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Background: EMD is characterized by a subclone of aggressive MM cells that thrive and grow independent of the bone marrow microenvironment and is often associated with poor-risk features including high-risk cytogenetics, increased proliferation, evasion of apoptosis, and resistance to therapies in MM (Bladé et al. J Clin Oncol. 2011;29:3805; Deng et al. Clin Lymphoma Myeloma Leuk. 2015;15:286). Prognosis for pts with EMD is poor, particularly in the RRMM setting. Additionally, prognosis is usually poorer for pts with hematogenous-spread soft-tissue plasmacytomas than for those with bone-related plasmacytomas (Gagelmann et al. Haematologica. 2018;103:890; Mangiacavalli et al. Ann Hematol. 2017;96:73). No standard therapy has been established for this high-unmet need population (Usmani et al. Blood. 2016;128:37; Jimenez-Segura et al. Eur J Haematol. 2019;102:389), and outcomes are considerably worse than those for pts without EMD; for example, a recent analysis of isatuximab + pomalidomide + dex showed a median progression free survival (PFS) of 4.6 mo vs 11.5 mo in the total population (Beksac et al. EHA 2020. Abs. EP978). Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that targets aminopeptidases and rapidly releases alkylating agents into tumor cells. In the phase 2 HORIZON study (OP-106; NCT02963493), melflufen + dex showed clinically meaningful efficacy (overall response rate [ORR], 29%; median PFS, 4.2 mo; median overall survival [OS], 11.6 mo) and a manageable safety profile in pts with heavily pretreated RRMM, including in pts with triple-class-refractory MM (Richardson et al. EHA 2020. Abs. EP945). This analysis presents additional data for the largest cohort of pts with EMD in a clinical trial setting to date. Methods: Pts with RRMM must have received ≥2 lines of prior therapy, including an IMiD and a proteasome inhibitor, and been refractory to pomalidomide and/or an anti-CD38 monoclonal antibody. Pts received melflufen 40 mg (intravenous; d1 of each 28-d cycle) and dex 40 mg/wk until progressive disease or unacceptable toxicity. The primary endpoint was ORR (≥ partial response [PR]; investigator-assessed per International Myeloma Working Group [IMWG] criteria). Secondary endpoints included PFS, OS, duration of response (DOR), and safety. For pts with known or suspected EMD, defined as either isolated soft-tissue and/or bone-related extramedullary plasmacytomas with soft-tissue extension, an assessment was required at screening and to confirm a response per IMWG criteria. Results: Of 157 pts enrolled and treated (data cutoff date, Jan 14, 2020), 55 (35%) had EMD (49% soft-tissue and 51% bone-related soft-tissue plasmacytoma). In pts with EMD, median age was 64 y (range, 43-82); median time since diagnosis was 5.6 y (range, 0.7-14.5); 35% had high-risk cytogenetics; 33% had International Staging System stage 3; median prior lines of therapy was 5 (range, 2-12); 60% had disease that was refractory to prior alkylator therapy; and 91% had triple-class-refractory MM. ORR (95% CI) was 24% (13-37) in pts with EMD and 29% (22-37) overall (N=157). In pts with EMD and the overall population, respectively, median (95% CI) DOR was 5.5 mo (1.8-not evaluable [NE]) and 5.5 mo (3.9-7.6), PFS was 2.9 mo (2.0-3.8) and 4.2 mo (3.4-4.9), and median OS was 6.5 mo (5.1-9.7) and 11.6 mo (9.3-15.4;) (Table). In pts with EMD who achieved ≥PR (n=13), median (95% CI) PFS was 17.3 mo (5.3-NE), and OS was 18.5 mo (8.7-NE). Due to low event numbers, the results in pts with ≥PR may be overestimated. The safety profile of melflufen + dex in pts with EMD was consistent with that in the overall population, with grade 3/4 treatment-emergent adverse events (TEAEs) reported in 78% and 89% of pts, respectively. In pts with EMD, the most common grade 3/4 TEAEs were anemia (42%), thrombocytopenia (40%), and neutropenia (38%); the most common nonhematologic grade 3/4 TEAE of interest was pneumonia (9%). No treatment-related deaths with melflufen + dex were reported. Conclusions: Melflufen + dex showed activity in advanced RRMM with EMD, with encouraging PFS and OS in pts with confirmed stable disease or better. The safety profile of melflufen + dex was consistent with previous reports. To date, this clinical study provides the largest cohort of pts with EMD demonstrating benefit in this population with a high unmet medical need. These data support further evaluation of melflufen + dex in RRMM with EMD. Disclosures Richardson: Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Mateos:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees. 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Harmenberg:Ultupharma AB: Current equity holder in private company; Medivir AB: Current equity holder in publicly-traded company; Oncopeptides AB: Consultancy, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Harlin:Oncopeptides AB: Consultancy, Current equity holder in publicly-traded company. Blade Creixenti:Takeda: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: This is a phase 2 investigational study of melflufen in RRMM.

