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This article endeavors to navigate the clinical journey of bispecific antibodies (BsAbs), from elucidating common toxicities and management strategies to examining novel agents and broadening access in community health care. These drugs, commonly through T-cell activation, result in shared adverse events such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. Variations in target antigens and designs, however, might introduce unique toxicities for different BsAbs, warranting specific management approaches. Recent US Food and Drug Administration approvals of BsAbs targeting CD3 + T cells linked to CD20 for non-Hodgkin lymphoma and to B-cell maturation antigen or GPRC5D for multiple myeloma have transformed the treatment landscape for hematologic malignancies. Emerging new agents promise further enhancement and safety, exploring novel antigen targets, innovative structures such as trispecific antibodies, and the engagement of diverse immune cells. Simultaneously, the expansion of BsAbs into community practices is underway, demanding a multifaceted strategy that encompasses educational initiatives, operational adaptations, and collaborative frameworks. This ensures comprehensive treatment access, allowing every patient, irrespective of geographical or socioeconomic status, to benefit from these advancements in cancer therapy.

Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell disorder characterized by the presence of a predominant monoclonal antibody (i.e., M-protein) in serum, without clinical symptoms. Here we present a case study in which we detect MGUS by liquid-chromatography coupled with mass spectrometry (LC-MS) profiling of IgG1 in human serum. We detected a Fab-glycosylated M-protein and determined the full heavy and light chain sequences by bottom-up proteomics techniques using multiple proteases, further validated by top-down LC-MS. Moreover, the composition and location of the Fab-glycan could be determined in CDR1 of the heavy chain. The outlined approach adds to an expanding mass spectrometry-based toolkit to characterize monoclonal gammopathies such as MGUS and multiple myeloma, with fine molecular detail. The ability to detect monoclonal gammopathies and determine M-protein sequences straight from blood samples by mass spectrometry provides new opportunities to understand the molecular mechanisms of such diseases.

Background: G protein-coupled receptor, family C, group 5, member D (GPRC5D) is an orphan receptor expressed in malignant plasma cells. Talquetamab, a bispecific antibody against CD3 and GPRC5D, redirects T cells to mediate killing of GPRC5D-expressing myeloma cells., Methods: In a phase 1 study, we evaluated talquetamab administered intravenously weekly or every other week (in doses from 0.5 to 180 μg per kilogram of body weight) or subcutaneously weekly, every other week, or monthly (5 to 1600 μg per kilogram) in patients who had heavily pretreated relapsed or refractory multiple myeloma that had progressed with established therapies (a median of six previous lines of therapy) or who could not receive these therapies without unacceptable side effects. The primary end points - the frequency and type of dose-limiting toxic effects (study part 1 only), adverse events, and laboratory abnormalities - were assessed in order to select the recommended doses for a phase 2 study., Results: At the data-cutoff date, 232 patients had received talquetamab (102 intravenously and 130 subcutaneously). At the two subcutaneous doses recommended for a phase 2 study (405 μg per kilogram weekly [30 patients] and 800 μg per kilogram every other week [44 patients]), common adverse events were cytokine release syndrome (in 77% and 80% of the patients, respectively), skin-related events (in 67% and 70%), and dysgeusia (in 63% and 57%); all but one cytokine release syndrome event were of grade 1 or 2. One dose-limiting toxic effect of grade 3 rash was reported in a patient who had received talquetamab at the 800-μg dose level. At median follow-ups of 11.7 months (in patients who had received talquetamab at the 405-μg dose level) and 4.2 months (in those who had received it at the 800-μg dose level), the percentages of patients with a response were 70% (95% confidence interval [CI], 51 to 85) and 64% (95% CI, 48 to 78), respectively. The median duration of response was 10.2 months and 7.8 months, respectively., Conclusions: Cytokine release syndrome, skin-related events, and dysgeusia were common with talquetamab treatment but were primarily low-grade. Talquetamab induced a substantial response among patients with heavily pretreated relapsed or refractory multiple myeloma. (Funded by Janssen Research and Development; MonumenTAL-1 ClinicalTrials.gov number, NCT03399799.)., (Copyright © 2022 Massachusetts Medical Society.)

