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We performed retrospective analysis of relapsed/refractory multiple myeloma (RRMM) patients previously exposed to daratumumab treated with ixazomib, lenalidomide, dexamethasone (IRd) regimen in real clinical practice. Our aim was to evaluate efficacy of IRd in these patients and select a subset of patients that would benefit from this treatment the most. In total, we analyzed 43 daratumumab-exposed RRMM patients treated in our center. Minimal response or better was achieved by 53.5% of patients from the cohort. Median progression free survival (PFS) was 4.56 months (95% CI: 2.56, 8.03) and median overall survival (OS) was 28.92 months (95% CI: 5.4, NR). Duration of response (DOR) was evaluable in 28 patients and reached a median of 21.3 months (95% CI: 6.85, NR). Next, we evaluated hazard ratios (HR) for OS and PFS. There was improved OS in patients that were not-triple refractory or worse (HR = 0.39, 95%Cl (0.14; 1.10), p = .07) and in patients, that had less than three previous lines of treatment (LOT) (HR = 0.13, 95%Cl (0.03; 0.6) p = .003). Similar to OS, there was improved PFS in patients, that were not triple-refractory or worse (HR = 0.52, 95%Cl (0.25; 1.10), p = .08). We concluded, that the best survival benefit for RRMM patients pretreated with daratumumab to IRd regimen was observed in patients that were not triple-refractory and had less than three previous lines of treatment (LOT). The DOR in these patients was 21.3 months (95% CI: 6.85, NR)., (© 2024 The Author(s). European Journal of Haematology published by John Wiley & Sons Ltd.)

