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Simple Summary: Outcomes for high-risk myeloma patients are still poor, despite many advances in treatment. In addition, scarce data exist on double maintenance in transplant-eligible high-risk newly diagnosed multiple myeloma (NDMM) patients. We present the results of a prospective study on 120 transplant-eligible NDMM patients with prolonged cytogenetic risk-based all-oral maintenance with lenalidomide + ixazomib (IR) for high-risk patients and lenalidomide (R) alone for non-high-risk patients after ixazomib–lenalidomide–dexamethasone (IRD) induction plus autologous stem cell transplantation followed by IRD consolidation. We found that high-risk cytogenetics had no impact on the proportion of patients achieving sustained undetectable minimal residual disease or on the rate of progression-free survival with IR maintenance. Our data suggest that prolonged use of all-oral double maintenance with IR with reasonable adverse effects would be a potential option for high-risk myeloma patients. Scarce data exist on double maintenance in transplant-eligible high-risk (HR) newly diagnosed multiple myeloma (NDMM) patients. This prospective phase 2 study enrolled 120 transplant-eligible NDMM patients. The treatment consisted of four cycles of ixazomib–lenalidomide–dexamethasone (IRD) induction plus autologous stem cell transplantation followed by IRD consolidation and cytogenetic risk-based maintenance therapy with lenalidomide + ixazomib (IR) for HR patients and lenalidomide (R) alone for NHR patients. The main endpoint of the study was undetectable minimal residual disease (MRD) with sensitivity of <10−5 by flow cytometry at any time, and other endpoints were progression-free survival (PFS) and overall survival (OS). We present the preplanned analysis after the last patient has been two years on maintenance. At any time during protocol treatment, 28% (34/120) had MRD < 10−5 at least once. At two years on maintenance, 66% of the patients in the HR group and 76% in the NHR group were progression-free (p = 0.395) and 36% (43/120) were CR or better, of which 42% (18/43) had undetectable flow MRD <10−5. Altogether 95% of the patients with sustained MRD <10−5, 82% of the patients who turned MRD-positive, and 61% of those with positive MRD had no disease progression at two years on maintenance (p < 0.001). To conclude, prolonged maintenance with all-oral ixazomib plus lenalidomide might improve PFS in HR patients. [ABSTRACT FROM AUTHOR]

Abstract: Lenalidomide (Len) plus dexamethasone (Dex) is approved for the treatment of relapsed or refractory multiple myeloma (RRMM). It is possible that single‐agent Len may be effective as prolonged treatment regimen in RRMM once patients demonstrate an initial response to Len+Dex induction. Patients with RRMM who responded to first‐line Len+Dex in an observational study (NCT01430546) received up to 24 cycles of either Len (25 mg/day) or Len+Dex (25 mg/day and 40 mg/week) as prolonged treatment in a subsequent phase 2 clinical trial (NCT01450215). In the observational study (N = 133), median time to response was 1.7 (range 0.6–9.6) months. A complete response to all treatments received in both studies was observed in 11% of patients; very good partial response and partial response rates were 31% and 38%, respectively. Corresponding response rates in the subgroup of patients who did not enter the phase 2 trial (n = 71) were 3%, 18%, and 39%, respectively. Rates of disease progression at 2 years in the phase 2 trial were 47% versus 31% for Len versus Len+Dex (P = 0.14). After 36 months median follow‐up in surviving patients, median time to progression was not reached with Len+Dex and was 24.9 months (95% confidence interval 12.5–not calculable, P < 0.001) with Len. Three‐year OS among the total observational study population was 61% (95% CI, 52–69%). The corresponding rate among patients who entered the phase 2 clinical trial was 73% (95% CI, 60–83%) and was significantly lower among those patients who achieved ≥PR but did not proceed into the phase 2 trial (55%; P = 0.01). In the phase 2 trial, OS was 73% in both treatment arms (P = 0.70). Neutropenia and thrombocytopenia were more common with prolonged (phase 2 trial) versus short‐term (observational study) Len administration but remained manageable. Prolonged treatment with Len with or without Dex provides sustained, clinically relevant responses and demonstrates an acceptable safety profile. [ABSTRACT FROM AUTHOR]