In this Policy Review, the Bone Working Group of the International Myeloma Working Group updates its clinical practice recommendations for the management of multiple myeloma-related bone disease. After assessing the available literature and grading recommendations using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) method, experts from the working group recommend zoledronic acid as the preferred bone-targeted agent for patients with newly diagnosed multiple myeloma, with or without multiple myeloma-related bone disease. Once patients achieve a very good partial response or better, after receiving monthly zoledronic acid for at least 12 months, the treating physician can consider decreasing the frequency of or discontinuing zoledronic acid treatment. Denosumab can also be considered for the treatment of multiple myeloma-related bone disease, particularly in patients with renal impairment. Denosumab might prolong progression-free survival in patients with newly diagnosed multiple myeloma who have multiple myeloma-related bone disease and who are eligible for autologous stem-cell transplantation. Denosumab discontinuation is challenging due to the rebound effect. The Bone Working Group of the International Myeloma Working Group also found cement augmentation to be effective for painful vertebral compression fractures. Radiotherapy is recommended for uncontrolled pain, impeding or symptomatic spinal cord compression, or pathological fractures. Surgery should be used for the prevention and restoration of long-bone pathological fractures, vertebral column instability, and spinal cord compression with bone fragments within the spinal route. © 2021 Elsevier Ltd

In this Policy Review, the Bone Working Group of the International Myeloma Working Group updates its clinical practice recommendations for the management of multiple myeloma-related bone disease. After assessing the available literature and grading recommendations using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) method, experts from the working group recommend zoledronic acid as the preferred bone-targeted agent for patients with newly diagnosed multiple myeloma, with or without multiple myeloma-related bone disease. Once patients achieve a very good partial response or better, after receiving monthly zoledronic acid for at least 12 months, the treating physician can consider decreasing the frequency of or discontinuing zoledronic acid treatment. Denosumab can also be considered for the treatment of multiple myeloma-related bone disease, particularly in patients with renal impairment. Denosumab might prolong progression-free survival in patients with newly diagnosed multiple myeloma who have multiple myeloma-related bone disease and who are eligible for autologous stem-cell transplantation. Denosumab discontinuation is challenging due to the rebound effect. The Bone Working Group of the International Myeloma Working Group also found cement augmentation to be effective for painful vertebral compression fractures. Radiotherapy is recommended for uncontrolled pain, impeding or symptomatic spinal cord compression, or pathological fractures. Surgery should be used for the prevention and restoration of long-bone pathological fractures, vertebral column instability, and spinal cord compression with bone fragments within the spinal route.