Background: Bortezomib, lenalidomide, and dexamethasone (VRd) is a preferred first-line treatment option for patients with newly diagnosed multiple myeloma. Whether the addition of the anti-CD38 monoclonal antibody isatuximab to the VRd regimen would reduce the risk of disease progression or death among patients ineligible to undergo transplantation is unclear., Methods: In an international, open-label, phase 3 trial, we randomly assigned, in a 3:2 ratio, patients 18 to 80 years of age with newly diagnosed multiple myeloma who were ineligible to undergo transplantation to receive either isatuximab plus VRd or VRd alone. The primary efficacy end point was progression-free survival. Key secondary end points included a complete response or better and minimal residual disease (MRD)-negative status in patients with a complete response., Results: A total of 446 patients underwent randomization. At a median follow-up of 59.7 months, the estimated progression-free survival at 60 months was 63.2% in the isatuximab-VRd group, as compared with 45.2% in the VRd group (hazard ratio for disease progression or death, 0.60; 98.5% confidence interval, 0.41 to 0.88; P<0.001). The percentage of patients with a complete response or better was significantly higher in the isatuximab-VRd group than in the VRd group (74.7% vs. 64.1%, P = 0.01), as was the percentage of patients with MRD-negative status and a complete response (55.5% vs. 40.9%, P = 0.003). No new safety signals were observed with the isatuximab-VRd regimen. The incidence of serious adverse events during treatment and the incidence of adverse events leading to discontinuation were similar in the two groups., Conclusions: Isatuximab-VRd was more effective than VRd as initial therapy in patients 18 to 80 years of age with newly diagnosed multiple myeloma who were ineligible to undergo transplantation. (Funded by Sanofi and a Cancer Center Support Grant; IMROZ ClinicalTrials.gov number, NCT03319667.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Isatuximab is an anti-CD38 monoclonal antibody approved for the treatment of relapsed or refractory multiple myeloma. Previous analyses of the IKEMA trial showed prolonged progression-free survival in patients with this disease who received isatuximab in combination with carfilzomib-dexamethasone as compared with those who received carfilzomib-dexamethasone alone. Herein, we report the analysis of overall survival from the IKEMA trial., Methods: This prospective, randomised, open-label, active-controlled, phase 3 study included patients with relapsed or refractory multiple myeloma aged 18 years or older, who had received one to three previous lines of treatment from 69 study centres in 16 countries across North America, South America, Europe, and the Asia-Pacific region. Patients were randomly allocated (3:2) to treatment with either isatuximab plus carfilzomib-dexamethasone (isatuximab group) or carfilzomib-dexamethasone (control group). In the isatuximab group, patients received intravenous isatuximab (10 mg/kg on days 1, 8, 15, and 22 of the first 28-day cycle, and days 1 and 15 of subsequent 28-day cycles). In both treatment groups, intravenous carfilzomib (20 mg/m 2 on days 1 and 2 of the first cycle; and 56 mg/m 2 on days 8, 9, 15, and 16 of the first cycle, and days 1, 2, 8, 9, 15, and 16 of subsequent cycles) and intravenous or oral dexamethasone (20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23) were administered. The primary endpoint of the trial was progression-free survival, which was reported previously. Treatment continued until progression, unacceptable toxicity, or patient request to discontine. The overall survival analysis reported here was planned to be conducted 3 years after the primary progression-free survival analysis in the intention-to-treat population. Additional analyses were conducted on the secondary endpoints of time to next treatment and second-progression-free survival. Reported p values are non-inferential due to hierarchical testing. This trial is registered with ClinicalTrials.gov (NCT03275285)., Findings: Between Nov 15, 2017, and March 21, 2019, 302 patients were enrolled and randomly allocated: 179 (59%) to the isatuximab group and 123 (41%) to the control group. 169 (56%) patients were male, 133 (44%) were female, 214 (71%) were White, 50 (17%) were Asian, nine (3%) were Black or African American, and three (1%) were multiracial. At data cutoff for this overall survival analysis (Feb 7, 2023), 79 (44%) overall survival events in the isatuximab group and 59 (48%) in the control group had occurred (median follow-up 56·61 months [IQR 54·90-58·02]). Median overall survival (in months) was not reached (NR; 95% CI 52·17-NR) in the isatuximab group and was 50·60 months (38·93-NR) in the control group (hazard ratio [HR] 0·855 [95% CI 0·608-1·202], nominal one-sided p=0·18). Survival probability at 48 months was 59·7% (95% CI 52·0-66·7) in the isatuximab group and 52·2% (95% CI 42·7-60·8) in the control group (based on Kaplan-Meier analysis). Improvements in time to next treatment (HR 0·583 [95% CI 0·429-0·792], nominal one-sided p=0·0002) and second-progression-free survival (0·663 [0·491-0·895], nominal one-sided p=0·0035) were observed in the isatuximab group. The most common treatment-emergent adverse events were infusion reactions (82 [46%] patients in the isatuximab group and four [3%] in the control group) and upper respiratory tract infections (71 [40%] and 34 [28%], respectively). Discontinuations due to treatment-emergent adverse events were similar between treatment groups (24 [14%] in the isatuximab group and 22 [18%] in the control group), despite an additional 30 weeks of exposure in the isatuximab group. 