Background: Iberdomide is a novel cereblon E3 ligase modulator with enhanced tumouricidal and immune-stimulatory effects compared with immunomodulatory drugs. In preclinical myeloma models, iberdomide has shown synergy with dexamethasone, proteasome inhibitors, and CD38 monoclonal antibodies. We aimed to evaluate the safety and clinical activity of iberdomide plus dexamethasone in patients with heavily pretreated relapsed or refractory multiple myeloma., Methods: We conducted a multicohort, open-label, phase 1/2 trial (CC-220-MM-001) at 42 treatment centres in Europe, Canada, and the USA. Patients aged 18 years or older with multiple myeloma who had received at least two previous lines of therapy, including lenalidomide or pomalidomide and a proteasome inhibitor, were enrolled into the dose-escalation cohort. Patients received escalating doses of oral iberdomide (0·3-1·6 mg on days 1-21 of each 28-day cycle) plus oral dexamethasone (40 mg [20 mg if age >75 years] once per week). A dose-expansion cohort at the recommended phase 2 dose was planned for patients who had received at least three previous lines of therapy and had triple-class refractory disease (refractory to immunomodulatory drugs, proteasome inhibitors, and CD38 antibodies). Treatment continued until progressive disease or unacceptable toxicity. The primary outcomes were the recommended phase 2 dose (in the dose-escalation cohort, phase 1) and overall response rate (defined as complete response or partial response; in the dose-expansion cohort, phase 2) in the full analysis set. This trial is ongoing and is registered with ClinicalTrials.gov, NCT02773030., Findings: Between Dec 5, 2016, and Dec 16, 2020, 460 patients were assessed for eligibility across all cohorts and 197 were enrolled and treated with iberdomide plus dexamethasone (90 patients in the dose-escalation cohort and 107 in the dose-expansion cohort). In the dose-escalation cohort, 47 (52%) patients were female and 43 (48%) were male, 70 (78%) were White, and the median number of previous lines of therapy was 5 (IQR 4-8). In the dose-expansion cohort, 47 (44%) were female and 60 (56%) were male, 84 (79%) were White, and the median number of previous lines of therapy was 6 (IQR 5-8). At data cutoff (June 2, 2021), median follow-up was 5·8 months (IQR 3·0-13·7) in the dose-escalation cohort and 7·7 months (5·3-11·4) in the dose-expansion cohort. Two dose-limiting toxicities (both infections, at 1·2 mg and 1·3 mg) were observed in the dose-escalation cohort, and 1·6 mg was selected as the recommended phase 2 dose. In the dose-escalation cohort, the overall response rate was 32% (95% CI 23-43; 29 of 90 patients) across all doses, and the maximum tolerated dose was not reached. In the dose-expansion cohort, the overall response rate was 26% (95% CI 18-36; 28 of 107 patients). The most common grade 3 or worse adverse events were neutropenia (48 [45%] of 107 patients), anaemia (30 [28%]), infection (29 [27%]), and thrombocytopenia (23 [22%]). Serious adverse events occurred in 57 (53%) patients. There was one (1%) treatment-related death (sepsis) and five (5%) patients discontinued iberdomide due to adverse events., Interpretation: Iberdomide plus dexamethasone was generally safe and showed meaningful clinical activity in heavily pretreated patients with multiple myeloma, including in disease that was refractory to immunomodulatory drugs. These data suggest that further evaluation of iberdomide plus dexamethasone or other standard antimyeloma therapies is warranted., Funding: Bristol Myers Squibb., Competing Interests: Declaration of interests SL reports consulting fees from AbbVie, Bristol Myers Squibb, GlaxoSmithKline, Janssen Pharmaceuticals, and Takeda; institution grants or contracts from Bristol Myers Squibb, Janssen, and Takeda; membership on an entity's Board of Directors or advisory committees for TG Therapeutics; and stock ownership in TG Therapeutics. RP reports honoraria and travel grants from Bristol Myers Squibb. CH reports honoraria from AbbVie, Amgen, Bristol Myers Squibb, Cilag, Janssen Pharmaceuticals, Sanofi, and Takeda. SJ reports consulting fees from Bristol Myers Squibb, Elsevier, Janssen Pharmaceuticals, Karyopharm Therapeutics, Legend Biotech, Sanofi, and Takeda. AO reports honoraria and consulting fees from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Janssen Pharmaceuticals, and Sanofi. PGR reports institution grants or contracts from Bristol Myers Squibb, Karyopharm Therapeutics, Oncopeptides, and Takeda; consulting fees from AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Karyopharm Therapeutics, Oncopeptides, Protocol Intelligence, Regeneron, Secura Bio, Sanofi, and Takeda. KW reports institution grants or contracts from Amgen, Bristol Myers Squibb, Celgene, Janssen Pharmaceuticals, GlaxoSmithKline, and Sanofi; honoraria and consulting fees from AbbVie, Adaptive Biotechnologies, Amgen, Bristol Myers Squibb, GlaxoSmithKline, Karyopharm Therapeutics, Novartis, Oncopeptides, Pfizer, Roche, Sanofi, and Takeda; and membership of an advisory board for German Society for Hematology and Medical Oncology and Stiftung Immunonkologie. MCM reports honoraria from Alnylam Pharmaceuticals, Bristol Myers Squibb, Cilag, Gilead Sciences, Janssen Pharmaceuticals, and Medscape; travel grants from Celgene, a Bristol Myers Squibb Company; and membership on an entity's Board of Directors or advisory committees for Bristol Myers Squibb. AZB reports research support from GlaxoSmithKline. SK reports honoraria, research support, and consulting fees from Bristol Myers Squibb. EAS reports institution grants or contracts from AbbVie and Bristol Myers Squibb; consulting fees from AbbVie, Amgen, Bristol Myers Squibb, and GlaxoSmithKline; and membership on an entity's Board of Directors or advisory committees for Amgen. YC, TVN, AA, and TP are employees of Bristol Myers Squibb and have stock ownership in Bristol Myers Squibb. MA is an employee of Bristol Myers Squibb, has stock ownership in Bristol Myers Squibb, and has received travel grants from Bristol Myers Squibb. MC is an employee of Bristol Myers Squibb. NWCJvdD reports institution grants or contracts from Amgen, Cellectis, and Janssen Pharmaceuticals; and membership on an entity's Board of Directors or advisory committees for Adaptive Biotechnologies, Amgen, GlaxoSmithKline, Janssen Pharmaceuticals, Novartis, Roche Sanofi, and Takeda. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

In the phase 3 ANDROMEDA trial, patients treated with daratumumab, bortezomib, cyclophosphamide, and dexamethasone (D-VCd) had significantly higher rates of organ and hematologic response compared with patients who received VCd alone. Here, we present patient-reported outcomes (PROs) from the ANDROMEDA trial. PROs were assessed through cycle 6 using three standardized questionnaires. Treatment effect through cycle 6 was measured by a repeated-measures, mixed-effects model. The magnitude of changes in PROs versus baseline was generally low, but between-group differences favored the D-VCd group. Results were generally consistent irrespective of hematologic, cardiac, or renal responses. More patients in the D-VCd group experienced meaningful improvements in PROs; median time to improvement was more rapid in the D-VCd group versus the VCd group. After cycle 6, patients in the D-VCd group received daratumumab monotherapy and their PRO assessments continued, with improvements in health-related quality of life (HRQoL) reported through cycle 19. PROs of subgroups with renal and cardiac involvement were consistent with those of the intent-to-treat population. These results demonstrate that the previously reported clinical benefits of D-VCd were achieved without decrement to patients' HRQoL and provide support of D-VCd in patients with AL amyloidosis., (© 2022 Wiley Periodicals LLC.)

