Induction and consolidation with a quadruplet therapy of a CD38-targeting monoclonal antibody, a proteasome inhibitor, an immunomodulatory drug and dexamethasone are a standard-of-care treatment in transplant-eligible (TE) patients with newly diagnosed multiple myeloma (NDMM) with the optimal drugs to be used still under debate. The ongoing, phase 3 EMN24 IsKia trial randomized 302 TE patients with NDMM aged ≤70 years 1:1 to isatuximab–carfilzomib–lenalidomide–dexamethasone (Isa-KRd) versus KRd pretransplant induction and post-transplant consolidation. The primary endpoint was the rate of measurable residual disease (MRD) negativity (sensitivity of 10 ⁻⁵ or better) by next-generation sequencing (NGS) after consolidation. Key secondary endpoints were the rates of NGS-MRD negativity after induction and progression-free survival (PFS). MRD negativity rates at higher sensitivity (10 ⁻⁶ or better) were exploratory. Post-consolidation MRD negativity was significantly higher with Isa-KRd versus KRd at the 10 ⁻⁵ (77% versus 67%; odds ratio (OR) 1.67, P = 0.049) and 10 ⁻⁶ (68% versus 48%; OR 2.36, P = 0.0004) sensitivities. Deep MRD responses were rapid (post-induction Isa-KRd versus KRd: 10 ⁻⁵ 46% versus 27%, OR 2.32, P = 0.0007; 10 ⁻⁶ 28% versus 14%, OR 2.44, P = 0.0029) and durable (1-year sustained 10 ⁻⁶ MRD negativity 52% versus 38%, OR 1.82, P = 0.012). At current follow-up, PFS data were immature. Grade 3–4 non-hematologic adverse events (AEs), treatment discontinuations and deaths due to AEs were similar in the two arms. Isa-KRd significantly improved NGS-MRD negativity in TE patients with NDMM, with a manageable safety profile. ClinicalTrials.gov registration: NCT04483739 .

Multiple myeloma (MM) is associated with increased venous thromboembolism (VTE) risk. Current guidelines recommend aspirin or low-molecular-weight heparin for thromboprophylaxis depending on VTE risk. Nevertheless, VTE risks remain high: a recent meta-analysis reported an incidence of 6.2% during the entire MM course. Direct oral anticoagulants (DOACs) showed promising results in other malignancies. This systematic review provides an overview of evidence on DOAC thromboprophylaxis in MM. PubMed and Embase were searched up to November 21, 2023, for studies evaluating MM and DOAC thromboprophylaxis (PROSPERO: CRD42022376152). Two authors independently screened titles, abstracts, and texts, assessed bias using a modified version of the Newcastle Ottawa Scale and certainty of evidence with the Grading of Recommendations Assessment, Development and Evaluation approach, and performed data extraction and analysis. Seven articles comprising 416 patients with DOAC thromboprophylaxis were included, primarily involving newly diagnosed patients with MM (56.3%) receiving lenalidomide-based regimens (69.1%). Overall Newcastle Ottawa Scale study quality was moderate. Four studies reported follow-up duration ranging from 90 days after induction to 7 months. VTE proportions ranged from 0% to 23.5%, with 4 studies reporting 0%. The proportions of minor, clinically relevant nonmajor, and major bleeding ranged from 0% to 18.2%, 0% to 7.7%, and 0% to 4.5%, respectively. Arterial thrombosis proportions ranged from 0% to 2.9%. Only 2 studies reported on mortality (2% and 7.1%). Overall Grading of Recommendations Assessment, Development and Evaluation certainty of evidence was very low for all outcomes. Current evidence regarding routine DOACs in MM is insufficient, warranting further research to establish the DOAC thromboprophylaxis risk-to-benefit ratio in MM.

In the primary analysis of ANDROMEDA, addition of subcutaneous daratumumab to bortezomib/cyclophosphamide/dexamethasone (D-VCd) significantly improved hematologic complete response (CR) rate versus VCd, establishing D-VCd as the only approved therapy for light-chain (AL) amyloidosis. We present results from the preplanned final analysis. In this phase 3 trial, we randomly assigned 388 patients with newly diagnosed AL amyloidosis to six cycles of VCd alone (control group) or with subcutaneous daratumumab (D-VCd) followed by single-agent daratumumab every 4 weeks for up to 24 total cycles. The primary endpoint was hematologic CR. The updated hematologic CR rate was 59.5% for D-VCd versus 19.2% for VCd (odds ratio, 6.03; 95% confidence interval [CI], 3.80-9.58; P<0.0001). Median time to hematologic CR was shorter with D-VCd (67.5 days [range, 8.0-879.0]) versus VCd (85.0 days [range, 14.0-617.0]). With a median follow-up of 61.4 months, significant improvement was observed with D-VCd versus VCd in major organ deterioration-progression-free survival (hazard ratio, 0.44; 95% CI, 0.31-0.63; P<0.0001) and overall survival (hazard ratio, 0.62; 95% CI, 0.42-0.90; P=0.0121). Cardiac and renal response rates were 2-3 times higher with D-VCd versus VCd. Achieving hematologic or cardiac CR was associated with improved major organ deterioration-progression-free survival and overall survival. Adverse events were consistent with the known safety profiles for VCd and daratumumab. Adding daratumumab to VCd resulted in deeper and more rapid hematologic responses and recovery of organ function, translating to statistically significant improvement in both overall survival and major organ deterioration-progression-free survival in newly diagnosed AL amyloidosis. ClinicalTrials.gov NCT03201965.