12 (7%) patients in the isatuximab group and six (5%) patients in the control group had a treatment-related adverse event with a fatal outcome during study treatment., Interpretation: At the time of the current analysis, a difference in overall survival could not be detected between the treatment groups, and no new safety signals were observed. Collectively, the evidence suggests that isatuximab plus carfilzomib-dexamethasone is a key treatment for patients with relapsed or refractory multiple myeloma., Funding: Sanofi., Competing Interests: Declaration of interests KY declares research support from BMS, Janssen, and Sanofi; honoraria from Amgen, Sanofi, and Takeda; and advisory roles for Janssen and Sanofi. TM declares research support from Sanofi. M-AD declares honoraria from Amgen, BeiGene, BMS, Janssen, Sanofi, and Takeda. JM declares consulting for Amgen, BMS, GSK, Janssen, Karyopharm, Sanofi, and Takeda. MC declares honoraria from BMS, Janssen, and Sanofi; and advisory roles for Janssen and Sanofi. RH declares research support from Amgen, BMS, Celgene, Janssen, Novartis, and Takeda; consulting for AbbVie, Amgen, BMS, Celgene, Janssen, Novartis, PharmaMar, and Takeda; honoraria from Amgen, BMS, Celgene, Janssen, PharmaMar, Takeda; and advisory roles for Amgen, BMS, GSK, Janssen, Oncopeptides, Sanofi, Takeda. IS declares research support from and consulting for Amgen, BMS, Celgene, Janssen-Cilag, Novartis, PharmMar, Sanofi, and Takeda. RB declares research support from AbbVie, Acerta Pharma, Alexion, Amgen, Bayer, BeiGene, BMS, Boehringer Ingelheim, Celgene, CSL Behring, Daiichi Sankyo, Janssen-Cilag, MorphoSys, Pfizer, Pharmaxis, Portola, Rigel Pharmaceuticals, Roche, Sanofi, Takeda, and Technoclone; honoraria from Bayer, BMS, Cardinal Health, Janssen-Cilag, and Roche; and advisory roles for Janssen-Cilag, Pharmaxis, and Roche. KK declares consulting for LG Chemistry; and advisory roles for Amgen, GSK, and Janssen. AO declares honoraria from Amgen, BMS/Celgene, GSK, and Sanofi. YK declares honoraria from Amgen, GSK, and Janssen. KS declares honoraria from AbbVie, Amgen, BMS, Janssen, Novartis, ONO, Sanofi, and Takeda; consulting for Amgen, BMS, and Takeda; and research funding from BMS. FC, SM, and M-LR are employees of Sanofi and may hold stock or stock options. PM declares advisory roles for AbbVie, Amgen, Celgene, GSK, Janssen, and Sanofi. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Triplet or quadruplet therapies incorporating proteasome inhibitors, immunomodulators, and anti-CD38 antibodies have led to prolonged survival among patients with newly diagnosed multiple myeloma; however, most patients have a relapse. Frontline lenalidomide therapy has increased the number of patients with lenalidomide-refractory disease at the time of the first relapse., Methods: In this phase 3, randomized, open-label trial, we evaluated belantamab mafodotin, pomalidomide, and dexamethasone (BPd), as compared with pomalidomide, bortezomib, and dexamethasone (PVd), in lenalidomide-exposed patients who had relapsed or refractory myeloma after at least one line of therapy. The primary end point was progression-free survival. Disease response and safety were also assessed., Results: A total of 302 patients underwent randomization; 155 were assigned to the BPd group, and 147 to the PVd group. At a median follow-up of 21.8 months (range, <0.1 to 39.2), the 12-month estimated progression-free survival with BPd was 71% (95% confidence interval [CI], 63 to 78), as compared with 51% (95% CI, 42 to 60) with PVd (hazard ratio for disease progression or death, 0.52; 95% CI, 0.37 to 0.73; P<0.001). Data on overall survival were immature. The percentage of patients with a response to treatment (partial response or better) was 77% (95% CI, 70 to 84) in the BPd group and 72% (95% CI, 64 to 79) in the PVd group; 40% (95% CI, 32 to 48) and 16% (95% CI, 11 to 23), respectively, had a complete response or better. Grade 3 or higher adverse events occurred in 94% of the patients in the BPd group and 76% of those in the PVd group. Ocular events occurred in 89% of the patients who received BPd (grade 3 or 4 in 43%) and 30% of those who received PVd (grade 3 or 4 in 2%); ocular events in the BPd group were managed with belantamab mafodotin dose modification. Ocular events led to treatment discontinuation in 9% of the patients in the BPd group and in no patients in the PVd group., Conclusions: Among lenalidomide-exposed patients with relapsed or refractory myeloma, BPd conferred a significantly greater benefit than PVd with respect to progression-free survival, as well as deeper, more durable responses. Ocular events were common but were controllable by belantamab mafodotin dose modification. (Funded by GSK; DREAMM-8 ClinicalTrials.gov number, NCT04484623; EudraCT number, 2018-004354-21.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: In the phase 3 ALCYONE study, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) versus bortezomib/melphalan/prednisone (VMP) significantly improved progression-free survival (PFS) and overall survival (OS) in transplant-ineligible, newly diagnosed multiple myeloma (NDMM) patients. We present a subgroup analysis of ALCYONE by patient frailty status., Patients and Methods: Frailty assessment was performed retrospectively using age, Charlson comorbidity index, and baseline Eastern Cooperative Oncology Group performance status score. Patients were classified as fit (0), intermediate (1), or frail (≥2); a nonfrail category combined fit and intermediate patients., Results: Among randomized patients (D-VMP, n = 350; VMP, n = 356), 391 (55.4%) were nonfrail (D-VMP, 187 [53.4%]; VMP, 204 [57.3%]) and 315 (44.6%) were frail (163 [46.6%]; 152 [42.7%]). After 40.1-months median follow-up, nonfrail patients had longer PFS and OS than frail patients, but benefits of D-VMP versus VMP were maintained across subgroups: PFS nonfrail (median, 45.7 vs. 19.1 months; hazard ratio [HR], 0.36; P < .0001), frail (32.9 vs. 19.5 months; HR, 0.51; P < .0001); OS nonfrail (36-month rate, 83.6% vs. 74.5%), frail (71.4% vs. 59.0%). Improved greater than or equal to complete response and minimal residual disease (10 - 5 )-negativity rates were observed for D-VMP versus VMP across subgroups. The 2 most common grade 3/4 treatment-emergent adverse events were neutropenia (nonfrail: 39.2% [D-VMP] and 42.4% [VMP]; frail: 41.3% and 34.4%) and thrombocytopenia (nonfrail: 32.8% and 36.9%; frail: 36.9% and 39.1%)., Conclusion: Our findings support the clinical benefit of D-VMP in transplant-ineligible NDMM patients enrolled in ALCYONE, regardless of frailty status., (Copyright © 2021 Janssen Research & Development, LLC. Published by Elsevier Inc. All rights reserved.)

