Cereblon gene expression and correlation with clinical outcomes in patients with relapsed/refractory multiple myeloma treated with pomalidomide: an analysis of STRATUS

We analyzed gene expression levels of CRBN, cMYC, IRF4, BLIMP1, and XBP1 in 224 patients with multiple myeloma treated with pomalidomide and low-dose dexamethasone in the STRATUS study (ClinicalTrials.gov: NCT01712789; EudraCT number: 2012-001888-78). Clinical responses were observed at all CRBN expression levels. A trend in progression-free survival (PFS; p = .038) and a potential trend in overall survival (OS; p = .059) favoring high CRBN expressers were observed; however, no notable difference in overall response rate (ORR) was observed. ORR (30%), median PFS (17.7 weeks), and median OS (52.3 weeks) in low-CRBN expressers were comparable to those in the STRATUS intent-to-treat population (ORR, 33%; median PFS, 20.0 weeks; median OS, 51.7 weeks). A trend in ORR (p = .050) favoring higher cMYC expressers was observed with no notable difference in PFS or OS. This analysis does not support exploring CRBN as a biomarker for selecting patients for pomalidomide therapy.The authors received editorial assistance from William Ho, PhD, and Peter J Simon, PhD, funded by Celgene Corporation

Deepening responses associated with improved progression-free survival with ixazomib versus placebo as posttransplant maintenance in multiple myeloma

n/

Pomalidomide – An Appraisal of Its Clinical Development and Role in the Treatment of Relapsed/Refractory Multiple Myeloma

Pomalidomide is a distinct immunomodulatory agent with significant activity in relapsed/refractory multiple myeloma (RRMM). The optimal treatment schedule in patients with RRMM who have received multiple lines of treatment, including bortezomib and lenalidomide, is 4 mg/day on days 1–21 of a 28-day cycle in combination with weekly low-dose dexamethasone. Improved responses and outcomes relative to traditional therapies continue to be confirmed in recently completed and ongoing trials. Pomalidomide exhibits direct tumoricidal, immunomodulatory, anti-angiogenic and anti-inflammatory activities, which facilitate combination therapy with agents with complementary mechanisms of action, resulting in greater anti-myeloma effects than single-agent therapy or previous combination therapies. For example, in combination with proteasome inhibitors and traditional chemotherapeutic agents in doublet or triplet regimens, pomalidomide provides high rates of durable response, and represents an important new treatment option for patients with RRMM requiring effective new therapies. Additionally, pomalidomide maintains its efficacy and tolerability profile in difficult-to-treat patients, including the elderly, patients with poor cytogenetics and those with renal impairment. This review summarises the clinical development of pomalidomide and discusses this effective agent for the treatment of patients with RRMM in the context of current myeloma treatment options, as well as potential future directions to further improve patient outcomes

Pomalidomide plus low-dose dexamethasone in patients with relapsed/refractory multiple myeloma and moderate renal impairment: a pooled analysis of three clinical trials

Renal impairment (RI) is a major comorbidity in patients with multiple myeloma (MM). Here we present the pooled safety and efficacy analysis of three clinical trials (MM-002, MM-003, and MM-010) of pomalidomide + low-dose dexamethasone (POM + LoDEX) in patients with moderate RI (creatinine clearance [CrCl] ≥ 30 to <60 mL/min) and without RI (≥ 60 mL/min). Trial protocols were approved by the institutional review board of each site involved. Patients with RI were older than patients without RI, although other baseline characteristics were similar. The dosing and safety profile of POM + LoDEX was similar across RI subgroups. Median overall response rate, progression-free survival, time to progression, and duration of response were not significantly different between RI subgroups. However, patients with vs. without RI had significantly shorter median overall survival (10.5 vs. 14.0 months, respectively; p = .004). This analysis demonstrates that POM + LoDEX is a safe and effective treatment for patients with moderate RI. The trials were registered at ClinicalTrials.gov as NCT00833833 (MM-002), NCT01311687 (MM-003), and NCT01712789 (MM-010) and at EudraCT as 2010-019820-30 (MM-003) and 2012-001888-78 (MM-010)

Daratumumab, Bortezomib, and Dexamethasone Versus Bortezomib and Dexamethasone in Patients With Previously Treated Multiple Myeloma: Three-year Follow-up of CASTOR