The efficacy of daratumumab depends partially on CD38 expression on multiple myeloma (MM) cells. We have previously shown that all-trans retinoic acid (ATRA) upregulates CD38 expression and reverts daratumumab-resistance ex vivo. We therefore evaluated the optimal dose, efficacy, and safety of daratumumab combined with ATRA in patients with daratumumab-refractory MM in a phase 1/2 study (NCT02751255). In part A of the study, 63 patients were treated with daratumumab monotherapy. Fifty patients with daratumumab-refractory MM were subsequently enrolled in part B and treated with daratumumab (reintensified schedule) combined with ATRA until disease progression. The recommended phase 2 dose of ATRA in combination with daratumumab was defined as 45 mg/m2. At this dose, the overall response rate (ORR) was 5%, indicating that the primary endpoint (ORR ≥15%) was not met. However, most patients (66%) achieved at least stable disease. After a median follow-up of 43 months, the median progression-free survival (PFS) for all patients was 2.8 months. Patients who previously achieved at least a partial response or minimal response/stable disease with prior daratumumab monotherapy had a significantly longer PFS compared with patients who immediately progressed during daratumumab as single agent (median PFS 3.4 and 2.8 vs 1.3 months). The median overall survival was 19.1 months. The addition of ATRA did not increase the incidence of adverse events. Flow cytometric analysis revealed that ATRA temporarily increased CD38 expression on immune cell subsets. In conclusion, the addition of ATRA and reintensification of daratumumab had limited activity in patients with daratumumab-refractory MM, which may be explained by the transient upregulation of CD38 expression. This trial was registered at www.clinicaltrials.gov as #NCT02751255., (© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Identification of risk factors for early mortality (EM) in multiple myeloma (MM) patients may contribute to different therapeutic approaches in patients at risk for EM. This population-based study aimed to assess trends in EM and risk factors for EM among MM patients diagnosed in the Netherlands. All MM patients, newly diagnosed between 1989 and 2018, were identified in the Netherlands Cancer Registry. Patients were categorized into three calendar periods (1989-1998, 1999-2008, 2009-2018) and into five age groups (≤65, 66-70, 71-75, 76-80, >80 years). EM was defined as death by any cause ≤180 days post-diagnosis. We included 28,328 MM patients (median age 70 years; 55% males). EM decreased from 22% for patients diagnosed in 1989-1998 to 13% for patients diagnosed in 2009-2018 (P < 0.01) and this decrease was observed among all age groups. Exact causes of death could not be elucidated. Besides patient's age, we found that features related to a more aggressive disease presentation, and patient characteristics reflecting patients' physical condition were predictive of EM. In summary, EM decreased from 1999 onwards. Nevertheless, EM remains high, especially for patients aged >70 years. Therefore, novel strategies should be explored to improve the outcome of patients at risk for EM., (© 2021. The Author(s).)