Background: In the phase III ALCYONE trial, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) significantly improved overall response rate and progression-free status compared with VMP alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). Here, we present patient-reported outcomes (PROs) from ALCYONE., Methods: The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) and EuroQol 5-dimensional descriptive system (EQ-5D-5L) questionnaire were administered at baseline, every 3 months (year 1) and every 6 months (until progression). Treatment effects were assessed using a repeated-measures, mixed-effects model., Results: Compliance with PRO assessments was comparable at baseline (> 90%) and throughout study (> 76%) for both treatment groups. Improvements from baseline were observed in both groups for EORTC QLQ-C30 Global Health Status (GHS), most functional scales, symptom scales and EQ-5D-5L visual analog scale (VAS). Between-group differences were significant for GHS (p = 0.0240) and VAS (p = 0.0160) at month 3. Improvements in pain were clinically meaningful in both groups at all assessment time points. Cognitive function declined in both groups, but the magnitude of the decline was not clinically meaningful., Conclusions: Patients with transplant-ineligible NDMM demonstrated early and continuous improvements in health-related quality of life, including improvements in functioning and symptoms, following treatment with D-VMP or VMP., Trial Registration: ClinicalTrials.gov identifier NCT02195479 , registered September 21, 2014.

Elderly and frail patients with multiple myeloma (MM) are more vulnerable to the toxicity of combination therapies, often resulting in treatment modifications and suboptimal outcomes. The phase 3 BOSTON study showed that once-weekly selinexor and bortezomib with low-dose dexamethasone (XVd) improved PFS and ORR compared with standard twice-weekly bortezomib and moderate-dose dexamethasone (Vd) in patients with previously treated MM. This is a retrospective subgroup analysis of the multicenter, prospective, randomized BOSTON trial. Post hoc analyses were performed to compare XVd versus Vd safety and efficacy according to age and frailty status (<65 and ≥65 years, nonfrail and frail). Patients ≥65 years with XVd had higher ORR (OR 1.77, p = .024), ≥VGPR (OR, 1.68, p = .027), PFS (HR 0.55, p = .002), and improved OS (HR 0.63, p = .030), compared with Vd. In frail patients, XVd was associated with a trend towards better PFS (HR 0.69, p = .08) and OS (HR 0.62, p = .062). Significant improvements were also observed in patients <65 (ORR and TTNT) and nonfrail patients (PFS, ORR, ≥VGPR, and TTNT). Patients treated with XVd had a lower incidence of grade ≥ 2 peripheral neuropathy in ≥65 year-old (22% vs. 37%; p = .0060) and frail patients (15% vs. 44%; p = .0002). Grade ≥3 TEAEs were not observed more often in older compared to younger patients, nor in frail compared to nonfrail patients. XVd is safe and effective in patients <65 and ≥65 and in nonfrail and frail patients with previously treated MM., (© 2021 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Patients with relapsed/refractory multiple myeloma (RRMM) experience several relapses, and become refractory to successive therapies. In the ICARIA-MM trial (NCT02990338), isatuximab plus pomalidomide-dexamethasone prolonged median progression-free survival (PFS) in patients with RRMM. This subgroup analysis of ICARIA-MM assessed the treatment benefit of isatuximab by prior lines of therapy and refractory status. A total of 307 patients were randomized to isatuximab-pomalidomide-dexamethasone (n = 154) or pomalidomide-dexamethasone (n = 153). Isatuximab (10 mg/kg intravenously) was given weekly in the first 28-day cycle, then every other week. Standard pomalidomide-dexamethasone doses were given. PFS was assessed by prior lines and refractory status. Overall, 102 (66 %) patients receiving isatuximab-pomalidomide-dexamethasone and 101 (66 %) patients receiving pomalidomide-dexamethasone had received 2-3 prior lines; 52 (34 %) and 52 (34 %) had received >3 prior lines, respectively. Median PFS was higher with isatuximab-pomalidomide-dexamethasone versus pomalidomide-dexamethasone for patients who received 2-3 prior lines of therapy (12.3 vs. 7.8 months) and >3 prior lines of therapy (9.4 vs. 4.3 months). Median PFS was higher with isatuximab-pomalidomide-dexamethasone versus pomalidomide-dexamethasone for patients who were lenalidomide-refractory (11.4 vs. 5.6 months), lenalidomide-refractory at last line (11.6 vs. 5.7 months), refractory to a proteasome inhibitor (PI) (11.4 vs. 5.6 months), and double-refractory (11.2 vs. 4.8 months). Overall response rate (ORR) in patients receiving isatuximab-pomalidomide-dexamethasone versus pomalidomide-dexamethasone was 59.0 % versus 31.4 % in lenalidomide-refractory; 60.2 % versus 32.2 % in PI-refractory; and 58.6 % versus 29.9 % in double-refractory patients. Isatuximab-pomalidomide-dexamethasone improved PFS and ORR regardless of prior lines of therapy or refractory status, consistent with the benefit in the overall population., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Daratumumab is a CD38-targeting monoclonal antibody approved for intravenous (IV) infusion for multiple myeloma (MM). We describe the Phase II PLEIADES study of a subcutaneous formulation of daratumumab (DARA SC) in combination with standard-of-care regimens: DARA SC plus bortezomib/lenalidomide/dexamethasone (D-VRd) for transplant-eligible newly diagnosed MM (NDMM); DARA SC plus bortezomib/melphalan/prednisone (D-VMP) for transplant-ineligible NDMM; and DARA SC plus lenalidomide/dexamethasone (D-Rd) for relapsed/refractory MM. In total, 199 patients were treated (D-VRd, n = 67; D-VMP, n = 67; D-Rd, n = 65). The primary endpoints were met for all cohorts: the ≥very good partial response (VGPR) rate after four 21-day induction cycles for D-VRd was 71·6% [90% confidence interval (CI) 61·2-80·6%], and the overall response rates (ORRs) for D-VMP and D-Rd were 88·1% (90% CI 79·5-93·9%) and 90·8% (90% CI 82·6-95·9%). With longer median follow-up for D-VMP and D-Rd (14·3 and 14·7 months respectively), responses deepened (ORR: 89·6%, 93·8%; ≥VGPR: 77·6%, 78·5%), and minimal residual disease-negativity (10 -5 ) rates were 16·4% and 15·4%. Infusion-related reactions across all cohorts were infrequent (≤9·0%) and mild. The median DARA SC administration time was 5 min. DARA SC with standard-of-care regimens demonstrated comparable clinical activity to DARA IV-containing regimens, with low infusion-related reaction rates and reduced administration time., (© 2020 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

The regimen of carfilzomib, daratumumab, and dexamethasone (KdD) shows activity in patients with relapsed/refractory multiple myeloma. KdD at the twice-weekly 56 mg/m 2 carfilzomib dose (KdD56) was used in the randomized phase 3 CANDOR study (NCT03158688), whereas KdD at the once-weekly 70 mg/m 2 carfilzomib dose (KdD70) was used in the phase 1 b EQUULEUS study (NCT01998971). We analyzed efficacy data from comparable CANDOR and EQUULEUS patients using inverse probability of treatment weighting (IPTW)-adjusted models. These weights were calculated from propensity scores derived to balance prespecified baseline covariates. The side-by-side and adjusted comparisons showed similar efficacy for overall response rates and progression-free survival in the two groups, with a series of sensitivity analyses showing consistent findings. Safety data were generally consistent with the known safety profiles of each individual drug. Once-weekly KdD70 is comparable to twice-weekly KdD56 in terms of efficacy and safety while being a more convenient dosing option.

Background: We have performed a head to head comparison of all-oral triplet combination of ixazomib, lenalidomide and dexamethasone (IRD) versus lenalidomide and dexamethasone (RD) in patients with relapsed and refractory multiple myeloma (RRMM) in the routine clinical practice., Methods: A total of 344 patients treated with IRD (N = 127) or RD (N = 217) were selected for analysis from the Czech Registry of Monoclonal Gammopathies (RMG). Descriptive statistics were used to assess patient's characteristics associated with the respective therapy. The primary endpoint was progression free survival (PFS), secondary end points included response rates and overall survival (OS). Survival endpoints were plotted using Kaplan-Meier methodology at 95% Greenwood confidence interval. Univariable and multivariable Cox proportional hazards models were used to evaluate the effect of treatment regimens and the significance of uneven variables. Statistical tests were performed at significance level 0.05., Results: In the whole cohort, median PFS for IRD was 17.5 and for RD was 11.5 months favoring the all-oral triplet, p = 0.005; in patients within relapse 1-3, the median PFS was 23.1 vs 11.6 months, p = 0.001. The hazard ratio for PFS was 0.67 (95% confidence interval [CI] 0.51-0.89, p = 0.006). The PFS advantage translated into improved OS for patients treated with IRD, median 36.6 months vs 26.0 months (p = 0.008). The overall response rate (ORR) was 73.0% in the IRD group vs 66.2% in the RD group with a complete response rate (CR) of 11.1% vs 8.8%, and very good partial response (VGPR) 22.2% vs 13.9%, IRD vs RD respectively. The IRD regimen was most beneficial in patients ≤75 years with ISS I, II, and in the first and second relapse. Patients with the presence of extramedullary disease did not benefit from IRD treatment (median PFS 6.5 months). Both regimens were well tolerated, and the incidence of total as well as grade 3/4 toxicities was comparable., Conclusions: Our analysis confirms the results of the TOURMALINE-MM1 study and shows benefit of all-oral triplet IRD treatment versus RD doublet. It demonstrates that the addition of ixazomib to RD improves key survival endpoints in patients with RRMM in a routine clinical setting.