Background: In the phase III CASTOR study in relapsed or refractory multiple myeloma, daratumumab, bortezomib, and dexamethasone (D-Vd) demonstrated significant clinical benefit versus Vd alone. Outcomes after 40.0 months of median follow-up are discussed. Patients and Methods: Eligible patients had received ≥ 1 line of treatment and were administered bortezomib (1.3 mg/m2) and dexamethasone (20 mg) for 8 cycles with or without daratumumab (16 mg/kg) until disease progression. Results: Of 498 patients in the intent-to-treat (ITT) population (D-Vd, n = 251; Vd, n = 247), 47% had 1 prior line of treatment (1PL; D-Vd, n = 122; Vd, n = 113). Median progression-free survival (PFS) was significantly prolonged with D-Vd versus Vd in the ITT population (16.7 vs. 7.1 months; hazard ratio [HR], 0.31; 95% confidence interval [CI], 0.25-0.40; P < .0001) and the 1PL subgroup (27.0 vs. 7.9 months; HR, 0.22; 95% CI, 0.15-0.32; P < .0001). In lenalidomide-refractory patients, the median PFS was 7.8 versus 4.9 months (HR, 0.44; 95% CI, 0.28-0.68; P = .0002) for D-Vd (n = 60) versus Vd (n = 81). Minimal residual disease (MRD)–negativity rates (10−5) were greater with D-Vd versus Vd (ITT: 14% vs. 2%; 1PL: 20% vs. 3%; both P < .0001). PFS2 was significantly prolonged with D-Vd versus Vd (ITT: HR, 0.48; 95% CI, 0.38-0.61; 1PL: HR, 0.35; 95% CI, 0.24-0.51; P < .0001). No new safety concerns were observed. Conclusion: After 3 years, D-Vd maintained significant benefits in patients with relapsed or refractory multiple myeloma with a consistent safety profile. D-Vd provided the greatest benefit at first relapse and increased MRD-negativity rates.CASTOR showed the significant clinical benefit of daratumumab plus bortezomib and dexamethasone for patients with previously treated multiple myeloma. With ∼3 years median follow-up, this regimen continues to demonstrate significantly improved progression-free survival with higher minimal residual dis

Meta-analysis of ciltacabtagene autoleucel versus physician’s choice therapy for the treatment of patients with relapsed or refractory multiple myeloma

[Objective]: In the absence of head-to-head trials, indirect treatment comparisons (ITCs) between ciltacabtagene autoleucel (cilta-cel; in CARTITUDE-1) and treatments used in real-world clinical practice (physician’s choice of treatment [PCT]), were previously conducted. We conducted multiple meta-analyses using available ITC data to consolidate the effectiveness of cilta-cel versus PCT for patients with triple-class exposed relapsed or refractory multiple myeloma (RRMM). [Methods]: Five ITCs were assessed for similarity to ensure robust comparisons using meta-analysis. Effectiveness outcomes were overall survival (OS), progression-free survival (PFS), time to next treatment (TTNT), and overall response rate (ORR). A robust variance estimator was used to account for the use of CARTITUDE-1 in each pairwise ITC. Analyses were conducted in both treated and enrolled populations of CARTITUDE-1. [Results]: Four ITCs were combined for evaluation of OS. Results were statistically significantly in favor of cilta-cel versus PCT in treated patients (hazard ratio [HR]: 0.24, 95% confidence interval [CI]: 0.22–0.26). Three ITCs were combined for evaluation of PFS and TTNT. Cilta-cel reduced the risk of progression and receiving a subsequent treatment by 80% (HR: 0.20 [95% CI: 0.06, 0.70]) and 83% (HR: 0.17 [95% CI: 0.12, 0.26]), respectively. Three ITCs were combined for evaluation of ORR. Cilta-cel increased the odds of achieving an overall response by 86-times versus PCT in treated patients. Findings were consistent in the enrolled populations and across sensitivity analyses. [Conclusions]: Evaluating multiple indirect comparisons, cilta-cel demonstrated a significantly superior advantage over PCT, highlighting its effectiveness as a therapy in patients with triple-class exposed RRMM.The CARTITUDE-1 study and these analyses were funded by Janssen Research & Development, LLC, and Legend Biotech, Inc. Medical writing support was provided by EVERSANA and funded by Janssen Global Services, LLC

LocoMMotion:a prospective, non-interventional, multinational study of real-life current standards of care in patients with relapsed and/or refractory multiple myeloma