Purpose: To address the role of consolidation treatment for newly diagnosed, transplant eligible patients with multiple myeloma in a controlled clinical trial., Patients and Methods: The EMN02/HOVON95 trial compared consolidation treatment with two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) or no consolidation after induction and intensification therapy, followed by continuous lenalidomide maintenance. Primary study end point was progression-free survival (PFS)., Results: Eight hundred seventy-eight eligible patients were randomly assigned to receive VRD consolidation (451 patients) or no consolidation (427 patients). At a median follow-up of 74.8 months, median PFS with adjustment for pretreatment was prolonged in patients randomly assigned to VRD consolidation (59.3 v 42.9 months, hazard ratio [HR] = 0.81; 95% CI, 0.68 to 0.96; P = .016). The PFS benefit was observed across most predefined subgroups, including revised International Staging System (ISS) stage, cytogenetics, and prior treatment. Revised ISS3 stage (HR, 2.00; 95% CI, 1.41 to 2.86) and ampl1q (HR, 1.67; 95% CI, 1.37 to 2.04) were significant adverse prognostic factors. The median duration of maintenance was 33 months (interquartile range 13-86 months). Response ≥ complete response (CR) after consolidation versus no consolidation before start of maintenance was 34% versus 18%, respectively ( P < .001). Response ≥ CR on protocol including maintenance was 59% with consolidation and 46% without ( P < .001). Minimal residual disease analysis by flow cytometry in a subgroup of 226 patients with CR or stringent complete response or very good partial response before start of maintenance demonstrated a 74% minimal residual disease-negativity rate in VRD-treated patients. Toxicity from VRD was acceptable and manageable., Conclusion: Consolidation treatment with VRD followed by lenalidomide maintenance improves PFS and depth of response in newly diagnosed patients with multiple myeloma as compared to maintenance alone., Competing Interests: Pieter SonneveldConsulting or Advisory Role: Celgene, Janssen, Amgen, Karyopharm Therapeutics, CARsgen TherapeuticsResearch Funding: Janssen, Amgen, Skyline Diagnostics Meletios A. DimopoulosHonoraria: Amgen, Takeda, Janssen-Cilag, Bristol Myers Squibb, BeigeneConsulting or Advisory Role: Amgen, Janssen-Cilag, Takeda, Bristol Myers Squibb, Beigene Meral BeksacConsulting or Advisory Role: Amgen, Janssen, Sanofi, Oncopeptides, TakedaTravel, Accommodations, Expenses: Amgen, Janssen, Takeda, Sanofi Meral BeksacConsulting or Advisory Role: Celgene, Janssen-Cilag, Amgen, Takeda, Sanofi Pasteur, OncopeptidesSpeakers' Bureau: Amgen, Celgene, Janssen-Cilag, Sanofi Pasteur Heinz LudwigConsulting or Advisory Role: Amgen, Janssen-Cilag, Sanofi, Seattle GeneticsSpeakers' Bureau: Celgene, Bristol Myers Squibb, Janssen-Cilag, Amgen, TakedaResearch Funding: Takeda, Amgen Sonja ZweegmanConsulting or Advisory Role: Janssen-Cilag, Takeda, Celgene, Sanofi, OncopeptidesResearch Funding: Janssen-Cilag, Takeda, CelgeneTravel, Accommodations, Expenses: Janssen-Cilag, Takeda, Celgene Elena ZamagniHonoraria: Janssen-Cilag, Celgene, Amgen, Bristol Myers Squibb, Takeda, GlaxoSmithKline, Oncopeptides, SanofiConsulting or Advisory Role: Celgene, Janssen-Cilag, Amgen, SanofiTravel, Accommodations, Expenses: Janssen-Cilag, Celgene, Amgen Ruth WesterHonoraria: Sanofi Roman HajekConsulting or Advisory Role: Takeda, Amgen, Celgene, AbbVie, BMS, PharmaMar, Janssen-Cilag, NovartisSpeakers' Bureau: Takeda, AmgenResearch Funding: Novartis, BMS, Amgen, Celgene, Takeda Lucia PantaniHonoraria: Celgene, Janssen, Takeda, Amgen Francesca GayHonoraria: Amgen, Bristol Myers Squibb, Celgene, Takeda, AbbVie, Janssen, GlaxoSmithKlineConsulting or Advisory Role: AbbVie, Adaptive Biotechnologies, Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Oncopeptides, Roche, Takeda, Janssen, Bluebird bio Stefania OlivaHonoraria: Amgen, Celgene/Bristol Myers Squibb, JanssenConsulting or Advisory Role: Adaptive Biotechnologies, Janssen, Amgen, Takeda Vincent van de VeldenResearch Funding: BD Biosciences, Pfizer, Janssen, Novartis/Navigate, Agilent/DAKOPatents, Royalties, Other Intellectual Property: Patent EuroFlow MRD antibody tubes. No financial relationship KaLung WuConsulting or Advisory Role: Janssen Oncology Gerard BosEmployment: CiMaasLeadership: CiMaasStock and Other Ownership Interests: CIMaasHonoraria: CiMaas Mark-David LevinHonoraria: AbbVie, Celgene, Janssen, TakedaTravel, Accommodations, Expenses: Takeda, Janssen Annemiek BroijlHonoraria: Amgen, Sanofi, Celgene, Bristol Myers Squibb/Celgene, JanssenTravel, Accommodations, Expenses: Bristol Myers Squibb/Celgene Monique MinnemaConsulting or Advisory Role: Janssen-Cilag, Alnylam, Gilead SciencesSpeakers' Bureau: Celgene/Bristol Myers SquibbTravel, Accommodations, Expenses: Celgene Anders WaageHonoraria: Janssen OncologySpeakers' Bureau: Janssen Oncology Cecilie BlimarkHonoraria: Bristol Myers Squibb/Celgene, Janssen, Takeda, AmgenConsulting or Advisory Role: Adaptive Biotechnologies, Janssen, GlaxoSmithKline Niels W. C. J. van de DonkConsulting or Advisory Role: Janssen, Celgene, Bristol Myers Squibb, Novartis, Amgen, Servier, Takeda, BayerSpeakers' Bureau: Janssen Research & Development, Celgene, Amgen, Bristol Myers SquibbResearch Funding: Janssen, Celgene, Amgen, Novartis, Bristol Myers Squibb, Cellectis Massimo OffidaniHonoraria: BMS, Janssen, CelgeneConsulting or Advisory Role: Janssen Giuseppe A. PalumboConsulting or Advisory Role: Novartis, Janssen Oncology, AOP Orphan Pharmaceuticals, AbbVie, AstraZeneca, Celgene/Bristol Myers SquibbSpeakers' Bureau: Novartis, Celgene/Bristol Myers Squibb, AbbVieTravel, Accommodations, Expenses: Takeda, Novartis Andrew SpencerHonoraria: Janssen-Cilag, BMSConsulting or Advisory Role: Janssen-Cilag, BMSSpeakers' Bureau: Janssen-CilagResearch Funding: Janssen-Cilag Mario BoccadoroHonoraria: Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol Myers Squibb, AbbVieConsulting or Advisory Role: Janssen, GlaxoSmithKlineResearch Funding: Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol Myers Squibb, Mundipharma Michele CavoHonoraria: Janssen, Bristol Myers Squibb, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm Therapeutics, Adaptive BiotechnologiesConsulting or Advisory Role: Janssen, Bristol Myers Squibb, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm Therapeutics, Adaptive BiotechnologiesSpeakers' Bureau: Janssen, CelgeneNo other potential conflicts of interest were reported.