In this review, two types of soft-tissue involvement in multiple myeloma are defined: (i) extramedullary (EMD) with haematogenous spread involving only soft tissues and (ii) paraskeletal (PS) with tumour masses arising from skeletal lesions. The incidence of EMD and PS plasmacytomas at diagnosis ranges from 1·7% to 4·5% and 7% to 34·4% respectively. EMD disease is often associated with high-risk cytogenetics, resistance to therapy and worse prognosis than in PS involvement. In patients with PS involvement a proteasome inhibitor-based regimen may be the best option followed by autologous stem cell transplantation (ASCT) in transplant eligible patients. In patients with EMD disease who are not eligible for ASCT, a proteasome inhibitor-based regimen such as lenalidomide-bortezomib-dexamethasone (RVD) may be the best option, while for those eligible for high-dose therapy a myeloma/lymphoma-like regimen such as bortezomib, thalidomide and dexamethasone (VTD)-RVD/cisplatin, doxorubicin, cyclophosphamide and etoposide (PACE) followed by SCT should be considered. In both EMD and PS disease at relapse many strategies have been tried, but this remains a high-unmet need population. © 2021 British Society for Haematology and John Wiley & Sons Ltd

This Policy Review presents the International Myeloma Working Group's clinical practice recommendations for the treatment of relapsed and refractory multiple myeloma. Based on the results of phase 2 and phase 3 trials, these recommendations are proposed for the treatment of patients with relapsed and refractory disease who have received one previous line of therapy, and for patients with relapsed and refractory multiple myeloma who have received two or more previous lines of therapy. These recommendations integrate the issue of drug access in both low-income and middle-income countries and in high-income countries to help guide real-world practice and thus improve patient outcomes. © 2021 Elsevier Ltd

Patients with multiple myeloma are generally older and vary in fitness levels, which may influence the clinical benefit of treatment. Patients from the large, phase 3 FIRST trial in newly diagnosed multiple myeloma (NDMM) were retrospectively investigated to determine outcomes based on frailty using scores for age, Charlson Comorbidity Index (CCI), and Eastern Cooperative Oncology Group performance status (ECOG PS), instead of the EQ-5D quality-of-life questionnaire, as previously reported. ECOG PS (n = 1618) was investigated in frailty groups: frail (49%) and nonfrail (51%). Frail patients experienced worse progression-free and overall survival vs nonfrail patients. Prognostic assessment was improved when combining frailty and International Staging System stage (I/II vs III). Frail patients had a higher risk of developing grade 3/4 treatment-emergent adverse events. Treatment effects observed in the FIRST trial were confirmed per frailty group and per frailty and ISS group. The use of this ECOG PS–containing frailty scale as a predictive measure of clinical outcomes in patients with transplant-ineligible NDMM is supported by data from the FIRST trial. This score, based on age, CCI, and ECOG PS, can be easily replicated and may help design future myeloma studies in frail or nonfrail elderly patients. © 2019, The Author(s).

Smoldering multiple myeloma (SMM) is an asymptomatic precursor state of multiple myeloma (MM). Recently, MM was redefined to include biomarkers predicting a high risk of progression from SMM, thus necessitating a redefinition of SMM and its risk stratification. We assembled a large cohort of SMM patients meeting the revised IMWG criteria to develop a new risk stratification system. We included 1996 patients, and using stepwise selection and multivariable analysis, we identified three independent factors predicting progression risk at 2 years: serum M-protein >2 g/dL (HR: 2.1), involved to uninvolved free light-chain ratio >20 (HR: 2.7), and marrow plasma cell infiltration >20% (HR: 2.4). This translates into 3 categories with increasing 2-year progression risk: 6% for low risk (38%; no risk factors, HR: 1); 18% for intermediate risk (33%; 1 factor; HR: 3.0), and 44% for high risk (29%; 2–3 factors). Addition of cytogenetic abnormalities (t(4;14), t(14;16), +1q, and/or del13q) allowed separation into 4 groups (low risk with 0, low intermediate risk with 1, intermediate risk with 2, and high risk with ≥3 risk factors) with 6, 23, 46, and 63% risk of progression in 2 years, respectively. The 2/20/20 risk stratification model can be easily implemented to identify high-risk SMM for clinical research and routine practice and will be widely applicable. © 2020, The Author(s).