Despite treatment advances, patients with multiple myeloma (MM) often progress through standard drug classes including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies (mAbs). LocoMMotion (ClinicalTrials.gov identifier: NCT04035226) is the first prospective study of real-life standard of care (SOC) in triple-class exposed (received at least a PI, IMiD, and anti-CD38 mAb) patients with relapsed/refractory MM (RRMM). Patients (N = 248; ECOG performance status of 0–1, ≥3 prior lines of therapy or double refractory to a PI and IMiD) were treated with median 4.0 (range, 1–20) cycles of SOC therapy. Overall response rate was 29.8% (95% CI: 24.2–36.0). Median progression-free survival (PFS) and median overall survival (OS) were 4.6 (95% CI: 3.9–5.6) and 12.4 months (95% CI: 10.3–NE). Treatment-emergent adverse events (TEAEs) were reported in 83.5% of patients (52.8% grade 3/4). Altogether, 107 deaths occurred, due to progressive disease (n = 74), TEAEs (n = 19), and other reasons (n = 14). The 92 varied regimens utilized demonstrate a lack of clear SOC for heavily pretreated, triple-class exposed patients with RRMM in real-world practice and result in poor outcomes. This supports a need for new treatments with novel mechanisms of action

Ixazomib-lenalidomide-dexamethasone in routine clinical practice: Effectiveness in relapsed/refractory multiple myeloma

[Aim]: To evaluate the effectiveness and safety of ixazomib-lenalidomide-dexamethasone (IRd) in relapsed/refractory multiple myeloma in routine clinical practice. Patients & methods: Patient-level data from the global, observational INSIGHT MM and the Czech Registry of Monoclonal Gammopathies were integrated and analyzed.[Results]: At data cut-off, 263 patients from 13 countries were included. Median time from diagnosis to start of IRd was 35.8 months; median duration of follow-up was 14.8 months. Overall response rate was 73%, median progression-free survival, 21.2 months and time-to-next therapy, 33.0 months. Ixazomib/lenalidomide dose reductions were required in 17%/36% of patients; 32%/30% of patients discontinued ixazomib/lenalidomide due to adverse events.[Conclusion]: The effectiveness and safety of IRd in routine clinical practice are comparable to those reported in TOURMALINE-MM1.This work was supported by Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited

Elotuzumab, lenalidomide, and dexamethasone in RRMM: final overall survival results from the phase 3 randomized ELOQUENT-2 study

Prolonging overall survival (OS) remains an unmet need in relapsed or refractory multiple myeloma (RRMM). In ELOQUENT-2 (NCT01239797), elotuzumab plus lenalidomide/dexamethasone (ERd) significantly improved progression-free survival (PFS) versus lenalidomide/dexamethasone (Rd) in patients with RRMM and 1–3 prior lines of therapy (LoTs). We report results from the pre-planned final OS analysis after a minimum follow-up of 70.6 months, the longest reported for an antibody-based triplet in RRMM. Overall, 646 patients with RRMM and 1–3 prior LoTs were randomized 1:1 to ERd or Rd. PFS and overall response rate were co-primary endpoints. OS was a key secondary endpoint, with the final analysis planned after 427 deaths. ERd demonstrated a statistically significant 8.7-month improvement in OS versus Rd (median, 48.3 vs 39.6 months; hazard ratio, 0.82 [95.4% Cl, 0.68–1.00]; P = 0.0408 [less than allotted α of 0.046]), which was consistently observed across key predefined subgroups. No additional safety signals with ERd at extended follow-up were reported. ERd is the first antibody-based triplet regimen shown to significantly prolong OS in patients with RRMM and 1–3 prior LoTs. The magnitude of OS benefit was greatest among patients with adverse prognostic factors, including older age, ISS stage III, IMWG high-risk disease, and 2–3 prior LoTs

Prevention and management of adverse events of novel agents in multiple myeloma: a consensus of the European Myeloma Network

During the last few years, several new drugs have been introduced for treatment of patients with multiple myeloma, which have significantly improved the treatment outcome. All of these novel substances differ at least in part in their mode of action from similar drugs of the same drug class, or are representatives of new drug classes, and as such present with very specific side effect profiles. In this review, we summarize these adverse events, provide information on their prevention, and give practical guidance for monitoring of patients and for management of adverse events