Novel combination therapies have markedly improved the lifespan of patients with multiple myeloma (MM), but drug resistance and disease relapse remain major clinical problems. Dexamethasone and other glucocorticoids are a cornerstone of conventional and new combination therapies for MM, although their use is accompanied by serious side effects. We aimed to uncover drug combinations that act in synergy and, as such, allow reduced dosing while remaining effective. Dexamethasone and the myeloid cell leukemia 1 (MCL-1) inhibitor S63845 (MCL-1i) proved the most potent combination in our lethality screen and induced apoptosis of human myeloma cell lines (HMCLs) that was 50% higher compared with an additive drug effect. Kinome analysis of dexamethasone-treated HMCLs revealed a reduction in serine/threonine peptide phosphorylation, which was predicted to result from reduced Akt activity. Biochemical techniques showed no dexamethasone-induced effects on FOXO protein or GSK3 but did show a 50% reduction in P70S6K phosphorylation, downstream of the Akt-mTORC1 axis. Replacing dexamethasone by the P70S6K1 isoform-specific inhibitor PF-4708671 (S6K1i) revealed similar and statistically significant synergistic apoptosis of HMCLs in combination with MCL-1i. Interestingly, apoptosis induced by the P70S6K1i and MCL-1i combination was more-than-additive in all 9 primary MM samples tested; this effect was observed for 6 of 9 samples with the dexamethasone and MCL-1i combination. Toxicity on stem and progenitor cell subsets remained minimal. Combined, our results show a strong rationale for combination treatments using the P70S6K inhibitor in MM. Direct and specific inhibition of P70S6K may also provide a solution for patients ineligible or insensitive to dexamethasone or other glucocorticoids., (© 2021 by The American Society of Hematology.)

Belantamab mafodotin (belamaf) is a BCMA-targeted antibody-drug conjugate recently approved as monotherapy for adults with relapsed/refractory multiple myeloma who have received ≥4 prior therapies. Belamaf binds to BCMA and eliminates myeloma cells by multimodal mechanisms of action. The cytotoxic and potential immunomodulatory properties of belamaf have led to novel combination studies with other anticancer therapies. Here, we describe the rationale and design of DREAMM-5, an ongoing Phase I/II platform study evaluating the safety and efficacy of belamaf combined with novel agents, including GSK3174998 (OX40 agonist), feladilimab (an ICOS; GSK3359609), nirogacestat (a gamma-secretase inhibitor; PF-03084014) and dostarlimab (a PD-1 blocker) versus belamaf monotherapy for patients with relapsed/refractory multiple myeloma. Clinical trial registration: NCT04126200 (ClinicalTrials.gov).

Multiple myeloma (MM), a treatable but incurable malignancy, is characterized by the growth of clonal plasma cells in protective niches in the bone marrow. MM cells depend on expression of BCL-2 family proteins, in particular MCL-1, for survival. The regulation of MCL-1 is complex and cell type-dependent. Unraveling the exact mechanism by which MCL-1 is overexpressed in MM may provide new therapeutic strategies for inhibition in malignant cells, preferably limiting side effects in healthy cells. In this study, we reveal that one cause of overexpression could be stabilization of the MCL-1 protein. We demonstrate this in a subset of MM and diffuse large B cell lymphoma (DLBCL) cell lines and MM patient samples. We applied a phosphatase siRNA screen to identify phosphatases responsible for MCL-1 stabilization in MM, and revealed PP2A as the MCL-1 stabilizing phosphatase. Using the PP2A inhibitor okadaic acid, we validated that PP2A dephosphorylates MCL-1 at Ser159 and/or Thr163, and thereby stabilizes MCL-1 in MM cells with long MCL-1 half-life, but not in DLBCL cells. Combined kinase and phosphatase inhibition experiments suggest that the MCL-1 half-life in MM is regulated by the counteracting functions of JNK and PP2A. These findings increase the understanding of the mechanisms by which MCL-1 is post-translationally regulated, which may provide novel strategies to inhibit MCL-1 in MM cells.

Great progress in the treatment of patients with multiple myeloma (MM) has been made due to the development of novel drugs. Patients with relapsed/refractory MM (RRMM) can be enrolled in early-phase clinical trials, but their performance across the last decade is unknown. We conducted a meta-analysis on the overall response rate (ORR) and toxicity. PubMed, Embase, and Cochrane Library were systematically searched for phase I and phase II trials investigating an experimental compound as a single agent or in combination with dexamethasone, published from January 1, 2010 to July 1, 2020. Eighty-eight articles were included, describing 61 phase I trials involving 1835 patients and 37 phase II trials involving 2644 patients. There was a high degree of heterogeneity. Using a random-effects model, the 95% CIs of the estimated ORR were 8-17% for phase I trials and 18-28% for phase II trials. There were significant subgroup differences in ORR between the years of publication in phase I trials and between drug classes in both phase I and phase II trials. The ORR in early-phase clinical trials in RRMM is substantial, especially in phase II trials, but due to high heterogeneity a general assessment of clinical benefit before participation is difficult to offer to patients.

