Renal Response Rate Research Articles

Longitudinal Assessment and Prognostic Importance of Minimal Residual Disease (MRD) By Multiparametric Flow Cytometry in Patients with Systemic Light Chain (AL) Amyloidosis

Background:Minimal residual disease (MRD) assessment can provide an index of robust disease control, particularly if MRD negativity is sustained over time. Whereas MRD status has well-established prognostic implications in multiple myeloma, its role in light chain (AL) amyloidosis-a related but biologically distinct plasma cell disorder-is presently under investigation.Aims:The aims of our study were to evaluate (1) major organ deterioration-progression-free survival (MOD-PFS) based on MRD status and (2) MRD evolution patterns during disease surveillance for patients with AL amyloidosis in hematologic complete response (hemCR) after therapy.Methods:We established MRD status using multiparametric 10-color flow cytometry of bone marrow aspirates. At least 2 x 10 6 events were measured using a Beckman Coulter Navios Flow Cytometer and analyzed by Kaluza Software (sensitivity level of ≤10 -5). Sequential MRD testing was performed (≥12 months apart) for patients returning for follow-up. We evaluated hematologic and organ responses or progression based on consensus guidelines (Palladini, 2012). MOD-PFS was defined as time from hemCR achievement to major organ deterioration (i.e., the kidney or heart), hematologic progression or death from any cause (whichever occurred first). Presence of MRD was not used to guide treatment decisions.Results:A total of 96 patients with hemCR after therapy were tested, of whom 46 (48%) were MRD negative and 50 (52%) MRD positive on first assessment. The median estimated clone size for those with MRD positivity was 3.4 x 10 -4 (range 1.4 x 10 -5 to 5.7 x 10 -3). Baseline characteristics were similar between groups, except for greater use of daratumumab and ≥2 lines of therapy to achieve hemCR in the MRD-negative group. MRD positivity correlated with a higher level of involved free light chains (iFLC) in the serum at the time of MRD assessment (23.4 mg/L vs 17.3 mg/L, P = .011). In regard to organ responses, patients with MRD negativity had a significantly higher rate of renal response (91% vs 67%, P = .017) but a similar rate of cardiac response (74% vs 68%, P = .668).After a median follow-up of 50 months from hemCR achievement, the MRD-negative group demonstrated a superior MOD-PFS (HR 0.38, 95% CI 0.16-0.88, P = .034). Progression or organ deterioration events in the MRD-negative group occurred early after hemCR achievement, while in the MRD-positive group these events continued to occur over time. A total of 8 patients had died, including 4 in each group.Sequential MRD testing (median 12 months apart, range 12-28 months) was performed for 43 patients, of whom 16/19 (84%) had sustained MRD negativity; 21/24 (88%) had persistent MRD positivity; and 6/43 (14%) had MRD conversion. No patient received therapy between MRD assessments. Among those with sustained MRD negativity, there were 2 major organ deterioration events. The 3 patients who experienced loss of MRD negativity (which occurred at 12, 107 and 114 months after last treatment) had no progression or organ deterioration events. Of those with persistent MRD positivity, 13 (62%) had durable hemCR and organ responses; moreover, 4/14 (29%) and 1/11 (9%) of these patients attained even deeper renal and cardiac responses, respectively, in the interval between sequential MRD testing. Clone progression (defined as >1-log growth in MRD clone size) was observed in 3/21 (14%) patients with persistent MRD positivity, none of whom demonstrated hematologic relapse.Conclusions:We evaluated the dynamics of MRD status in relation to clinical outcomes and found that patients with MRD negativity had longer survival free from hematologic progression, major organ deterioration or death. Longer prospective follow-up is needed to determine whether this translates into an overall survival benefit. MRD conversion occurred in a small proportion (14%) of patients, but was not linked to adverse outcomes. Understanding the role of cross-sectional MRD testing for clinical disease tracking in AL amyloidosis requires further analysis with larger sample size. [Display omitted] DisclosuresSanchorawala: Prothena: 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; Takeda: Research Funding; Pfizer: Honoraria; Karyopharm: Research Funding; Sorrento: Research Funding; Celgene: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; Oncopeptide: Research Funding.

Subcutaneous Daratumumab with Bortezomib, Cyclophosphamide, and Dexamethasone in Patients with Newly Diagnosed Light Chain (AL) Amyloidosis: 18-Month Analysis of the Phase 3 ANDROMEDA Study

Subcutaneous Daratumumab with Bortezomib, Cyclophosphamide, and Dexamethasone in Patients with Newly Diagnosed Light Chain (AL) Amyloidosis: 18-Month Analysis of the Phase 3 ANDROMEDA Study

OAB-034: Evaluating the impact of cytogenetic abnormalities on treatment outcomes in patients with AL amyloidosis: subanalyses from the ANDROMEDA study