Objectives Heavily pretreated patients with relapsed and refractory multiple myeloma are susceptible to treatment-related adverse events (AEs). Managing AEs are important to ensure patients continue therapy long enough to receive the best clinical benefit. Data from the MM-002, MM-003, and MM-010 trials were pooled to further characterize the safety profile of pomalidomide plus low-dose dexamethasone and AE management. Methods This analysis included 1088 patients who received ≥ 2 prior therapies, including lenalidomide and bortezomib, and progressed ≤ 60 days of last therapy. Patients received 28-day cycles of pomalidomide 4 mg/day on days 1-21 and low-dose dexamethasone 40 mg (20 mg if aged > 75 years) weekly until disease progression or unacceptable toxicity. Thromboprophylaxis was required. Results The most common grade 3/4 AEs were neutropenia (56.2%), anemia (32.3%), and thrombocytopenia (25.8%), which occurred within the first few cycles of treatment. Grade 3/4 infections occurred in 33.7% patients, of whom 13.9% had pneumonia, and 40.3% had neutropenia. Pomalidomide dose reductions or interruptions were reported in 24.2% and 66.0% of patients, respectively. AEs were managed by dose modifications and/or supportive care. Conclusions Pomalidomide plus low-dose dexamethasone showed an acceptable safety profile, and AEs were well managed according to study protocols and established guidelines. [ABSTRACT FROM AUTHOR]

Background: Smoldering multiple myeloma (SMM) is an indolent disease stage, considered to represent the transition phase from the premalignant MGUS (Monoclonal Gammopathy of Undetermined Significance) state towards symptomatic multiple myeloma (MM). Even though this diagnosis provides an opportunity for early intervention, few treatment studies have been done and the current standard of care is observation until progression. BI-505, a monoclonal antibody directed against intercellular adhesion molecule 1 (ICAM-1) with promising anti-myeloma activity in preclinical trials, is a possible treatment approach for this patient category with potential to eliminate tumor cells with minimal long-term side effects. BI-505 was well tolerated in an earlier phase 1 trial. Methods and findings: In this phase 2 trial the effects of BI-505 in patients with SMM were studied. Four patients were enrolled and three of them completed the first cycle of treatment defined as 5 doses of BI-505, a total of 43 mg/kg BW, over a 7-week period. In the three evaluable patients, BI-505 showed a benign safety profile. None of the patients achieved a response as defined per protocol. EudraCT number: 2012-004884-29. Conclusions: The study was conducted to assess the efficacy, safety and pharmacodynamics of BI-505 in patients with SMM. BI-505 showed no clinically relevant efficacy on disease activity in these patients with SMM, even if well tolerated. Trial registration: ClinicalTrials.gov Identifier: . [ABSTRACT FROM AUTHOR]

The Health outcomes and Understanding of MyelomA multi-National Study (HUMANS) was a large-scale, retrospective study conducted across Denmark, Finland and Sweden using linked data from national registries. We describe the characteristics, treatment patterns and clinical outcomes for patients with newly diagnosed multiple myeloma (NDMM) over 2010–2018. Patients with NDMM who received MM-specific, first-line treatments, were categorised by treatment (autologous stem cell transplantation [ASCT] or a combination chemotherapy regimen based on bortezomib, lenalidomide or melphalan-prednisolone-thalidomide). 11,023 patients received treatment over 2010–2018. Time between diagnosis and treatment was shortest in Denmark (0.9 months), then Sweden (2.9 months) and Finland (4.6 months). Around one third of patients underwent ASCT. Lenalidomide-based regimens were prescribed to 23–28% of patients in Denmark and Finland, versus 12% in Sweden. Patients receiving lenalidomide had the longest wait for treatment, from 3.2 months (Denmark) to 12.1 months (Sweden). Treatment persistence was highest among patients receiving melphalan-prednisolone-thalidomide (7–8 months) in Finland and Sweden and lowest among those receiving bortezomib (3.5 months) in Finland. Overall survival (OS) was longest among patients with ASCT (7–10 years). Among patients receiving chemotherapy, OS (from diagnosis/treatment initiation), varied between cohorts. In a sensitivity analysis excluding patients with smouldering MM, OS decreased for all; for patients receiving bortezomib or lenalidomide, OS from diagnosis was 40–49 and 27–54 months, respectively. This population-based study of patients with NDMM receiving first-line MM-specific treatment, provides real-world data on treatment patterns and outcomes to complement data from randomised clinical trials. • Nordic patient registry data provide real-world evidence on treatments and outcomes. • Over 11,000 patients treated for multiple myeloma (2010–2018) in Nordic countries. • Time from diagnosis to treatment was shortest in Denmark. • Treatment persistence was highest in patients on melphalan-prednisolone-thalidomide. • Longest overall survival seen in patients with autologous stem cell transplantation. [ABSTRACT FROM AUTHOR]