Background: The emergence of highly active novel agents has led some to question the role of autologous haematopoietic stem-cell transplantation (HSCT) and subsequent consolidation therapy in newly diagnosed multiple myeloma. We therefore compared autologous HSCT with bortezomib–melphalan–prednisone (VMP) as intensification therapy, and bortezomib–lenalidomide–dexamethasone (VRD) consolidation therapy with no consolidation. Methods: In this randomised, open-label, phase 3 study we recruited previously untreated patients with multiple myeloma at 172 academic and community practice centres of the European Myeloma Network. Eligible patients were aged 18–65 years, had symptomatic multiple myeloma stage 1–3 according to the International Staging System (ISS), measurable disease (serum M protein >10 g/L or urine M protein >200 mg in 24 h or abnormal free light chain [FLC] ratio with involved FLC >100 mg/L, or proven plasmacytoma by biopsy), and WHO performance status grade 0–2 (grade 3 was allowed if secondary to myeloma). Patients were first randomly assigned (1:1) to receive either four 42-day cycles of bortezomib (1·3 mg/m2 administered intravenously or subcutaneously on days 1, 4, 8, 11, 22, 25, 29, and 32) combined with melphalan (9 mg/m2 administered orally on days 1–4) and prednisone (60 mg/m2 administered orally on days 1–4) or autologous HSCT after high-dose melphalan (200 mg/m2), stratified by site and ISS disease stage. In centres with a double HSCT policy, the first randomisation (1:1:1) was to VMP or single or double HSCT. Afterwards, a second randomisation assigned patients to receive two 28-day cycles of consolidation therapy with bortezomib (1·3 mg/m2 either intravenously or subcutaneously on days 1, 4, 8, and 11), lenalidomide (25 mg orally on days 1–21), and dexamethasone (20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12) or no consolidation; both groups received lenalidomide maintenance therapy (10 mg orally on days 1–21 of a 28-day cycle). The primary outcomes were progression-free survival from the first and second randomisations, analysed in the intention-to-treat population, which included all patients who underwent each randomisation. All patients who received at least one dose of study drugs were included in the safety analyses. This study is registered with the EU Clinical Trials Register (EudraCT 2009-017903-28) and ClinicalTrials.gov (NCT01208766), and has completed recruitment. Findings: Between Feb 25, 2011, and April 3, 2014, 1503 patients were enrolled. 1197 patients were eligible for the first randomisation, of whom 702 were assigned to autologous HSCT and 495 to VMP; 877 patients who were eligible for the first randomisation underwent the second randomisation to VRD consolidation (n=449) or no consolidation (n=428). The data cutoff date for the current analysis was Nov 26, 2018. At a median follow-up of 60·3 months (IQR 52·2–67·6), median progression-free survival was significantly improved with autologous HSCT compared with VMP (56·7 months [95% CI 49·3–64·5] vs 41·9 months [37·5–46·9]; hazard ratio [HR] 0·73, 0·62–0·85; p=0·0001). For the second randomisation, the number of events of progression or death at data cutoff was lower than that preplanned for the final analysis; therefore, the results from the second protocol-specified interim analysis, when 66% of events were reached, are reported (data cutoff Jan 18, 2018). At a median follow-up of 42·1 months (IQR 32·3–49·2), consolidation therapy with VRD significantly improved median progression-free survival compared with no consolidation (58·9 months [54·0–not estimable] vs 45·5 months [39·5–58·4]; HR 0·77, 0·63–0·95; p=0·014). The most common grade ≥3 adverse events in the autologous HSCT group compared to the VMP group included neutropenia (513 [79%] of 652 patients vs 137 [29%] of 472 patients), thrombocytopenia (541 [83%] vs 74 [16%]), gastrointestinal disorders (80 [12%] vs 25 [5%]), and infections (192 [30%] vs 18 [4%]). 239 (34%) of 702 patients in the autologous HSCT group and 135 (27%) of 495 in the VMP group had at least one serious adverse event. Infection was the most common serious adverse event in each of the treatment groups (206 [56%] of 368 and 70 [37%] of 189). 38 (12%) of 311 deaths from first randomisation were likely to be treatment related: 26 (68%) in the autologous HSCT group and 12 (32%) in the VMP group, most frequently due to infections (eight [21%]), cardiac events (six [16%]), and second primary malignancies (20 [53%]). Interpretation: This study supports the use of autologous HSCT as intensification therapy and the use of consolidation therapy in patients with newly diagnosed multiple myeloma, even in the era of novel agents. The role of high-dose chemotherapy needs to be reassessed in future studies, in particular in patients with undetectable minimal residual disease after four-drug induction regimens including a monoclonal antiboby combined with an immunomodulatory agent and a proteasome inhibitor plus dexamethasone. Funding: Janssen and Celgene. © 2020 Elsevier Ltd