<h3>Background</h3> Amyloid light chain (AL) amyloidosis is a plasma cell disease characterized by the production of light chains that form amyloid fibril deposits in tissues leading to organ dysfunction and death. Cytogenetic abnormalities are common in patients (pts) with AL amyloidosis, and some are associated with poor outcomes. The ANDROMEDA study (NCT03201965) showed that addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone (D-VCd) was superior to VCd alone, with higher rates of hematologic complete response (CR) and an acceptable safety profile. Here, we explore outcomes in pts with cytogenetic abnormalities in ANDROMEDA. <h3>Methods</h3> Pts (N=388) with newly diagnosed AL amyloidosis were randomized 1:1 to D-VCd or VCd for 6 28-day cycles; thereafter, pts in the D-VCd group received daratumumab alone every 4 weeks for ≤24 total cycles. The proportion of pts with t(11;14), amp1q21, del13q14, and del17p13 based on fluorescence in situ hybridization and/or karyotyping was calculated. Overall (at any time during the study) hematologic CR rate and cardiac and renal response rates at 6 months were evaluated for each subgroup and summarized with descriptive statistics. Within each treatment group, hematologic response among pts with and without t(11;14) or amp1q21 was compared. <h3>Results</h3> 321 pts had testing (D-VCd, n=155; VCd, n=166). In the D-VCd and VCd groups, respectively, 42.9% vs 40.0% had t(11;14), 25.4% vs 20.3% had amp1q21, 16.2% vs 22.0% had del13q14, and 6.7% vs 6.1% had del17p13. At a median follow-up of 20.3 months, the hematologic CR rate was higher with D-VCd vs VCd across all 4 cytogenetic subgroups, ranging from 56–72% vs 0–14% (P<0.05 for all). Organ response rates were numerically higher with D-VCd in all subgroups, except for cardiac response rate in the del17p13 subgroup. In the VCd group, rates of hematologic CR and very good partial response or better (≥VGPR) were 12.5% vs 23.8% and 46.4% vs 56.0% in pts with (n=56) vs without (n=84) t(11;14) and 10.7% vs 19.1% and 53.6% vs 50.0% in pts with (n=28) and without (n=110) amp1q21. In the D-VCd group, rates of hematologic CR and ≥VGPR were 59.3% vs 61.1% and 77.8% vs 80.6% in pts with (n=54) vs without (n=72) t(11;14) and 59.4% vs 59.6% and 81.3% vs 80.9% in pts with (n=32) and without (n=94) amp1q21. <h3>Conclusion</h3> Consistent with the primary analysis of ANDROMEDA, subgroup analyses showed the benefit of D-VCd vs VCd, irrespective of cytogenetic abnormalities. Rates of deep hematologic response were not impacted by t(11;14) and amp1q21 in patients treated with D-VCd, but were generally lower in VCd-treated patients with t(11;14) and amp1q21. These findings further support the use of D-VCd as standard of care in pts with newly diagnosed AL amyloidosis, regardless of cytogenetic abnormalities.

SUBCUTANEOUS DARATUMUMAB + BORTEZOMIB, CYCLOPHOSPHAMIDE, AND DEXAMETHASONE (VCD) IN PATIENTS WITH NEWLY DIAGNOSED LIGHT CHAIN (AL) AMYLOIDOSIS: UPDATED RESULTS FROM THE PHASE 3 ANDROMEDA STUDY

Systemic AL amyloidosis is a plasma cell disease characterized by the deposition of insoluble amyloid fibrils causing organ dysfunction and death. Primary results from the ANDROMEDA study showed that addition of subcutaneous (SC) daratumumab (DARA) to the standard of care combination of bortezomib, cyclophosphamide, and dexamethasone (VCd) was superior to VCd alone, with higher rates of hematologic complete response (CR) and an acceptable safety profile. DARA-VCd was approved for newly diagnosed AL amyloidosis in January 2021. Here we present an update of the primary ANDROMEDA study results with longer follow-up. ANDROMEDA is a randomized, open-label, active-controlled phase 3 study. Adult patients with newly diagnosed AL amyloidosis were randomized 1:1 to DARA-VCd or VCd and were treated for 6 cycles 28 days each. Bortezomib (1.3 mg/m 2 ), cyclophosphamide (300 mg/m 2 ; maximum weekly dose 500 mg), and dexamethasone (40 mg) were given weekly. DARA SC was given weekly (cycle 1–2) and every 2 weeks (cycle 3–6). After cycle 6, patients in the DARA-VCd group received DARA SC alone every 4 weeks for up to 24 cycles from first dose. Disease status was evaluated every 4 weeks in cycle 1–6 and every 8 weeks after cycle 7. The primary endpoint was overall hematologic CR rate in the intent-to-treat population. Secondary endpoints were major organ deterioration progression-free survival (PFS), organ response rate, time to hematologic response, survival, and safety. Of 388 randomized patients, 195 were randomized to DARA-VCd and 193 to VCd. As of November 2020, the median follow-up was 20.3 months (mo), with a median treatment duration of 18.5 mo for DARA-VCd and 5.3 mo for VCd; 78 patients (40%) in the DARA-VCd group were still on treatment. The overall hematologic CR rate continued to be higher with DARA-VCd than VCd (59% vs 19%; odds ratio [OR] 5.9; 95% CI 3.7–9.4; p < 0.0001). More patients achieved a very good partial response or better (≥VGPR) with DARA-VCd than VCd (79% vs 50%; OR 3.7; 95% CI 2.4–5.9; p < 0.0001). Among responders, median time from randomization to ≥VGPR was shorter for DARA-VCd than VCd (0.56 vs 0.82 months). Cardiac response rates were higher with DARA-VCd than VCd at 6 months (42% vs 22%) and at 12 months (57% vs 28%); renal response rates were 54% vs 27% at 6 months and 57% vs 27% at 12 months. A total of 71 deaths occurred (DARA-VCd, n = 31; VCd, n = 40). From cycle 7 onward in the DARA-VCd group, no grade 3/4 treatment-emergent adverse events occurred in ≥5% of patients. There were no systemic administration-related reactions with DARA-VCd after cycle 6. Analysis of major organ deterioration PFS will be updated after ̃200 events have occurred. DARA-VCd (versus VCd alone) demonstrated robust hematologic and organ responses with no new safety concerns with longer follow-up. Updated results from the ANDROMEDA study reinforce the clinical superiority of DARA-VCd over VCd in pts with newly diagnosed AL amyloidosis. Based on its recent approval, DARA-VCd represents a new standard of care in AL amyloidosis. This trial was registered at www.clinicaltrials.gov as NCT03201965.

Journal Club: Efficacy and Safety of Voclosporin Versus Placebo for Lupus Nephritis (AURORA 1): A Double-Blind, Randomized, Multicenter, Placebo-Controlled, Phase 3 Trial.