Objective: To study the outcome of patients with AL amyloidosis who were ineligible for high dose melphalan (HDM) and autologous stem cell transplantation (ASCT). Methods: A real-life retrospective observational cohort study of Dutch patients with AL amyloidosis ineligible for HDM and ASCT was performed at the University Medical Center Groningen from January 2001 until April 2017. Primary outcome measure was overall survival (OS). Secondary outcome measures were hematological response (HR), organ responses, and treatment toxicity. Results: Eighty-four patients were included. Ineligibility was due to NYHA class III/IV (n = 58), otherwise advanced disease (n = 11), advanced age (n = 14), or treatment refusal (n = 1). Early death (<3 months) rate was high (44%). Median OS improved from 4 months in period 2001–2009 (n = 36) to 8 months in period 2009–2017 (n = 48, p = .02). HR was seen in 29%, and 42% of the patients, respectively. Median OS was 36 months after induction treatment with bortezomib (n = 32) and 18 months with immunomodulatory imide drug (IMID) (n = 16), both higher than median OS (7 months) with other regimens (n = 27). Incidence of toxicity was high (51%). Conclusion: OS improved in this high-risk group over the years, especially after introduction of new treatment modalities. However, early death rate remains high, illustrating the need for more effective treatment.

Introduction: The introduction of new treatments over the past 2 decades has improved survival outcomes in patients with multiple myeloma (MM), yet MM remains incurable. Despite therapeutic advances, most patients with MM eventually relapse and/or become refractory to treatment, and cycle through standard drug classes of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies (mAbs), becoming triple-class exposed. These triple-class exposed patients represent a population with an urgent unmet clinical need and are a major focus for the development of new therapies. There are currently no prospective data outside of clinical trials on standard-of-care (SOC) in MM patients who progress after these treatment regimens. LocoMMotion (NCT04035226) is the first prospective study to assess the efficacy and safety of real-life SOC treatments in triple-class exposed patients with relapsed/refractory MM (RRMM). Initial analysis at a median follow-up of 3.7 months (range: 0.0-12.7) showed an overall response rate (ORR) of 20.1% (95% CI: 15.0-26.0), with only 5% of patients achieving very good partial response or better. Here, we report updated results from LocoMMotion with a longer median duration of follow-up (7.8 months), along with progression-free survival (PFS) and overall survival (OS) data. Methods: LocoMMotion is a non-interventional study of 246 patients across 10 countries (the US and 9 in Europe) and 75 sites. Patients (aged ≥18 years) with a documented diagnosis of MM were included if they received ≥3 prior lines of therapy or were double-refractory to a PI and IMiD; had measurable disease at screening; received at least a PI, an IMiD, and anti-CD38 mAb with documented progressive disease since their last line of therapy; and had an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1. Patient-level data and the most common SOC treatments were collected and analyzed during the study period (August 2019 through October 2020). Real-life SOC treatments were defined as those used in local clinical practice. Responses were assessed per International Myeloma Working Group response criteria. A review committee assessed the ORR (primary objective) of real-life current SOC as well as disease progression for the determination of PFS. Secondary objectives included evaluation of additional efficacy endpoints, including OS, and safety. Results: As of the data cut-off date of March 9, 2021, 246 patients were included with a median follow-up of 7.8 months (range: 0.1-16.9); 23 (9.3%) patients were from the US and 223 (90.7%) were from Europe. Median age was 68 years (range: 41-89), 133 (54.1%) were male, 180 (73.8%) had a baseline ECOG PS score of 1, and median time since initial MM diagnosis was 6.3 years (range: <1.0-22.8). Patients had received a median of 4.0 prior lines of therapy (range: 2-13); all patients were triple-class exposed, 185 (75.2%) were triple-class refractory, and 228 (92.7%) were refractory to last line of therapy. Ninety-three unique treatment regimens were used in the enrolled population, and 63% of patients were treated with a combination of ≥3 drugs. ORR with real-life SOC salvage therapy was 28.0% (95% CI: 22.5-34.1). For the 69 patients who responded, median duration of response was 5.1 months (95% CI: 4.4-NE). In all patients treated, the median PFS was 4.4 months (95% CI: 3.8-5.4), and median OS was 12.4 months (95% CI: 9.6-NE). Treatment-emergent adverse events (TEAEs) were reported in 192 (78.0%) patients; 122 (49.6%) patients had grade ≥3 TEAEs. The most common grade ≥3 TEAEs were anemia (9.8%), thrombocytopenia (13.4%), and neutropenia (11.8%). Nineteen (7.7%) patients died due to TEAEs during the study; the most common TEAE leading to death was infection (n=11). Eighty (32.5%) patients had ongoing SOC treatment after the median follow up of 7.8 months. The study is ongoing in 147 (59.8%) patients. Conclusions: Updated results of this first, prospective study of real-life SOC treatment in triple-class exposed patients with RRMM confirm rapid disease progression after application of salvage therapy and poor outcomes with currently available treatments. New treatment approaches with novel therapies are needed to improve outcomes in this patient population.