Introduction: Lenalidomide plus dexamethasone is effective and well tolerated in relapsed/refractory multiple myeloma (RRMM). In this observational, noninterventional European post-authorization safety study, the safety profile of lenalidomide plus dexamethasone was investigated and compared with that of other agents in the treatment of RRMM in a real-world setting., Patients and Methods: Patients had received ≥ 1 prior antimyeloma therapy; prior lenalidomide was excluded. Treatment was per investigator's routine practice. Adverse events were analyzed by incidence rates per 100 person-years to account for differences in observation length and treatment duration., Results: In total, 2150 patients initiated lenalidomide, and 1479 initiated any other antimyeloma therapy, predominately bortezomib (80.3%), which was primarily administered intravenously (74.3%). The incidence rate of neuropathy was lower with lenalidomide (10.5) than with bortezomib (78.9) or thalidomide (38.7). Lenalidomide also had a lower incidence rate of infections (68.7) versus bortezomib (95.9) and thalidomide (76.0). Conversely, the incidence rate of neutropenia was higher with lenalidomide (38.0) than with bortezomib (18.2) or thalidomide (25.7). The incidence rates of thrombocytopenia were 24.4, 40.4, and 14.4 with lenalidomide, bortezomib, and thalidomide, respectively., Conclusion: No new safety signals for lenalidomide were identified in this study, which is the largest prospective real-world European study of lenalidomide in patients with RRMM to date. These results confirm that the safety profile of lenalidomide plus dexamethasone in RRMM in a real-world setting is comparable to that reported in clinical trials., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Prosurvival BCL-2 family proteins are potent inhibitors of apoptosis and often overexpressed in lymphoid malignancies. In multiple myeloma (MM), MCL-1 expression contributes to survival of malignant plasma cells, and overexpression correlates with poor prognosis. In this study, we investigated whether sensitivity to the novel MCL-1 inhibitor S63845 could be predicted using cytogenetics, focusing on amplification of 1q21, the chromosomal region that contains the MCL1 locus. In addition, we studied the relation of MCL-1 inhibitor sensitivity with other diagnostic characteristics and BCL-2 family protein expression. In 31 human myeloma cell lines and in bone marrow aspirates from 47 newly diagnosed MM patients, we measured the effect of S63845 alone, or combined with BCL-2 inhibitor ABT-199 (venetoclax), and BCL-XL inhibitor A-1155463 or A-1331852 on cell viability. We demonstrated for the first time that MM cells from patients with 1q21 amplification are significantly more sensitive to inhibition of MCL-1. We suggest that this increased sensitivity results from high relative MCL1 expression resulting from amplification of 1q21. Additionally, and partially independent from 1q21 status, high serum β2 microglobulin level and presence of renal insufficiency correlated with increased sensitivity to MCL-1 inhibitor treatment. Combining S63845 with other BH3 mimetics synergistically enhanced apoptosis compared with single inhibitors, and sensitivity to inhibitor combinations was found in a large proportion of MM insensitive to MCL-1 inhibition alone. Collectively, our data indicate that amplification of 1q21 identifies an MM subset highly sensitive to MCL-1 inhibitor treatment and can be used as a predictive marker to guide selection of therapy., (© 2019 by The American Society of Hematology.)

Purpose: Liposomal drug delivery can improve the therapeutic index of treatments for multiple myeloma. However, an appropriate 3D model for the in vitro evaluation of liposomal drug delivery is lacking. In this study, we applied a previously developed 3D bone marrow (BM) myeloma model to examine liposomal drug therapy., Material and Methods: Liposomes of different sizes (~75-200 nm) were tested in a 3D BM myeloma model, based on multipotent mesenchymal stromal cells, endothelial progenitor cells, and myeloma cells cocultured in hydrogel. The behavior and efficacy of liposomal drug therapy was investigated, evaluating the feasibility of testing liposomal drug delivery in 3D in vitro. Intracellular uptake of untargeted and integrin α 4 β 1 (very late antigen-4) targeted liposomes was compared in myeloma and supporting cells, as well as the effectivity of free and liposome-encapsulated chemotherapy (bortezomib, doxorubicin). Either cocultured myeloma cell lines or primary CD138 + myeloma cells received the treatments., Results: Liposomes (~75-110 nm) passively diffused throughout the heterogeneously porous (~80-850 nm) 3D hydrogel model after insertion. Cellular uptake of liposomes was observed and was increased by targeting very late antigen-4. Liposomal bortezomib and doxorubicin showed increased cytotoxic effects toward myeloma cells compared with the free drugs, using either a cell line or primary myeloma cells. Cytotoxicity toward supporting BM cells was reduced using liposomes., Conclusion: The 3D model allows the study of liposome-encapsulated molecules on multiple myeloma and supporting BM cells, looking at cellular targeting, and general efficacy of the given therapy. The advantages of liposomal drug delivery were demonstrated in a primary myeloma model, enabling the study of patient-to-patient responses to potential drugs and treatment regimes., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: In patients with recently diagnosed multiple myeloma, the HOVON-50 phase 3 trial showed improved event-free survival for thalidomide-containing induction and maintenance regimens (in conjunction with high-dose melphalan and autologous stem cell transplantation [auto-SCT]) after a median of 52 months of follow-up, by comparison with regimens containing classical cytotoxic drugs. In this follow-up analysis, we aimed to determine the long-term effects of thalidomide in induction and maintenance therapy in multiple myeloma., Methods: In this open-label, phase 3 randomised controlled trial, patients with recently diagnosed multiple myeloma were recruited from 44 Dutch and Belgian hospitals. Participants had been diagnosed with multiple myeloma of Durie-Salmon stage II or III and were aged 18-65 years. Patients were randomly assigned (1:1) either to receive three 28-day cycles of vincristine (0·4 mg, intravenous rapid infusion on days 1-4), doxorubicin (9 mg/m 2 , intravenous rapid infusion on days 1-4) and dexamethasone (40 mg, orally on days 1-4, 9-12, and 17-20; control group); or to receive the same regimen, but with thalidomide (200-400 mg, orally on days 1-28) instead of vincristine (thalidomide group). No masking after assignment to intervention was used. Patients were randomly assigned to groups, stratified by centre and treatment policy (one vs two courses of high-dose melphalan and auto-SCT). After stem cell harvest, patients received one or two courses of 200 mg/m 2 melphalan intravenously with auto-SCT. Patients with at least a partial response to high-dose melphalan and auto-SCT were eligible for maintenance therapy, starting 2-3 months after high-dose melphalan. Patients in the control group received maintenance therapy with interferon alfa (3 ×  10 6 international units, subcutaneously, three times weekly). Patients in the thalidomide group received thalidomide as maintenance therapy (50 mg, orally, daily). Maintenance therapy was given until relapse, progression, or the occurrence of adverse events. The primary endpoint of the study was event-free survival (EFSc; censored at allogeneic stem cell transplantation), analysed by intention to treat. The study is closed for enrolment and this Article represents the final analysis. This trial was registered with the Netherlands Trial Register, number NTR238., Findings: Between Nov 27, 2001 and May 31, 2005, 556 patients were enrolled in the study, of whom 536 (96%) were eligible for evaluation and were randomly allocated (268 [50%] to the control group and 268 [50%] to the thalidomide group). These 536 patients were assessed for the primary endpoint of EFSc. At an extended median follow-up of 129 months (IQR 123-136), EFSc was significantly longer in the thalidomide group compared with the control group (multivariate analysis hazard ratio [HR] 0·62, 95% CI 0·50-0·77; p<0·0001). Thalidomide maintenance was stopped because of toxicity in 65 (42%) of 155 patients in the thalidomide group (neuropathy in 49 [75%] patients, skin reactions in four [6%] patients, fatigue in two [3%] patients, and as other symptoms [such as abdominal pain, pancreatitis, and dyspnoea] in ten [15%] patients). 24 (27%) of 90 patients in the control group discontinued protocol treatment during maintenance therapy with interferon alfa because of toxicity (five [21%] patients with psychiatric side-effects, five [21%] patients with flu-like symptoms, four [17%] patients with haematological toxicity [thrombocytopenia and leucocytopenia], three [13%] patients with skin reactions, and seven [29%] patients with other symptoms [such as infections, cardiomyopathy, and headache]). The frequency of second primary malignancies was similar in both groups. There were 23 second primary malignancies in 17 patients in the control group and 29 second primary malignancies in 24 patients in the thalidomide group. There were 19 treatment-related deaths in the control group, and 16 treatment-related deaths in the thalidomide group., Interpretation: Our data indicate that thalidomide-based treatment could be a treatment option for patients with multiple myeloma who are eligible for auto-SCT who live in countries without access to proteasome inhibitors or lenalidomide. However, careful follow-up and timely dose adjustments are important to prevent the development of thalidomide-induced neurotoxicity., Funding: The Dutch Cancer Foundation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

