Since the publication in 2021 of the European Hematology Association (EHA) Clinical Practice Guidelines for the treatment of patients with smouldering multiple myeloma (SMM) and multiple myeloma (MM), developed in collaboration with the European Society for Medical Oncology, a novel international staging system (R2-ISS) has been developed, several prognostic factors are entering clinical practice (such as minimal residual disease, circulating plasma cells and monoclonal protein assessed by mass spectrometry) and, at the time of writing, 14 novel regimens have been approved by the EMA and/or the FDA for the treatment of patients with MM. A multidisciplinary group of experts from the EHA and European Myeloma Network, based in various institutions mostly located in Europe, have updated the previous guidelines and produced algorithms for everyday clinical practice that incorporate levels of evidence and grades of recommendation based on the aforementioned new data. In these Evidence-Based Guidelines, we provide key treatment recommendations for both patients with newly diagnosed MM and those with relapsed and/or refractory MM, including guidance for the use of established drugs as well as contemporary immunotherapies. Novel approaches for the management of patients with SMM focus on those who might require early intervention. Finally, we provide recommendations for myeloma-related complications and adverse events, such as bone disease, renal impairment and infections, as well as for those associated with T cell-mobilizing therapies, such as cytokine-release syndrome and immune effector cell-associated neurotoxicity syndrome.

• MeSH
• Humans MeSH
• Evidence-Based Medicine MeSH
• Multiple Myeloma * diagnosis   therapy   MeSH
• Practice Guidelines as Topic * MeSH
• Neoplasm Staging MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

• MeSH
• Drug Resistance, Neoplasm MeSH
• Dexamethasone * therapeutic use   administration & dosage   MeSH
• Phenylalanine therapeutic use   analogs & derivatives   MeSH
• Quality of Life * MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Recurrence, Local drug therapy   MeSH
• Multiple Myeloma * drug therapy   MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   adverse effects   MeSH
• Recurrence MeSH
• Aged MeSH
• Treatment Outcome MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Dexamethasone * MeSH
• Phenylalanine MeSH

Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with ≥3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received ≥3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade ≥3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies.

• MeSH
• Transplantation, Autologous MeSH
• Dexamethasone therapeutic use   MeSH
• Phenylalanine * analogs & derivatives   MeSH
• Proteasome Inhibitors MeSH
• Humans MeSH
• Melphalan * analogs & derivatives   MeSH
• Multiple Myeloma * diagnosis   drug therapy   MeSH
• Antibodies, Monoclonal * MeSH
• Neoplasms, Plasma Cell * MeSH
• Neutropenia * MeSH
• Antineoplastic Combined Chemotherapy Protocols adverse effects   MeSH
• Hematopoietic Stem Cell Transplantation * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Randomized Controlled Trial MeSH
• Geographicals
• United States MeSH
• Names of Substances
• daratumumab MeSH Browser
• Dexamethasone MeSH
• Phenylalanine * MeSH
• Proteasome Inhibitors MeSH
• Melphalan * MeSH
• melflufen MeSH Browser
• Antibodies, Monoclonal * MeSH

Melphalan flufenamide (melflufen), a first-in-class, alkylating peptide-drug conjugate, demonstrated clinical benefit in combination with dexamethasone in triple-class refractory multiple myeloma (MM). The phase I/IIa ANCHOR study evaluated melflufen (30 or 40 mg) and dexamethasone (40 mg with daratumumab; 20 mg followed by 40 mg with bortezomib; dose reduced if aged ≥75 years) in triplet combination with daratumumab (16 mg/kg; daratumumab arm) or bortezomib (1.3 mg/m2; bortezomib arm) in patients with relapsed/refractory MM refractory to an immunomodulatory agent and/or a proteasome inhibitor and who had received one to four prior lines of therapy. Primary objectives were to determine the optimal dose of melflufen in triplet combination (phase I) and overall response rate (phase IIa). In total, 33 patients were treated in the daratumumab arm and 23 patients received therapy in the bortezomib arm. No dose-limiting toxicities were reported at either melflufen dose level with either combination. With both triplet regimens, the most common grade ≥3 treatment-emergent adverse events were thrombocytopenia and neutropenia; thrombocytopenia was the most common treatment-emergent adverse event leading to treatment discontinuation. In the daratumumab arm, patients receiving melflufen 30 mg remained on treatment longer than those receiving the 40-mg dose. In the daratumumab arm, the overall response rate was 73% and median progression-free survival was 12.9 months. Notably, in the bortezomib arm, the overall response rate was 78% and median progression-free survival was 14.7 months. Considering the totality of the data, melflufen 30 mg was established as the recommended dose for use with dexamethasone and daratumumab or bortezomib for future studies in relapsed/refractory MM.