Objective: We evaluated ibrutinib, a once-daily inhibitor of Bruton's tyrosine kinase, combined with bortezomib and dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma who had received 1-3 prior therapies., Methods: This was a phase 2, single-arm, open-label, multicentre study (NCT02902965). The primary endpoint was progression-free survival (PFS)., Results: Seventy-six patients were enrolled; 74 received ≥1 dose of study treatment. After median follow-up of 19.6 months, median PFS was 8.5 months (95% CI: 6.2-10.8); median overall survival was not reached. Overall response rate was 57% (95% CI: 45-68), and median duration of response was 9.5 months (95% CI: 6.9-10.6). Grade 3/4 AEs occurred in 73% of patients and fatal AEs occurred in 15% of patients. Incidence of major haemorrhage was 5%; one patient died from cerebral haemorrhage. After an observed increased incidence of serious (42%) and fatal (11%) infections, enrolment was suspended to implement risk-minimisation measures. The safety profile was otherwise consistent with known safety profiles of the individual drugs., Conclusion: Ibrutinib combined with bortezomib and dexamethasone elicited clinical responses. However, efficacy assessments conducted at potential restart of enrolment indicated that the targeted PFS could not be reached with additional patient enrolment, and the study was terminated., (© 2019 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd.)

Melflufen is a novel peptide-drug conjugate that rapidly delivers a cytotoxic payload into tumor cells. It has emerged as a potential new multiple myeloma treatment, particularly for late-stage forms of the disease. Here we describe the rationale and design of OCEAN (NCT03151811), a randomized, head-to-head, superiority, open-label, global, Phase III study evaluating the efficacy and safety of melflufen + dexamethasone versus pomalidomide + dexamethasone. Eligible patients with relapsed refractory multiple myeloma have received 2-4 previous treatments and are refractory to both lenalidomide and their last treatment. Patients are excluded if they have previously received pomalidomide. The primary endpoint is progression-free survival, and key secondary endpoints include overall response rate, duration of response and overall survival.

The phase 3 CLARION study compared carfilzomib-melphalan-prednisone (KMP) with bortezomib-melphalan-prednisone (VMP) in transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients. Patients were randomized 1:1 to KMP or VMP for nine 42-day cycles (C). Patients received carfilzomib on days (D) 1, 2, 8, 9, 22, 23, 29, 30 (20 mg/m 2 : C1D1, C1D2; 36 mg/m 2 thereafter) or bortezomib on D1, 4, 8, 11, 22, 25, 29, 32 (1.3 mg/m 2 ; D4, 11, 25, 32 omitted for C5-9). Melphalan (9 mg/m 2 ) and prednisone (60 mg/m 2 ) were administered on D1-4. The primary endpoint was progression-free survival (PFS). Nine hundred fifty-five patients were randomized (intention-to-treat population: KMP, n = 478; VMP, n = 477). Median PFS was 22.3 months with KMP vs 22.1 months with VMP (hazard ratio [HR], 0.906; 95% confidence interval [CI], 0.746-1.101; P = .159). Median overall survival was similar and not reached in either group (HR, 1.08; 95% CI, 0.82-1.43). Overall response rate was 84.3% for KMP and 78.8% for VMP. Complete response rate was 25.9% for KMP and 23.1% for VMP. Minimal residual disease-negative rates were 15.7% (KMP) and 15.5% (VMP). Adverse events (AEs) of interest (any grade) occurring with a ≥5% higher patient incidence in the KMP arm were acute renal failure (13.9% [KMP] vs 6.2% [VMP]) and cardiac failure (10.8% vs 4.3%). Grade ≥3 AE rates were 74.7% (KMP) and 76.2% (VMP). Grade ≥2 peripheral neuropathy was lower for KMP vs VMP (2.5% vs 35.1%). Treatment with KMP in CLARION did not yield a statistically significant difference in PFS vs VMP. This trial was registered at www.clinicaltrials.gov as #NCT01818752., (© 2019 by The American Society of Hematology.)

Introduction: Real-world data on patient outcomes and treatment patterns in multiple myeloma (MM) are limited., Materials and Methods: The present noninterventional, observational, retrospective analysis of prospectively collected Czech patient medical record data from the Registry of Monoclonal Gammopathies estimated real-world outcomes in adults with a diagnosis of symptomatic MM made between May 2007 and June 2014., Results: In total, 2446 patients had initiated first-line treatment. The median overall survival since the diagnosis (primary endpoint) was 50.3 months (95% confidence interval, 46.1-54.5 months) and decreased with each successive treatment line. A similar trend was observed for progression-free survival and the depth of response. In line with European guidelines and clinical practice, bortezomib-, thalidomide-, and lenalidomide-based regimens were most commonly used across all treatment lines (42.3%, 28.9%, and 18.4%, respectively). In the first line, bortezomib and thalidomide were used most often, with lenalidomide the most commonly used agent in the relapse setting (second to fourth lines). Exploratory analyses revealed that younger age (≤ 65 years), lower international staging system stage, and previous stem cell transplantation were associated with significant improvements in overall and progression-free survival, especially in the early treatment lines., Conclusion: The present study is the first analysis of Czech data from the Registry of Monoclonal Gammopathies, and it provides important insights into the real-world management of MM for physicians and healthcare providers., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The combination of bortezomib, melphalan, and prednisone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. Daratumumab has shown efficacy in combination with standard-of-care regimens in patients with relapsed or refractory multiple myeloma., Methods: In this phase 3 trial, we randomly assigned 706 patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation to receive nine cycles of bortezomib, melphalan, and prednisone either alone (control group) or with daratumumab (daratumumab group) until disease progression. The primary end point was progression-free survival., Results: At a median follow-up of 16.5 months in a prespecified interim analysis, the 18-month progression-free survival rate was 71.6% (95% confidence interval [CI], 65.5 to 76.8) in the daratumumab group and 50.2% (95% CI, 43.2 to 56.7) in the control group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.38 to 0.65; P<0.001). The overall response rate was 90.9% in the daratumumab group, as compared with 73.9% in the control group (P<0.001), and the rate of complete response or better (including stringent complete response) was 42.6%, versus 24.4% (P<0.001). In the daratumumab group, 22.3% of the patients were negative for minimal residual disease (at a threshold of 1 tumor cell per 10 5 white cells), as compared with 6.2% of those in the control group (P<0.001). The most common adverse events of grade 3 or 4 were hematologic: neutropenia (in 39.9% of the patients in the daratumumab group and in 38.7% of those in the control group), thrombocytopenia (in 34.4% and 37.6%, respectively), and anemia (in 15.9% and 19.8%, respectively). The rate of grade 3 or 4 infections was 23.1% in the daratumumab group and 14.7% in the control group; the rate of treatment discontinuation due to infections was 0.9% and 1.4%, respectively. Daratumumab-associated infusion-related reactions occurred in 27.7% of the patients., Conclusions: Among patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation, daratumumab combined with bortezomib, melphalan, and prednisone resulted in a lower risk of disease progression or death than the same regimen without daratumumab. The daratumumab-containing regimen was associated with more grade 3 or 4 infections. (Funded by Janssen Research and Development; ALCYONE ClinicalTrials.gov number, NCT02195479 .).