ObjectiveVoclosporin, a novel calcineurin inhibitor approved for the treatment of adults with lupus nephritis (LN), improved complete renal response rates in patients with LN in a phase 2 trial. This study aimed to evaluate the efficacy and safety of voclosporin for the treatment of LN.MethodsThis multicenter, double‐blind, randomized phase 3 trial was done in 142 hospitals and clinics across 27 countries. Patients with a diagnosis of systemic lupus erythematosus and LN, according to the American College of Rheumatology criteria, who had undergone a kidney biopsy within 2 years that showed class III, IV, or V (alone or in combination with class III or IV) were eligible for this study. Patients were randomly assigned (1:1) to receive oral voclosporin (23.7 mg twice daily) or a placebo, on a background of mycophenolate mofetil (1 g twice daily) and rapidly tapered low‐dose oral steroids, by use of an interactive web response system. The primary endpoint was complete renal response at 52 weeks, defined as a composite of urine protein creatinine ratio of 0.5 mg/mg or less, stable renal function (defined as estimated glomerular filtration rate [eGFR] ≥60 ml/min/1.73m2 or no confirmed decrease from baseline in eGFR of > 20%), no administration of rescue medication, and no more than 10 mg prednisone equivalent per day for 3 or more consecutive days or 7 or more days during Week 44 through Week 52 (just before the primary endpoint assessment). Safety was also assessed. Efficacy analysis was by intention to treat, and safety analysis was by randomized patients receiving at least one dose of study treatment.ResultsBetween April 13, 2017, and October 10, 2019, 179 patients were assigned to the voclosporin group and 178 were assigned to the placebo group. The primary endpoint of complete renal response at Week 52 was achieved in significantly more patients in the voclosporin group than in the placebo group (73 [41%] of 179 patients vs 40 [23%] of 178 patients; odds ratio, 2.65; 95% confidence interval [CI] 1.64‐4.27; P < 0·0001). The adverse event profile was balanced between the two groups; serious adverse events occurred in 37 (21%) of 178 patients in the voclosporin group and 38 (21%) of 178 patients in the placebo group. The most frequent serious adverse event involving infection was pneumonia, occurring in seven (4%) patients in the voclosporin group and in eight (4%) patients in the placebo group. A total of six patients died during the study or study follow‐up period (one [<1%] patient in the voclosporin group and five [3%] patients in the placebo group). None of the events leading to death were considered by the investigators to be related to the study treatments.ConclusionVoclosporin in combination with mycophenolate mofetil (MMF) and low‐dose steroids led to a clinically and statistically superior complete renal response rate versus MMF and low‐dose steroids alone, with a comparable safety profile. This finding is an important advancement in the treatment of patients with active LN.

Superior Efficacy of Carfilzomib and Dexamethasone (Kd56) Vs Bortezomib and Dexamethasone (Vd) in Multiple Myeloma (MM) Patients with Moderate or Serious Renal Failure: A Subgroup Analysis of the Phase 3 Endeavor Study

Abstract Background: Carfilzomib, a second generation selective proteasome inhibitor, is approved in the United States and other countries for the treatment of relapsed or refractory multiple myeloma (RRMM). In the randomized, phase 3 study ENDEAVOR, Kd56 demonstrated clinically and statistically significant improvement compared with Vd in both progression-free survival (PFS) (median 18.7 vs 9.4 months [mos]; hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.44-0.65; 1-sided P Methods: Adults with RRMM (1-3 prior regimens) and creatinine clearance (CrCL) ≥15 mL/min were eligible for the ENDEAVOR trial. The Cockcroft-Gault formula was used to calculate baseline, and on study, renal function. In the Kd56 arm, pts received carfilzomib (30-min intravenous [IV] infusion) on days (D) 1, 2, 8, 9, 15, and 16 (20 mg/m2 on D1, 2 [cycle 1]; 56 mg/m2 thereafter) and dexamethasone (20 mg) on D1, 2, 8, 9, 15, 16, 22, and 23 of 28-day cycles. Pts in the Vd arm received bortezomib (1.3 mg/m2; IV or subcutaneously) on D1, 4, 8, and 11 and dexamethasone (20 mg) on D1, 2, 4, 5, 8, 9, 11, and 12 of 21-day cycles. Pts were treated until disease progression, physician decision, unacceptable toxicity, withdrawal of consent, or mortality. The primary end point was PFS; secondary end points included OS, overall response rate (ORR), duration of response, rate of grade ≥2 peripheral neuropathy (PN), and safety. The present analyses examined efficacy and safety outcomes in pts grouped according to baseline renal function (CrCL ≥15 to Results: A total of 929 pts were enrolled (CrCL ≥15 to Conclusions: To our knowledge, ENDEAVOR is the largest randomized trial in RRMM to have included pts with severe renal impairment. Superior efficacy for Kd56 vs Vd was observed across all renal subgroups. The safety profile was consistent with the findings from the previous interim analysis. Overall, these data suggest that Kd56 has a favorable benefit-risk profile and should be considered as the new standard of care in pts with RRMM, regardless of baseline renal function. Download : Download high-res image (203KB) Download : Download full-size image Disclosures Dimopoulos: Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology: Consultancy, Honoraria, Other: Advisory Committee: Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology; Genesis Pharma: Research Funding; Novartis: Consultancy, Honoraria. Siegel: Celgene, Takeda, Amgen Inc, Novartis and BMS: Consultancy, Speakers Bureau; Merck: Consultancy. White: Bristol-Myers Squibb: Consultancy, Honoraria; Amgen, Celgene, Janssen, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccia: Pfizer Inc., Sandoz: Other: Advisory Board. Yang: Amgen Inc.: Employment, Equity Ownership. Kimball: Amgen: Employment, Equity Ownership. Iskander: Amgen: Employment, Equity Ownership. Mezzi: Amgen, Inc.: Employment, Equity Ownership. Ludwig: Janssen-Cilag: Consultancy, Speakers Bureau; Bristol-Meyers: Speakers Bureau; AMGEN: Consultancy, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau. Niesvizky: Amgen: Consultancy; Celgene: Consultancy; BMS: Consultancy; Janssen: Consultancy.