The combination of melphalan, prednisone, and thalidomide (MPT) is considered standard therapy for newlydiagnosed patientswithmultiplemyelomawho are ineligible for stem cell transplantation. Long-term treatment with thalidomide is hampered by neurotoxicity. Melphalan, prednisone, and lenalidomide, followed by lenalidomide maintenance therapy, showed promising results without severe neuropathy emerging. We randomly assigned 668 patients between nine 4-week cycles of MPT followed by thalidomide maintenance until disease progression or unacceptable toxicity (MPT-T) and thesameMP regimen with thalidomide being replaced by lenalidomide (MPR-R). This multicenter, open-label, randomized phase 3 trial was undertaken by Dutch-BelgiumCooperative Trial Group for Hematology Oncology and the Nordic Myeloma Study Group (the HOVON87/ NMSG18 trial). The primary end point was progression-free survival (PFS). A total of 318 patients were randomly assigned to receive MPT-T, and 319 received MPR-R. After a median follow-up of 36 months, PFS with MPT-T was 20 months (95% confidence interval [CI], 18-23 months) vs 23 months (95%CI, 19-27months)withMPR-R (hazard ratio, 0.87; 95% CI, 0.72-1.04; P = .12). Response rates were similar, with at least a very good partial response of 47% and 45%, respectively. Hematologic toxicity was more pronounced with MPR-R, especially grades 3 and 4 neutropenia: 64% vs 27%. Neuropathy of at least grade 3 was significantly higher in the MPT-T arm: 16% vs 2% in MPR-R, resulting in a significant shorter duration of maintenance therapy (5 vs 17 months in MPR-R), irrespective of age. MPR-R has no advantage over MPT-T concerning efficacy. The toxicity profile differed with clinically significant neuropathy during thalidomide maintenance vs myelosuppression with MPR. [ABSTRACT FROM AUTHOR]

Molecular characterization of malignant plasma cells is increasingly important for diagnostic and therapeutic stratification in multiple myeloma. However, the malignant plasma cells represent a relatively small subset of bone marrow cells, and need to be enriched prior to analysis. Currently, the cell surface marker CD138 (SDC1) is used for this enrichment, but has an important limitation in that its expression decreases rapidly after sampling. Seeking alternatives to CD138, we performed a computational screen for myeloma plasma cell markers and systematically evaluated 7 candidates. Our results conclusively show that the markers CD319 (SLAMF7/CS1) and CD269 (TNFRSF17/BCMA) are considerably more robust than CD138 and enable isolation of myeloma plasma cells under more diverse conditions, including the samples that have been delayed or frozen. Our results form the basis of improved procedures for characterizing cases of multiple myeloma in clinical practice. [ABSTRACT FROM AUTHOR]

High-dose melphalan with autologous hematopoietic stem cell transplantation (ASCT) is the standard of care for younger patients with newly diagnosed multiple myeloma and is aimed at achieving as deep and complete a response as possible after various combinations of induction therapy. However, it is frequently associated with infectious complications. This study investigated the effects of high-dose treatment with autologous stem cell support on patients' innate immunity, with a focus on subpopulations and functioning of recently released polymorphonuclear leukocytes (PMNs) and monocytes in peripheral blood. Flow cytometry-based analysis was used to measure the degree of PMN maturation and activation, before and after ASCT and compared with healthy controls. After high-dose treatment and ASCT, a smaller proportion of patients' PMNs had the capacity for oxidative burst. Moreover, patients' PMNs, both before and after ASCT, had a reduced capacity for phagocytosis. Eosinophils, which recently have been suggested to play a role in promoting malignant plasma cell proliferation, were markedly reduced after ASCT, with slow regeneration. HLA-DR expression by monocytes was significantly depressed after ASCT, a characteristic often attributed to monocytic myeloid-derived suppressor cells. Our results suggest that several aspects of phagocytic function are impaired for at least 20 days after ASCT. [ABSTRACT FROM AUTHOR]