Certain cytogenetic abnormalities are known to adversely impact outcomes in patients with multiple myeloma (MM). The phase 3 TOURMALINE-MM1 study demonstrated a significant improvement in progression-free survival (PFS) with ixazomib-lenalidomide-dexamethasone (IRd) compared with placebo-lenalidomide-dexamethasone (placebo-Rd). This preplanned analysis assessed the efficacy and safety of IRd vs placebo-Rd according to cytogenetic risk, as assessed using fluorescence in situ hybridization. High-risk cytogenetic abnormalities were defined as del(17p), t(4;14), and/or t(14;16); additionally, patients were assessed for 1q21 amplification. Of 722 randomized patients, 552 had cytogenetic results; 137 (25%) had high-risk cytogenetic abnormalities and 172 (32%) had 1q21 amplification alone. PFS was improved with IRd vs placebo-Rd in both high-risk and standard-risk cytogenetics subgroups: in high-risk patients, the hazard ratio (HR) was 0.543 (95% confidence interval [CI], 0.321-0.918; P = .021), with median PFS of 21.4 vs 9.7 months; in standard-risk patients, HR was 0.640 (95% CI, 0.462-0.888; P = .007), with median PFS of 20.6 vs 15.6 months. This PFS benefit was consistent across subgroups with individual high-risk cytogenetic abnormalities, including patients with del(17p) (HR, 0.596; 95% CI, 0.286-1.243). PFS was also longer with IRd vs placebo-Rd in patients with 1q21 amplification (HR, 0.781; 95% CI, 0.492-1.240), and in the "expanded high-risk" group, defined as those with high-risk cytogenetic abnormalities and/or 1q21 amplification (HR, 0.664; 95% CI, 0.474-0.928). IRd demonstrated substantial benefit compared with placebo-Rd in relapsed and/or refractory MM (RRMM) patients with high-risk and standard-risk cytogenetics, and improves the poor PFS associated with high-risk cytogenetic abnormalities. This trial was registered at www.clinicaltrials.gov as #NCT01564537., (© 2017 by The American Society of Hematology.)

Prior treatment exposure in patients with relapsed/refractory multiple myeloma may affect outcomes with subsequent therapies. We analyzed efficacy and safety according to prior treatment in the phase 3 TOURMALINE-MM1 study of ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) versus placebo-Rd. Patients with relapsed/refractory multiple myeloma received ixazomib-Rd or placebo-Rd. Efficacy and safety were evaluated in subgroups defined according to type (proteasome inhibitor [PI] and immunomodulatory drug) and number (1 vs. 2 or 3) of prior therapies received. Of 722 patients, 503 (70%) had received a prior PI, and 397 (55%) prior lenalidomide/thalidomide; 425 patients had received 1 prior therapy, and 297 received 2 or 3 prior therapies. At a median follow up of ~15 months, PFS was prolonged with ixazomib-Rd vs. placebo-Rd regardless of type of prior therapy received; HR 0.739 and 0.749 in PI-exposed and -naïve patients, HR 0.744 and 0.700 in immunomodulatory-drug-exposed and -naïve patients, respectively. PFS benefit with ixazomib-Rd vs. placebo-Rd appeared greater in patients with 2 or 3 prior therapies (HR 0.58) and in those with 1 prior therapy without prior transplant (HR 0.60) versus those with 1 prior therapy and transplant (HR 1.23). Across all subgroups, toxicity was consistent with that seen in the intent-to-treat population. In patients with relapsed/refractory multiple myeloma, ixazomib-Rd was associated with a consistent clinical benefit vs. placebo-Rd regardless of prior treatment with bortezomib or immunomodulatory drugs. Patients with 2 or 3 prior therapies, or 1 prior therapy without transplant seemed to have greater benefit than patients with 1 prior therapy and transplant. TOURMALINE-MM1 registered at clinicaltrials.gov identifier: 01564537., (Copyright© 2017 Ferrata Storti Foundation.)