FC 035VOCLOSPORIN INCREASES RENAL RESPONSE AT COMMONLY USED UPCR THRESHOLDS IN PATIENTS WITH LUPUS NEPHRITIS

Abstract Background and Aims Voclosporin is a novel calcineurin inhibitor with a favorable metabolic profile and a consistent dose-concentration relationship, potentially eliminating the need for therapeutic drug monitoring. We have previously reported the primary endpoint of the Phase 3 AURORA trial showing the addition of voclosporin to mycophenolate mofetil (MMF) and a low-dose glucocorticoid regimen results in significantly higher renal response (RR) rates at one year of treatment compared to MMF and low-dose glucocorticoids alone in patients with lupus nephritis (LN). For the primary endpoint, RR was defined as ≤0.5 mg/mg UPCR with stable renal function in the presence of low-dose glucocorticoids and no use of rescue medication. Several studies have demonstrated that proteinuria represents the best single predictor for long-term renal outcomes.1,2 Given the efficacy of voclosporin in terms of proteinuria reduction, we conducted a sensitivity analysis evaluating RR with additional UPCR targets. Method A total of 179 participants in the voclosporin (23.7 mg BID) arm and 178 participants in the control arm from the AURORA trial were included in this analysis. All participants received MMF (target 1 g BID) and low-dose oral glucocorticoids (initiated at 20-25 mg/day and tapered to 2.5 mg/day at 16 weeks). For this post hoc analysis, the UPCR component of RR was revised to include UPCR targets at 0.2 mg/mg intervals above and below the original ≤0.5 target used for the primary endpoint in AURORA (i.e., ≤0.7 mg/mg or ≤0.3 mg/mg, respectively). Odds ratios for RR at six months and one year of treatment were analyzed using a logistic regression model with terms for treatment, baseline UPCR, biopsy class, and MMF use at baseline and region. Results RR with UPCR ≤0.7 mg/mg was achieved by 46.9% of participants in the voclosporin arm vs 32.0% of participants in the control arm at one year of treatment (OR 2.07, p&amp;lt;0.0014) and 39.1% of participants in the voclosporin arm vs 24.7% of participants in the control arm at six months of treatment (OR 2.10, p=0.0020). RR with UPCR ≤0.3 mg/mg was achieved by 28.5% of participants in the voclosporin arm vs 15.7% of participants in the control arm at one year (OR 2.27, p=0.0023 and 22.9% of participants in the voclosporin arm vs 14.0% of participants in the control arm at six months of treatment (OR 1.90, p=0.0238; Table 1). Conclusion Participants treated with voclosporin in addition to MMF and low-dose glucocorticoids achieved statistically significantly increased renal response rates regardless of the level of UPCR used, including at an even more stringent ≤0.3 mg/mg target. This analysis further supports the efficacy observed with voclosporin in the Phase 3 AURORA and the prior Phase 2 AURA-LV global trials.

Subcutaneous daratumumab + bortezomib, cyclophosphamide, and dexamethasone (VCd) in patients with newly diagnosed light chain (AL) amyloidosis: Updated results from the phase 3 ANDROMEDA study.

8003 Background: Systemic AL amyloidosis is a plasma cell disease characterized by the deposition of insoluble amyloid fibrils causing organ dysfunction and death. Primary results from the ANDROMEDA study showed that addition of subcutaneous (SC) daratumumab (DARA) to the standard of care combination of bortezomib, cyclophosphamide, and dexamethasone (VCd) was superior to VCd alone, with higher rates of hematologic complete response (CR) and an acceptable safety profile. DARA-VCd was approved for newly diagnosed AL amyloidosis in January 2021. Here we present an update of the primary ANDROMEDA study results with longer follow-up. Methods: ANDROMEDA is a randomized, open-label, active-controlled phase 3 study. Adult patients (pts) with newly diagnosed AL amyloidosis were randomized 1:1 to DARA-VCd or VCd and were treated for 6 28-day Cycles (Cyc). Bortezomib (1.3 mg/m2), cyclophosphamide (300 mg/m2 maximum weekly dose 500 mg), and dexamethasone (40 mg) were given weekly. DARA SC was given weekly (Cyc 1–2) and every 2 weeks (wk) (Cyc 3–6). After Cyc 6, pts in the DARA-VCd group received DARA SC alone every 4 wk for up to 24 Cyc from first dose. Disease status was evaluated every 4 wk in Cyc 1–6 and every 8 wk after Cyc 7. The primary endpoint was overall hematologic CR rate in the intent-to-treat population. Secondary endpoints were major organ deterioration progression-free survival (PFS), organ response rate, time to hematologic response, survival, and safety. Results: Of 388 randomized pts, 195 were randomized to DARA-VCd and 193 to VCd. As of November 2020, the median treatment duration was 18.5 months (mo) for DARA-VCd and 5.3 mo for VCd; 78 pts (40%) in the DARA-VCd group were still on treatment. The overall hematologic CR rate continued to be higher with DARA-VCd than VCd (59% vs 19%; odds ratio [OR] 5.9; 95% CI 3.7–9.4; P&lt; 0.0001). More pts achieved a very good partial response or better (≥VGPR) with DARA-VCd than VCd (79% vs 50%; OR 3.7; 95% CI 2.4–5.9; P&lt; 0.0001). Among responders, median time from randomization to ≥VGPR was shorter for DARA-VCd than VCd (0.56 vs 0.82 mo). Cardiac response rates were higher with DARA-VCd than VCd at 6 mo (42% vs 22%) and at 12 mo (57% vs 28%); renal response rates were 54% vs 27% at 6 mo and 57% vs 27% at 12 mo. A total of 71 deaths occurred (DARA-VCd, n = 31; VCd, n = 40). From Cyc 7 onward in the DARA-VCd group, no grade 3/4 treatment-emergent adverse events occurred in ≥5% of pts. There were no systemic administration-related reactions with DARA-VCd after Cyc 6. Analysis of major organ deterioration PFS will be updated after ̃200 events have occurred. Conclusions: Updated results from the ANDROMEDA study reinforce the clinical superiority of DARA-VCd over VCd in pts with newly diagnosed AL amyloidosis. Based on its recent approval, DARA-VCd represents a new standard of care in AL amyloidosis. Clinical trial information: NCT03201965.

Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial

Voclosporin, a novel calcineurin inhibitor approved for the treatment of adults with lupus nephritis, improved complete renal response rates in patients with lupus nephritis in a phase 2 trial. This study aimed to evaluate the efficacy and safety of voclosporin for the treatment of lupus nephritis. This multicentre, double-blind, randomised phase 3 trial was done in 142 hospitals and clinics across 27 countries. Patients with a diagnosis of systemic lupus erythematosus with lupus nephritis according to the American College of Rheumatology criteria, and a kidney biopsy within 2 years that showed class III, IV, or V (alone or in combination with class III or IV) were eligible. Patients were randomly assigned (1:1) to oral voclosporin (23·7 mg twice daily) or placebo, on a background of mycophenolate mofetil (1 g twice daily) and rapidly tapered low-dose oral steroids, by use of an interactive web response system. The primary endpoint was complete renal response at 52 weeks defined as a composite of urine protein creatinine ratio of 0·5 mg/mg or less, stable renal function (defined as estimated glomerular filtration rate [eGFR] ≥60 mL/min/1·73 m2 or no confirmed decrease from baseline in eGFR of >20%), no administration of rescue medication, and no more than 10 mg prednisone equivalent per day for 3 or more consecutive days or for 7 or more days during weeks 44 through 52, just before the primary endpoint assessment. Safety was also assessed. Efficacy analysis was by intention-to-treat and safety analysis by randomised patients receiving at least one dose of study treatment. The trial is registered with ClinicalTrials.gov, NCT03021499. Between April 13, 2017, and Oct 10, 2019, 179 patients were assigned to the voclosporin group and 178 to the placebo group. The primary endpoint of complete renal response at week 52 was achieved in significantly more patients in the voclosporin group than in the placebo group (73 [41%] of 179 patients vs 40 [23%] of 178 patients; odds ratio 2·65; 95% CI 1·64-4·27; p<0·0001). The adverse event profile was balanced between the two groups; serious adverse events occurred in 37 (21%) of 178 in the voclosporin group and 38 (21%) of 178 patients in the placebo group. The most frequent serious adverse event involving infection was pneumonia, occurring in 7 (4%) patients in the voclosporin group and in 8 (4%) patients in the placebo group. A total of six patients died during the study or study follow-up period (one [<1%] patient in the voclosporin group and five [3%] patients in the placebo group). None of the events leading to death were considered by the investigators to be related to the study treatments. Voclosporin in combination with MMF and low-dose steroids led to a clinically and statistically superior complete renal response rate versus MMF and low-dose steroids alone, with a comparable safety profile. This finding is an important advancement in the treatment of patients with active lupus nephritis. Aurinia Pharmaceuticals.

Autologous stem cell transplantation in the age of ANDROMEDA

Autologous stem cell transplantation in the age of ANDROMEDA

Intestinal SIRT1 Deficiency-Related Intestinal Inflammation and Dysbiosis Aggravate TNFα-Mediated Renal Dysfunction in Cirrhotic Ascitic Mice.

In advanced cirrhosis, the TNFα-mediated intestinal inflammation and bacteria dysbiosis are involved in the development of inflammation and vasoconstriction-related renal dysfunction. In colitis and acute kidney injury models, activation of SIRT1 attenuates the TNFα-mediated intestinal and renal abnormalities. This study explores the impacts of intestinal SIRT1 deficiency and TNFα-mediated intestinal abnormalities on the development of cirrhosis-related renal dysfunction. Systemic and renal hemodynamics, intestinal dysbiosis [cirrhosis dysbiosis ratio (CDR) as marker of dysbiosis], and direct renal vasoconstrictive response (renal vascular resistance (RVR) and glomerular filtration rate (GFR)) to cumulative doses of TNFα were measured in bile duct ligated (BDL)-cirrhotic ascitic mice. In SIRT1IEC-KO-BDL-ascitic mice, the worsening of intestinal dysbiosis exacerbates intestinal inflammation/barrier dysfunction, the upregulation of the expressions of intestinal/renal TNFα-related pathogenic signals, higher TNFα-induced increase in RVR, and decrease in GFR in perfused kidney. In intestinal SIRT1 knockout groups, the positive correlations were identified between intestinal SIRT1 activity and CDR. Particularly, the negative correlations were identified between CDR and RVR, with the positive correlation between CDR and GFR. In mice with advanced cirrhosis, the expression of intestinal SIRT1 is involved in the linkage between intestinal dysbiosis and vasoconstriction/hypoperfusion-related renal dysfunction through the crosstalk between intestinal/renal TNFα-related pathogenic inflammatory signals.

Comparison of the renal response of bortezomib-based induction and conventional regimen in multiple myeloma patients with renal failure

Aim: Vincristine-doxorubicin-dexamethasone (VAD) was the commonly used first-line treatment for multiple myeloma (MM) patients with renal failure before bortezomib entered clinical practice. In this trial, we aimed to compare the effect of VAD and bortezomib-cyclophosphamide-dexamethasone (VCD) chemotherapy regimens on improving kidney function in MM patients with renal failure. Materials and Methods: The records of MM patients in our center between January 2010 and February 2020 were retrospectively analyzed. Patients who received VAD or VCD as a first treatment chemotherapy protocol and whose initially estimated glomerular filtration rate (eGFR) was 50 mL/min/1.73 m2 and below were included in the study. Patients were divided into two groups according to the chemotherapy regimens they received. Results: Sixty one MM patients (VAD: 26, VCD: 35) were included in the study. No significant difference was found between the VAD and VCD groups when the baseline, 1st and 2nd month eGFRs were compared (p>0.05). Overall renal response rate (at least minor response) in the VCD group at the end of the 1st month were higher than in the VAD group (p=0.002). Also, renal response rate in the VCD group at the end of the 2nd month were higher than in the VAD group (p=0.033). Conclusion: In MM patients with renal insufficiency, overall renal response rates have increased with the use of VCD instead of VAD as a standard induction regimen.