This single-centre retrospective observational study analysed the efficacy of retreatment with immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) after treatment with daratumumab monotherapy in patients with relapsed and/or refractory multiple myeloma (RRMM). In total 55 patients were treated with daratumumab monotherapy between 2010 and 2017. From this group 29 (53%) IMiD-refractory patients were retreated with an IMiD after daratumumab and 6 (11%) PI-refractory patients were retreated with a PI-based regimen. For the IMiD-refractory patients the overall response rate (ORR) was 52% (15/29 patients, partial response or better) upon IMiD retreatment, whereas the ORR to PI retreatment was 67% (4/6 patients) in the PI-refractory group. The immunomodulatory effects of daratumumab may play a role in these high response rates in previously refractory patients. Due to the >6 month-long persistence of daratumumab in the plasma the subsequent therapies can effectively be considered as combination therapy. Furthermore, the excellent tolerability of daratumumab treatment may enable patients to recover from prior lines of treatment and receive full dosing of subsequent therapies. In conclusion, a high proportion of RRMM patients benefitted from retreatment with IMiDs and PIs after daratumumab treatment. These retreatment options should therefore be explored in RRMM patients progressing on daratumumab monotherapy., (© 2018 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd and British Society for Haematology.)

Amyloid light chain (AL) amyloidosis and multiple myeloma (MM) are both clonal plasma cell disorders, and may be concurrently present in patients. However, symptomatic MM seldom develops in patients with AL amyloidosis, while the other way around is common. With this case report, we discuss the difficulties in the differential diagnosis between AL amyloidosis and MM, and extend on the possible mechanisms involved in the development of these overlapping disorders. In addition, we provide clinicians with tools that may help improve their management and monitoring of such patients.

The bone marrow microenvironment is the preferred location of multiple myeloma, supporting tumor growth and development. It is composed of a collection of interacting subniches, including the endosteal and perivascular niche. Current in vitro models mimic either of these subniches. By developing a model combining both niches, this study aims to further enhance the ability to culture primary myeloma cells in vitro. Also, the dependency of myeloma cells on each niche was studied. A 3D bone marrow model containing two subniches was created using 3D bioprinting technology. We used a bioprintable pasty calcium phosphate cement (CPC) scaffold with seeded osteogenic multipotent mesenchymal stromal cells (O-MSCs) to model the endosteal niche, and Matrigel containing both endothelial progenitor cells (EPCs) and MSCs to model the perivascular niche. Within the model containing one or both of the niches, primary CD138 + myeloma cells were cultured and analyzed for both survival and proliferation. The 3D bone marrow model with combined subniches significantly increasing the proliferation of CD138 + myeloma cells compared to both environments separately. The developed model showed an essential role of the perivascular niche over the endosteal niche in supporting myeloma cells. The developed model can be used to study the expansion of primary myeloma cells and their interactions with varying bone marrow subniches.

Allogeneic stem cell transplantation (allo-SCT) has the potential to induce sustained remissions in patients with multiple myeloma (MM). Currently, allo-SCT is primarily performed in high-risk MM patients, most often in the setting of early relapse after first-line therapy with autologous SCT. However, the implementation of allo-SCT for MM is jeopardized by high treatment-related mortality (TRM) rates as well as high relapse rates. In this systematic review, we aimed to identify a safe allo-SCT strategy that has optimal 1-year results regarding mortality, relapse and severe GvHD, creating opportunities for post-transplantation strategies to maintain remissions in the high-risk group of relapsed MM patients. Eleven studies were included. Median PFS ranged from 5.2 to 36.8 months and OS was 13.0 to 63.0 months. The relapse related mortality at 1 year varied between 0 and 50% and TRM between 8 and 40%. Lowest GvHD incidences were reported for conditioning regimens with T-cell depletion using ATG or graft CD34+ selection. Similar strategies could lay the foundation for a post-transplant immune platform, this should be further evaluated in prospective clinical trials.