Background: Ixazomib is an oral proteasome inhibitor that is currently being studied for the treatment of multiple myeloma., Methods: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 722 patients who had relapsed, refractory, or relapsed and refractory multiple myeloma to receive ixazomib plus lenalidomide-dexamethasone (ixazomib group) or placebo plus lenalidomide-dexamethasone (placebo group). The primary end point was progression-free survival., Results: Progression-free survival was significantly longer in the ixazomib group than in the placebo group at a median follow-up of 14.7 months (median progression-free survival, 20.6 months vs. 14.7 months; hazard ratio for disease progression or death in the ixazomib group, 0.74; P=0.01); a benefit with respect to progression-free survival was observed with the ixazomib regimen, as compared with the placebo regimen, in all prespecified patient subgroups, including in patients with high-risk cytogenetic abnormalities. The overall rates of response were 78% in the ixazomib group and 72% in the placebo group, and the corresponding rates of complete response plus very good partial response were 48% and 39%. The median time to response was 1.1 months in the ixazomib group and 1.9 months in the placebo group, and the corresponding median duration of response was 20.5 months and 15.0 months. At a median follow-up of approximately 23 months, the median overall survival has not been reached in either study group, and follow-up is ongoing. The rates of serious adverse events were similar in the two study groups (47% in the ixazomib group and 49% in the placebo group), as were the rates of death during the study period (4% and 6%, respectively); adverse events of at least grade 3 severity occurred in 74% and 69% of the patients, respectively. Thrombocytopenia of grade 3 and grade 4 severity occurred more frequently in the ixazomib group (12% and 7% of the patients, respectively) than in the placebo group (5% and 4% of the patients, respectively). Rash occurred more frequently in the ixazomib group than in the placebo group (36% vs. 23% of the patients), as did gastrointestinal adverse events, which were predominantly low grade. The incidence of peripheral neuropathy was 27% in the ixazomib group and 22% in the placebo group (grade 3 events occurred in 2% of the patients in each study group). Patient-reported quality of life was similar in the two study groups., Conclusions: The addition of ixazomib to a regimen of lenalidomide and dexamethasone was associated with significantly longer progression-free survival; the additional toxic effects with this all-oral regimen were limited. (Funded by Millennium Pharmaceuticals; TOURMALINE-MM1 ClinicalTrials.gov number, NCT01564537.).

Background: Bortezomib with dexamethasone is a standard treatment option for relapsed or refractory multiple myeloma. Carfilzomib with dexamethasone has shown promising activity in patients in this disease setting. The aim of this study was to compare the combination of carfilzomib and dexamethasone with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma., Methods: In this randomised, phase 3, open-label, multicentre study, patients with relapsed or refractory multiple myeloma who had one to three previous treatments were randomly assigned (1:1) using a blocked randomisation scheme (block size of four) to receive carfilzomib with dexamethasone (carfilzomib group) or bortezomib with dexamethasone (bortezomib group). Randomisation was stratified by previous proteasome inhibitor therapy, previous lines of treatment, International Staging System stage, and planned route of bortezomib administration if randomly assigned to bortezomib with dexamethasone. Patients received treatment until progression with carfilzomib (20 mg/m(2) on days 1 and 2 of cycle 1; 56 mg/m(2) thereafter; 30 min intravenous infusion) and dexamethasone (20 mg oral or intravenous infusion) or bortezomib (1·3 mg/m(2); intravenous bolus or subcutaneous injection) and dexamethasone (20 mg oral or intravenous infusion). The primary endpoint was progression-free survival in the intention-to-treat population. All participants who received at least one dose of study drug were included in the safety analyses. The study is ongoing but not enrolling participants; results for the interim analysis of the primary endpoint are presented. The trial is registered at ClinicalTrials.gov, number NCT01568866., Findings: Between June 20, 2012, and June 30, 2014, 929 patients were randomly assigned (464 to the carfilzomib group; 465 to the bortezomib group). Median follow-up was 11·9 months (IQR 9·3-16·1) in the carfilzomib group and 11·1 months (8·2-14·3) in the bortezomib group. Median progression-free survival was 18·7 months (95% CI 15·6-not estimable) in the carfilzomib group versus 9·4 months (8·4-10·4) in the bortezomib group at a preplanned interim analysis (hazard ratio [HR] 0·53 [95% CI 0·44-0·65]; p<0·0001). On-study death due to adverse events occurred in 18 (4%) of 464 patients in the carfilzomib group and in 16 (3%) of 465 patients in the bortezomib group. Serious adverse events were reported in 224 (48%) of 463 patients in the carfilzomib group and in 162 (36%) of 456 patients in the bortezomib group. The most frequent grade 3 or higher adverse events were anaemia (67 [14%] of 463 patients in the carfilzomib group vs 45 [10%] of 456 patients in the bortezomib group), hypertension (41 [9%] vs 12 [3%]), thrombocytopenia (39 [8%] vs 43 [9%]), and pneumonia (32 [7%] vs 36 [8%])., Interpretation: For patients with relapsed or refractory multiple myeloma, carfilzomib with dexamethasone could be considered in cases in which bortezomib with dexamethasone is a potential treatment option., Funding: Onyx Pharmaceuticals, Inc., an Amgen subsidiary., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Bendamustine with bortezomib and dexamethasone was evaluated in 79 patients with relapsed/refractory multiple myeloma. Median age was 64 years, and patients had a median of 2 prior treatment lines (range, 1 to 6 lines). Bendamustine 70 mg/m(2) days 1 and 4; bortezomib 1.3 mg/m(2) intravenously days 1, 4, 8, and 11; and dexamethasone 20 mg days 1, 4, 8, and 11 once every 28 days was given for up to 8 cycles. Primary end point was overall response rate (ORR). Secondary end points were progression-free survival (PFS), overall survival, time to response, and toxicity. ORR was 60.8%, and when minor responses were included, 75.9%. Median time to response was 31 days. ORR rate was similar in patients previously exposed to bortezomib, lenalidomide, and bortezomib plus lenalidomide. PFS was 9.7 and OS was 25.6 months. Multivariate analysis showed high lactate dehydrogenase, ≥3 prior treatment lines, and low platelet counts correlating with short survival. Grade 3/4 thrombocytopenia was noted in 38%, and grade 3/4/5 infections were noted in 23%. Grade ≤2 polyneuropathy increased from 19% at baseline to 52% at cycle 8 and grade 4, from 0% to 7%. Bendamustine-bortezomib-dexamethasone is active and well tolerated in patients with relapsed/refractory myeloma. This trial was registered in the EudraCT database as No. 2008-006421-13.