Pattern of Use and Efficacy of Daratumumab-Based Therapy in Patients with AL Amyloidosis: A Single Institution Experience

Introduction: Light chain Amyloidosis (AL) is a systemic disease caused by abnormal clonal plasma cells which produce excessive light chains that further misfold and deposit into vital organs. Currently, treatment options for AL amyloidosis are relatively limited. Daratumumab (dara), a novel monoclonal antibody that targets CD38 on the surface of plasma cells, has shown remarkable efficacy in AL amyloidosis. Our objective was to explore the pattern of use, safety and efficacy of dara therapy among AL amyloid patients in a real-world setting at a single institution. Methods: We performed a retrospective analysis of patients with AL amyloidosis diagnosed by tissue biopsy who received dara-based therapy from 11/16/2015 to 3/16/2020 at Tufts Medical Center. The study was approved by the Tufts Medical Center Institutional Review Board. Baseline demographics, clinical characteristics and therapy-related data from patients were extracted from the electronic medical records. Kaplan-Meier method was used to estimate time to hematologic response, time to organ response and progression free survival (PFS) after dara initiation. Log-rank tests were applied to compare PFS among subgroups and to explore the impact of involved free light chain (iFLC) levels on organ response. Results were considered to be significant if two-sided P-value was less than or equal to 0.05. R software was used for statistics. Results: Forty AL patients were included in the study with a median age of 66 years, ranging from 35 to 80 years. Among these patients, 22 (55%) were male and 35 (87.5%) were non-Hispanic White. Cardiac involvement was present in 30 subjects (75%) and renal involvement was present in 20 (50%). By cytogenetic stratification, 10 (25%) individuals had translocation (11;14). Table 1 highlights the clinical characteristics of the study population including the combinations of dara with traditional therapies. Dara was well tolerated in the majority of cases with only one instance of discontinuation due to frequent upper respiratory tract infections. The major therapy-related adverse events are highlighted in table 2. The overall hematologic response rate was 87.5%, including 16 complete responses (CR), 15 very good partial responses (VGPR), and 4 partial responses (PR). The estimated median time to hematologic response was 1.5 months (95% confidence interval (1.0, 2.0 months). The overall cardiac response rate after dara treatment was 46.7%, and the estimated median time to cardiac response was 8.25 months (95% CI, 5.5, 13.0 months). Likewise, the overall renal response rate was 25.0% with the estimated median time to renal response being not evaluable (NE) (95% CI, 12.0, NE). There were 31 patients who had hematologic progression through the study period; the median PFS was 12.0 months (95% CI, 8.25, 18.50 months). The median PFS among those who had translocation (11;14) was 24.1 months. Further log-ranks tests showed that there was no significant difference in PFS when subgrouping patients based on line of treatment (1st vs. 2nd/3rd vs. &amp;gt;3rd, P = 0.322) or pattern of therapy (dara monotherapy vs. combination with PI vs. IMiD vs. PI + alkylating agents vs. NEOD001, P = 0.151). Among the subjects who achieved at least a VGPR, iFLC levels (&amp;lt;10 vs. 10-20 vs. &amp;gt;20) did not show significant impact on the rate and time to organ response (cardiac, P = 0.551 or renal, P = 0.260). In the same population, it was also found that line of treatment (1st vs. 2nd/3rd vs. &amp;gt;3rd) was not associated with organ response (cardiac, P=0.950 or renal, P=0.817). Conclusions: Among the AL amyloidosis patients at Tufts Medical Center treated with dara over the last 5 years, the overall hematologic response was high (87.5%) and the median time to response was rapid (1.5 months), consistent with findings from prior trials. Most importantly, dara was well-tolerated. Patients with t(11;14) had a mPFS that was double the rest of the population (24 vs. 12 months) These results are promising for the disseminated use of dara in AL given its good tolerability and rapid onset of action, regardless of line of therapy. This is especially important in a disease where time is a critical factor in organ recovery. Disclosures Comenzo: Takeda: Consultancy, Research Funding; Caleum: Consultancy; Sanofi: Consultancy; Unum: Consultancy; Prothena: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Amgen: Consultancy; Karyopharm: Consultancy, Research Funding.

Rapid and Deep Hematologic Responses Are Associated with Improved Major Organ Deterioration Progression-Free Survival in Newly Diagnosed AL Amyloidosis: Results from Andromeda

