Totally 37 deaths occurred during follow-up, 14 (26.9%) in the capecitabine maintenance group and 23 (44.2%) in the BSC group. Overall survival data was immature. No deaths in the capecitabine maintenance group were deemed treatment related. Conclusions: Capecitabine maintenance significantly improved PFS in patients with newly diagnosed metastatic NPC who achieved disease control after induction chemotherapy compared to BSC and exhibited low grade and manageable toxicities. Clinical trial information: NCT02460419.

Maintenance Therapy With Bortezomib and Dexamethasone for Transplant-ineligible Patients With Multiple Myeloma

Background/Aim: Here, we investigated whether bortezomib as a maintenance therapy affected outcomes in transplant-ineligible patients with multiple myeloma (MM). Patients and Methods: Following induction therapy with bortezomib, maintenance therapy with bortezomib (1.3 mg/m2) and dexamethasone (20 mg) was administered once or twice every 4 weeks until disease progression. The endpoints of this study were time to next treatment and overall survival. Results: Seventy-six newly diagnosed, transplant-ineligible patients were treated with a bortezomib-based regimen; 28 discontinued induction therapy, 27 did not receive maintenance therapy after induction therapy (the non-maintenance group), and 21 did (the maintenance group). In the three groups, the median times to the next required treatment were 3, 14, and 37 months, respectively. The 3-year overall survival rates were 55%, 69%, and 85%, respectively. There were no significant differences in patient characteristics between the non-maintenance and maintenance groups, except for poorer estimated glomerular filtration rates in the maintenance group. Conclusion: Bortezomib maintenance therapy may be a useful option for transplant-ineligible patients with MM.

Propensity-Score Matched Analysis of the Efficacy of Maintenance/Continuous Therapy in Newly Diagnosed Patients With Multiple Myeloma: A Multicenter Retrospective Collaborative Study of the Japanese Society of Myeloma

Maintenance/continuous therapy is considered a standard of care for both transplant-eligible and -ineligible patients with multiple myeloma (MM). However, long-term benefits of such therapy have not yet been clarified in the context of clinical practice. We retrospectively analyzed the efficacy of maintenance/continuous therapy in newly diagnosed MM patients using the cohort data by propensity-score matching based on age, gender, revised International Staging System (R-ISS) stage, and implementation of transplantation to reduce the bias due to confounding variables. Among 720 patients, 161 were identified for each of the maintenance and no maintenance groups. Maintenance/continuous therapy employed immunomodulatory drugs (n = 83), proteasome inhibitors (n = 48), combination of both (n = 29), or dexamethasone alone (n = 1). Progression-free survival (PFS) was significantly prolonged in the maintenance group compared with the no maintenance group (median, 37.7 and 21.9 months, p = 0.0002, respectively). Prolongation of PFS was observed in both transplanted and non-transplanted patients (p = 0.017 and p = 0.0008, respectively), with standard risk (p < 0.00001), R-ISS stage I (p = 0.037) and stage II (p = 0.00094), and those without obtaining complete response (p = 0.0018). There was no significant difference in overall survival (p = 0.19), but it appeared to be better in non-transplanted patients by continuous therapy. These results support the usefulness of maintenance/continuous therapy in the management of MM.

Which patients with systemic lupus erythematosus in remission can withdraw low dose steroids? Results from a single inception cohort study

Background A progressive tapering until withdrawal of glucocorticoids (GC) is considered one of the main goals of Systemic Lupus Erythematosus (SLE) management. However, which patient may be a candidate for safe GC withdrawal has not been determined yet. This study aimed to evaluate the rate of low-dose GC withdrawal in SLE patients in remission and to identify predictors of flares. Methods Eligible patients were SLE patients in prolonged clinical remission defined by a cSLEDAI = 0 for at least 2 years and on a stable SLE treatment (including daily 5 mg prednisone). Flares were defined by SELENA-SLEDAI Flare Index. Predictors of flares after GC withdrawal were analyzed by Cox regression. Results We selected 56 patients in whom a GC withdrawal was attempted. 98 patients were in the prednisone maintenance group. The proportion of patients experiencing a flare was not significantly lower in the maintenance group than in the withdrawal group (p = 0.81). However, among the withdrawal group, the rate of flares was significantly higher in serologically active clinically quiescent (SACQ) patients (p < 0,0001). At Cox regression analysis, duration of hydroxychloroquine (HCQ) therapy and ≥5 year remission at withdrawal were protective factors, while a SACQ disease and history of lupus nephritis increased the risk of disease flare. Conclusion GC withdrawal is an achievable target in SLE and may be attempted in patients in complete remission.However, it might underline a caution in patients with SACQ disease who may be at greater risk forflare when GCare discontinued. HCQ therapy and durable remission can significantly reduce the risk.