We analyzed 1156 multiple myeloma (MM) patients treated with thalidomide. The overall response rate was 63.6%, with complete remission in 13.4%. Combined regimens had better outcomes than thalidomide plus dexamethasone or single agent thalidomide. Thalidomide was not able to overcome adverse cytogenetics. Superior results were seen in patients undergoing subsequent autologous stem cell transplantation. The rate of adverse events was low. Thalidomide has a strong potential to improve response and survival measures in patients with standard risk MM. Combined regimens should be used, with lower doses of thalidomide. High risk myelomas should be treated individually., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Patients (pts) with fulminant progression (FPG) of multiple myeloma (MM) after autologous stem cell transplantation (ASCT) have poor prognosis. Pancytopenia, extramedullary disease, and/or renal impairment are often present, and treatment options are limited. We have retrospectively evaluated 31 pts with FPG of MM after ASCT who were treated upfront salvage therapy with melphalan 100 mg/m(2) (MEL 100) followed by PBSC support and consolidation therapy using regimens containing thalidomide (n = 16) or bortezomib (n = 15). The overall response rate (ORR) was 58% (18/31). After MEL 100, one patient achieved complete remission (3%), 26% of pts very good partial remission, 29% of pts partial remission, and 42% of pts stable disease. Progression within 3 months after MEL 100 occurred in 35% of pts. The median follow-up from MEL 100 was 8 months. The median TTP was 5 months (range, 2-15 months), and the median OS was 8 months (range, 3-23 months). There were no treatment-related deaths. In fulminant progression of MM, upfront MEL 100 is a safe salvage regimen with good response rate (ORR, 58%). Treatment with upfront MEL 100 followed by a thalidomide- or bortezomib-based regimen can prolong overall survival to more than 12 months in 33% of pts with fulminant progression of MM.

Monoclonal gammopathy-associated IgA pemphigus is a debilitating skin disorder with inconsistent response to treatment. A 61-year-old woman with IgA pemphigus and monoclonal gammopathy of unknown significance had been treated unsuccessfully with cyclophosphamide/dexamethasone and then with rituximab. When the monoclonal gammopathy progressed to multiple myeloma, the patient received treatment with cyclophosphamide/doxorubicin/dexamethasone but there was no clinical response. Second-line therapy with a thalidomide/cyclophosphamide/dexamethasone combination led to severe exacerbation of the skin disorder. However, therapy with a combination regimen that included bortezomib, cyclophosphamide and dexamethasone resulted in complete and durable remission of multiple myeloma and IgA pemphigus. This suggests that bortezomib-based therapy is useful for the treatment of the rare dermatologic disorder associated with IgA gammopathy.

The prognostic significance of 1q21 gain, del(13)(q14), del(17)(p13), t(4;14)(p16.3;q32), and t(11;14)(q13;q32) detected by interphase fluorescein in situ hybridization (FISH) was studied in a cohort of 91 patients with newly diagnosed multiple myeloma (MM). 1q21 gain was detected in 37 of 91 patients (40.7%). In comparison with patients lacking 1q21 gain, patients with 1q21 gain had significantly shorter progression-free survival (PFS) (14.9 versus 27.4 months; P = .044) and worse 4-year overall survival (OS) (40.1% versus 76.2% of patients; P = <.001). PFS or OS were not influenced by the presence or absence of the other studied chromosomal abnormalities. Although the occurrence of 1q21 gain correlated with deletion of 13q14, the presence of 1q21 gain can be considered an independent prognostic factor, as no impact of del(13)(q14) as an isolated chromosomal abnormality on either PFS or OS has been observed. In comparison with patients lacking 1q21 gain, patients with 1q21 gain were significantly more likely to discontinue the preplanned treatment protocol because of disease progression or death. We conclude that 1q21 gain defines a prognostically unfavorable group of MM patients., (Copyright (c) 2010 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

In the phase 3 BOSTON study, patients with multiple myeloma (MM) after 1-3 prior regimens were randomized to once-weekly selinexor (an oral inhibitor of exportin 1 [XPO1]) plus bortezomib-dexamethasone (XVd) or twice-weekly bortezomib-dexamethasone (Vd). Compared with Vd, XVd was associated with significant improvements in median progression-free survival (PFS), overall response rate (ORR), and lower rates of peripheral neuropathy, with trends in overall survival (OS) favoring XVd. In BOSTON, 141 (35.1%) patients had MM with high-risk (presence of del[17p], t[4;14], t[14;16], or ≥4 copies of amp1q21) cytogenetics (XVd, n = 70; Vd, n = 71), and 261 (64.9%) exhibited standard-risk cytogenetics (XVd, n = 125; Vd, n = 136). Among patients with high-risk MM, median PFS was 12.91 months for XVd and 8.61 months for Vd (HR, 0.73 [95% CI, (0.4673, 1.1406)], p = 0.082), and ORRs were 78.6% and 57.7%, respectively (OR 2.68; p = 0.004). In the standard-risk subgroup, median PFS was 16.62 months for XVd and 9.46 months for Vd (HR 0.61; p = 0.004), and ORRs were 75.2% and 64.7%, respectively (OR 1.65; p = 0.033). The safety profiles of XVd and Vd in both subgroups were consistent with the overall population. These data suggest that selinexor can confer benefits to patients with MM regardless of cytogenetic risk. ClinicalTrials.gov identifier: NCT03110562.