PURPOSE Oral melphalan and dexamethasone (MDex) were considered a standard of care in light-chain (AL) amyloidosis. In the past decade, bortezomib has been increasingly used in combination with alkylating agents and dexamethasone. We prospectively compared the efficacy and safety of MDex and MDex with the addition of bortezomib (BMDex). METHODS This was a phase III, multicenter, randomized, open-label trial. Patients were stratified according to cardiac stage. Patients with advanced cardiac stage (stage IIIb) amyloidosis were not eligible. The primary end point was hematologic response rate at 3 months. This trial is registered with ClinicalTrials.gov identifier NCT01277016. RESULTS A total of 109 patients, 53 in the BMDex and 56 in the MDex group, received $1 dose of therapy (from January 2011 to February 2016). Hematologic response rate at 3 months was higher in the BMDex arm (79% v 52%; P 5 .002). Higher rates of very good partial or complete response rates (64% v 39%; hazard ratio [HR], 2.47; 95% CI, 1.30 to 4.71) and improved overall survival, with a 2-fold decrease in mortality rate (HR, 0.50; 95% CI, 0.27 to 0.90), were observed in the BMDex arm. Grade 3 and 4 adverse events (the most common being cytopenia, peripheral neuropathy, and heart failure) were more common in the BMDex arm, occurring in 20% versus 10% of cycles performed. CONCLUSION BMDex improved hematologic response rate and overall survival. To our knowledge, this is the first time a controlled study has demonstrated a survival advantage in AL amyloidosis. BMDex should be considered a new standard of care for AL amyloidosis. © 2020 by American Society of Clinical Oncology.

Chemotherapy and extracorporeal treatment reduce serum free light chains (FLCs) allowing the recovery of acute kidney injury (AKI) caused by myeloma cast nephropathy (MCN). We report the first case of recovery from AKI in a patient with MCN who underwent the removal of FLCs using the PEPA filter, with an undisclosed cut-off, combined with chemotherapy for multiple myeloma (MM).

Survival of myeloma patients has greatly improved with the use of autologous stem cell transplantation and novel agents, such as proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies. Compared to bortezomib- and lenalidomide-based regimens alone, the addition of high-dose melphalan followed by autologous transplantation significantly improves progression-free survival; although an overall survival benefit was not observed in all trials. Moreover, follow-up of recent trials is still too short to show any difference in survival. In the light of these findings, novel agent-based induction followed by autologous transplantation is considered the standard upfront treatment for eligible patients (level of evidence: 1A). Post-transplant consolidation and maintenance treatment can further improve patient outcome (1A). The availability of several novel agents has led to the development of multiple combination regimens as salvage treatment options. In this context, the role of salvage autologous transplantation and allotransplant have not been extensively evaluated. In case of prolonged remission after upfront autologous transplantation, another autologous transplantation at relapse can be considered (2B). Patients who experience early relapse and/or have high-risk features have a poor prognosis and may be considered as candidates for clinical trials that - in young and fit patients - may also include an allograft in combination with novel agents (2B). Ongoing studies are evaluating the role of novel cellular therapies, such as inclusion of antibody-based triplets and quadruplets and Chimeric Antigen Receptor-T cells: despite preliminary encouraging results, longer follow-up and larger patient numbers are needed before their clinical use can be widely recommended.