Background: As immunoglobulin light chains present in AL amyloidosis are considered to be toxic to involved organs, especially the heart, rapid and deep hematologic remission with reduction of these light chains with frontline therapy may be crucial to improving long-term clinical outcomes. ANDROMEDA (NCT03201965) is the first phase 3 study in this patient population to evaluate major organ deterioration progression-free survival (MOD-PFS), a composite endpoint of time to end-stage cardiac disease (requiring cardiac transplant, left ventricular assist device, or intra-aortic balloon pump); end-stage renal disease (requiring hemodialysis or renal transplant); hematologic progression per consensus guidelines1; and death. Here, we report the impact of early and deep hematologic responses on MOD-PFS. Methods: ANDROMEDA is a randomized, open-label, active-controlled phase 3 study of patients with newly diagnosed AL amyloidosis who received cyclophosphamide, bortezomib, and dexamethasone (VCd) ± daratumumab subcutaneous (DARA SC; DARA 1800 mg coformulated with recombinant human hyaluronidase PH20 in 15 mL). Key eligibility criteria were newly diagnosed AL amyloidosis with measurable hematologic disease, ≥1 involved organ, cardiac stage I-IIIA, eGFR ≥20 mL/min, and absence of symptomatic multiple myeloma. Disease evaluations occurred every 4 weeks during Cycles 1-6. Hematologic responses were adjudicated by an Independent Review Committee. Landmark analyses for response were performed at 1 and 3 months (± 7 days). Analyses of hematologic responses and MOD-PFS were performed on the intent-to-treat analysis set. Patients without a baseline or post-baseline assessment were censored at randomization for the MOD-PFS analysis. Hazard ratios and corresponding 95% confidence intervals were estimated based on Cox proportional hazard model. Results: A total of 388 patients were randomized to DARA-VCd (n=195) or VCd alone (n=193). Baseline characteristics were well balanced between groups. The proportions of patients with heart and kidney involvement were 71% and 59%, respectively. Median follow-up was 11.4 months (range, 0.03-21.3+). For the 1- and 3-month landmark analysis, hematologic response was available for 356 and 289 patients, respectively. Hematologic response rates by treatment group at 1 and 3 months are shown in the Table. MOD-PFS was longer in patients with complete response (CR)/very good partial response (VGPR) at 1 and 3 months vs patients with lower levels of response (Figure). CR/VGPR at 1 and 3 months was associated with reduced risk of death or major organ deterioration in a multivariate analysis adjusting for baseline difference between involved and uninvolved free light chains and cardiac stage, (HR: 0.399, P=0.0006 and HR: 0.262, P=0.0003, respectively). At 1 and 3 months, cardiac and renal response rates were higher in those who achieved early and deep hematologic responses (CR and VGPR). Conclusions: CR/VGPR at 1 and 3 months was associated with a reduced risk of major organ deterioration and death in patients with newly diagnosed AL amyloidosis. These data confirm that initial therapy that achieves rapid and deep hematological responses is essential to improving long-term outcomes in AL amyloidosis. Reference 1. Comenzo RL, et al. Leukemia. 2012;26(11):2317-25 Disclosures Wechalekar: Janssen: Honoraria, Other: Advisory; Caelum: Other: Advisory; Celgene: Honoraria; Takeda: Honoraria, Other: Travel. Palladini:Celgene: Other: Travel support; Jannsen Cilag: Honoraria, Other. Comenzo:Caleum: Consultancy; Unum: Consultancy; Sanofi: Consultancy; Takeda: Consultancy, Research Funding; Amgen: Consultancy; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Prothena: Consultancy, Research Funding. Jaccard:Celgene: Honoraria, Other: A.J. has served in a consulting or advisory role for Janssen and has received honoraria from, received research funding from, and had travel, accommodations, or other expenses paid for or reimbursed by Celgene., Research Funding; Janssen: Consultancy, Honoraria, Other: A.J. has served in a consulting or advisory role for Janssen and has received honoraria from, received research funding from, and had travel, accommodations, or other expenses paid for or reimbursed by Janssen., Research Funding. Tran:Janssen: Current Employment, Current equity holder in publicly-traded company. Pei:Janssen: Current Employment, Current equity holder in publicly-traded company. Vasey:Janssen Research &amp; Development: Current Employment, Current equity holder in publicly-traded company. Tromp:Janssen: Current Employment, Current equity holder in publicly-traded company. Weiss:Janssen: Current Employment, Current equity holder in publicly-traded company. Vermeulen:Janssen: Current Employment, Current equity holder in publicly-traded company. Kastritis:Pfizer: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding.

Outcomes By Cardiac Stage in Newly Diagnosed AL Amyloidosis: Results from Andromeda

Outcomes By Cardiac Stage in Newly Diagnosed AL Amyloidosis: Results from Andromeda

Daratumumab with Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma and Severe Renal Impairment: Results on Efficacy and Safety of the Phase 2 Dare Study

Daratumumab with Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma and Severe Renal Impairment: Results on Efficacy and Safety of the Phase 2 Dare Study

The role of induction therapy before autologous stem cell transplantation in low disease burden AL amyloidosis patients

Background Induction therapy is recommended before autologous stem cell transplantation (ASCT) for AL amyloidosis patients with high disease burden [bone marrow plasma cells (BMPCs) > 10%], but the role of induction therapy before ASCT in patients with low disease burden (BMPCs ≤ 10%) is still unknown. Methods A total of 227 patients with AL amyloidosis were included in this study. Among 227 patients, 124 patients received bortezomib-based induction prior to ASCT and were defined as group A, 35 patients received other chemotherapeutic induction and were defined as group B, and the other 68 patients without induction were defined as group C. We compared the differences of efficacy and prognosis between the three groups. Results The haematological overall response rates (ORR) of groups A, B and C were 91%, 67% and 75%, respectively. The complete response rates (CR) of groups A, B and C were 50%, 25% and 20%, respectively. Both the ORR and CR rates of group A were significantly higher than those of groups B and C. The renal response rates of groups A, B and C were 64%, 46% and 47%, respectively. The cardiac response rates of groups A, B and C were 74%, 45% and 40%, respectively. The renal and cardiac responses rates of group A were also significantly higher than those of the other two groups. After a median follow-up of 44 months, the median OS was not reached. The 5-year estimated overall survival (OS) rates of groups A, B and C were 81%, 57% and 67%, respectively. The median progression-free survival (PFS) was 83 months for all patients. The 5-year estimated PFS rates of groups A, B and C were 61%, 38% and 49%, respectively. Both the OS and PFS of group A were higher than those of both group B and group C. On multivariate analysis, baseline dFLC > 50 mg/L was associated with worse survival, but induction with bortezomib was associated with better survival. Conclusion Our study demonstrated that low disease burden AL patients who are eligible for ASCT may benefit from bortezomib-based induction therapy.

Severe renal impairment as an adverse prognostic factor for survival in newly diagnosed multiple myeloma patients.