• MeSH
• Bortezomib therapeutic use   MeSH
• Dexamethasone therapeutic use   MeSH
• Phenylalanine * analogs & derivatives   MeSH
• Humans MeSH
• Melphalan * analogs & derivatives   MeSH
• Multiple Myeloma * diagnosis   drug therapy   MeSH
• Antibodies, Monoclonal * MeSH
• Neoplasms, Plasma Cell * MeSH
• Neutropenia * chemically induced   MeSH
• Antineoplastic Combined Chemotherapy Protocols adverse effects   MeSH
• Aged MeSH
• Thrombocytopenia * MeSH
• Check Tag
• Humans MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase I MeSH
• Clinical Trial, Phase II MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Bortezomib MeSH
• daratumumab MeSH Browser
• Dexamethasone MeSH
• Phenylalanine * MeSH
• Melphalan * MeSH
• melflufen MeSH Browser
• Antibodies, Monoclonal * MeSH

PURPOSE: Primary plasma cell leukemia (PCL) is the most aggressive monoclonal gammopathy. It was formerly characterized by ≥ 20% circulating plasma cells (CTCs) until 2021, when this threshold was decreased to ≥ 5%. We hypothesized that primary PCL is not a separate clinical entity, but rather that it represents ultra-high-risk multiple myeloma (MM) characterized by elevated CTC levels. METHODS: We assessed the levels of CTCs by multiparameter flow cytometry in 395 patients with newly diagnosed transplant-ineligible MM to establish a cutoff for CTCs that identifies the patients with ultra-high-risk PCL-like MM. We tested the cutoff on 185 transplant-eligible patients with MM and further validated on an independent cohort of 280 transplant-ineligible patients treated in the GEM-CLARIDEX trial. The largest published real-world cohort of patients with primary PCL was used for comparison of survival. Finally, we challenged the current 5% threshold for primary PCL diagnosis. RESULTS: Newly diagnosed transplant-ineligible patients with MM with 2%-20% CTCs had significantly shorter progression-free survival (3.1 v 15.6 months; P < .001) and overall survival (14.6 v 33.6 months; P = .023) than patients with < 2%. The 2% cutoff proved to be applicable also in transplant-eligible patients with MM and was successfully validated on an independent cohort of patients from the GEM-CLARIDEX trial. Most importantly, patients with 2%-20% CTCs had comparable dismal outcomes with primary PCL. Moreover, after revealing a low mean difference between flow cytometric and morphologic evaluation of CTCs, we showed that patients with 2%-5% CTCs have similar outcomes as those with 5%-20% CTCs. CONCLUSION: Our study uncovers that ≥ 2% CTCs is a biomarker of hidden primary PCL and supports the assessment of CTCs by flow cytometry during the diagnostic workup of MM.

• MeSH
• Humans MeSH
• Multiple Myeloma * drug therapy   MeSH
• Biomarkers, Tumor MeSH
• Neoplastic Cells, Circulating * pathology   MeSH
• Plasma Cells pathology   MeSH
• Leukemia, Plasma Cell * MeSH
• Prognosis MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Biomarkers, Tumor MeSH