BackgroundRenal impairment (RI) is associated with poor survival in newly diagnosed multiple myeloma (MM) patients. Renal function recovery has been one of the main therapeutic goals in those patients.MethodsThe records from 393 newly diagnosed MM patients in our hospital between January 2012 and December 2016 were retrospectively analyzed. RI was defined as an eGFR < 40 mL/min according to the novel IMWG criteria. RI patients were categorized based on their renal function at diagnosis: severe RI: eGFR < 30 mL/min, and mild RI: 30 mL/min ≤ eGFR <40 mL/min. We explored whether RI, and particularly severe RI, was an adverse prognostic factor for survival, and investigated the impact of renal function recovery on survival.ResultsSevere RI, hemoglobin <100 g/L, LDH ≥ 245 U/L, hyperuricemia, 1q21 amplification, and lack of novel agent treatment were associated with decreased overall survival (OS). Severe RI patients with renal response had a median OS of 27 months compared with 18 months for those patients without renal response (P = .030), but their median OS was still significantly lower than that for patients without severe RI, which was 51 months. In severe RI patients, the overall renal response rate in bortezomib‐based regimens was significantly higher than that in nonbortezomib‐based regimens.ConclusionOur results suggest that severe RI is an adverse prognostic factor for survival in newly diagnosed MM patients, restoration of renal function may improve survival, and bortezomib‐based regimens may be the preferred treatment in patients with severe RI.

Randomized Trial Comparing Double Versus Triple Bortezomib-Based Regimen in Patients With Multiple Myeloma and Acute Kidney Injury Due to Cast Nephropathy.

We report a multicenter controlled trial comparing renal recovery and tolerance profile of doublet versus triplet bortezomib-based regimens in patients with initial myeloma cast nephropathy (CN) and acute kidney injury (AKI) without need for dialysis. After symptomatic measures and high-dose dexamethasone, patients were randomly assigned to receive bortezomib plus dexamethasone (BD), or BD plus cyclophosphamide (C-BD). In patients with < 50% reduction of serum free light chains (sFLCs) after 3 cycles, chemotherapy was reinforced with either cyclophosphamide (BD group) or thalidomide (C-BD group). Ninety-two patients were enrolled in each group. At random assignment, characteristics of the 2 groups were similar, including median age (68 years) and serum creatinine level (305.5 and 273.5 µmol/L in BD and C-BD group, respectively). At 3 months, renal response rate (primary end point) was not different (41 v 47 responders in the BD and C-BD groups, respectively; relative risk [RR], 0.87; P = .46). Very good partial response (free light chain reduction ≥ 90%) or more was achieved in 36 and 47 patients, respectively (RR, 0.76; P = .10). After 1 cycle of chemotherapy, 69 in the BD group and 67 patients in the C-BD group had achieved sFLC level ≤ 500 mg/L. Serious adverse events were recorded in 30 and 40 patients, respectively. At 12 months, 19 patients had died (9 in the BD group v 10 in the C-BD group), including 10 (6 in the BD group and 4 in the C-BD group) from myeloma progression and 3 (0 in the BD group and 3 in the C-BD group) from infection. Within median follow-up of 27 months, 43 and 42 patients switched to new therapy, respectively. Overall, 50 patients (24 in the BD group and 26 in the C-BD group) had died. This randomized study did not show any benefit of C-BD compared with BD on renal recovery of patients with initial CN not requiring dialysis. Adding cyclophosphamide did not sufficiently improve the efficacy-toxicity balance. Patients with myeloma with AKI are fragile, and indication for doublet or triplet regimen should be adapted to frailty.

SAT0166 BIOMARKERS OF B-CELL DEPLETION AND RESPONSE IN A RANDOMIZED, CONTROLLED TRIAL OF OBINUTUZUMAB FOR PROLIFERATIVE LUPUS NEPHRITIS

Background:Incomplete B-cell and plasmablast depletion, as measured using highly sensitive flow cytometry (HSFC), is associated with lower response rates following rituximab in SLE [1]. Enhanced B-cell depletion with the type II anti-CD20 mAb obinutuzumab resulted in increased renal responses in proliferative lupus nephritis (LN) in the NOBILITY trial (NCT02550652) and will be further evaluated in the Phase 3 REGENCY trial (NCT04221477).Objectives:To measure peripheral B-cells, B-cell subsets (naïve, memory and plasmablast) and B-cell activating factor (BAFF) levels and to assess associations between B-cell depletion and renal response in LN patients in a clinical trial of obinutuzumab.Methods:126 patients with active Class III/IV LN were randomized to obinutuzumab or placebo infusions in combination with mycophenolate and glucocorticoids. Peripheral B-cells were measured using a HSFC method with a lower limit of quantitation of 0.441 cells/μL. Serum levels of BAFF were evaluated using ELISA. Sustained depletion was defined by total B-cells below the limit of detection at both weeks 24 and 52. Renal response definitions from Phase 2 NOBILITY and Phase 3 REGENCY trials were used.Results:Obinutuzumab resulted in rapid and complete depletion of total B-cells, memory and naïve B-cells, and plasmablasts from peripheral blood, with 88% of obinutuzumab patients depleted to &lt; 0.441 total B-cells/μL at week 2 (Figure). Mean serum BAFF increased from 4,585 pg/mL at baseline to 14,601 pg/mL at week 52 in the obinutuzumab group. Sustained B-cell depletion was achieved in 32/52 (62%) of patients with complete data and was associated with higher renal response rate at week 76 (Table), although patients who achieved sustained depletion also had lower baseline proteinuria and serum creatinine.Conclusion:Obinutuzumab, a type II anti-CD20 mAb, mediated rapid, complete and sustained depletion of peripheral B-cells and plasmablasts and large increases in serum BAFF. Similar to previous reports, sustained B-cell depletion was associated with increased renal response though there may be confounding factors. REGENCY is being conducted to further evaluate the therapeutic hypothesis with obinutuzumab in LN.