The oral proteasome inhibitor ixazomib is approved in the United States, European Union and other countries, in combination with oral lenalidomide and dexamethasone (Rd), for the treatment of patients with multiple myeloma who have received at least one prior therapy. Approval was based on the global, randomised, double-blind, placebo-controlled Phase III TOURMALINE-MM1 study of ixazomib-Rd (IRd) versus placebo-Rd in patients with relapsed/refractory multiple myeloma. IRd resulted in a significant improvement in progression-free survival versus placebo-Rd (median: 20·6 vs. 14·7 months; hazard ratio 0·74). Common toxicities observed more commonly with IRd versus placebo-Rd were thrombocytopenia, nausea, vomiting, diarrhoea, constipation, rash, peripheral neuropathy, peripheral oedema and back pain; these were generally grade 1/2 in severity except for thrombocytopenia (19% vs. 9% grade 3/4), which appeared manageable and reversible, with no differences between arms in significant bleeding or dose discontinuations. No cumulative toxicities were observed, indicating the potential feasibility of long-term IRd treatment. Safety data from TOURMALINE-MM1 are reviewed and guidance for managing clinically relevant adverse events associated with IRd is provided. Most toxicities were manageable with supportive care and dose delays or reductions as needed. Clinicians should be aware of and understand these potential side effects to optimise and prolong patient benefit., (© 2017 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.)

The aim of this analysis is to assess (1) self-reported chemotherapy-induced peripheral neuropathy (CIPN) symptoms; (2) its association with sociodemographic and clinical characteristics; and (3) treatment dose modifications and its influence on the magnitude of neurotoxicity in a population-based cohort of patients with multiple myeloma (MM). MM patients (n = 156), diagnosed between 2000 and 2014, filled out the EORTC QLQ-CIPN20 (65% response). Data on treatment, outcomes, and dose modifications were extracted from the medical files. Fifty-three percent of patients reported at least one and on average three neuropathy symptoms that bothered them the most during the past week, with tingling toes/feet as most reported. In multivariate analysis, thalidomide, especially higher cumulative dose, was associated with neuropathy (β = 0.26, CI 95% 0.27-15.34, p = 0.04) and CIPN was not associated with age, sex, time since last course of therapy, number of prior therapies, osteoarthritis, or diabetes. Dose modifications were often applied (65%). Although not statistically significant, a trend towards higher sensory (22 vs. 15 vs. 12, p = 0.22) and motor neuropathy scores (21 vs. 15 vs. 11, p = 0.36) was observed among patients receiving dose modification because of CIPN (31%) compared to those receiving a dose modification for another reason or no dose modification, without altering treatment response. CIPN is a common dose limiting side effect in patients with MM. Severity of CIPN was mainly affected by treatment with thalidomide. In spite of dose modifications, patients still reported somewhat higher neuropathy scores without altered response rates. Early dose modification based on a more reliable tool for CIPN measurements may prove value.

Donor lymphocyte infusions (DLI) can induce durable remissions in multiple myeloma (MM) patients, but this occurs rather infrequently. As the graft-versus-tumor (GvT) effect of DLI depends on the presence of host-dendritic cells (DCs), we tested in a phase I/II trial whether the efficacy of DLI could be improved by simultaneous vaccination with host-DCs. We also analyzed the possibility of further improving the GvT effect by loading the DCs with peptides of mismatched hematopoietic cell-specific minor histocompatibility antigens (mHags). Fifteen MM patients not responding to a first DLI were included. Eleven patients could be treated with a second equivalent dose DLI combined with DC vaccinations, generated from host monocytes (moDC). For four patients, the DC products did not meet the quality criteria. In four of the treated patients the DCs were loaded with host mHag peptides. Toxicity was limited and no acute GvHD occurred. Most patients developed objective anti-host T-cell responses and in one patient a distinct mHag-specific T-cell response accompanied a temporary clinical response. These findings confirm that DLI combined with host-DC vaccination, either unloaded or loaded with mHag peptides, is feasible, safe and capable of inducing host-specific T-cell responses. The limited clinical effects may be improved by developing more immunogenic DC products or by combining this therapy with immune potentiating modalities like checkpoint inhibitors.

Monoclonal gammopathy of undetermined significance (MGUS) is a common haematological disorder characterized by the presence of a monoclonal protein (M-protein). MGUS is considered an asymptomatic 'innocent' pre-malignant precursor condition of - mostly - multiple myeloma, without indication for treatment. We present three cases illustrating that MGUS can lead to serious problems. The first patient, a 51-year-old female, presented with polyneuropathy due to anti-MAG antibodies related to IgM MGUS. The second patient, a 37-year-old female, presented with proteinuria due to immunotactoid glomerulopathy caused by renal monoclonal IgG deposition associated with MGUS. The third patient, a 55-year-old female, presented with severe bleeding caused by an aspecific inhibitor of the coagulation cascade as part of IgG MGUS. In conclusion, in addition to the risk of progression to an overt haematological malignancy, MGUS can lead to severe symptoms and significant organ damage by auto-antibody activity or pathological accumulation in tissues of its toxic M-protein.

Daratumumab, a human CD38 immunoglobulin G1 kappa (IgG1κ) monoclonal antibody, has activity as monotherapy in multiple myeloma (MM). This phase 1/2 study investigated daratumumab plus lenalidomide/dexamethasone in refractory and relapsed/refractory MM. Part 1 (dose escalation) evaluated 4 daratumumab doses plus lenalidomide (25 mg/day orally on days 1-21 of each cycle) and dexamethasone (40 mg/week). Part 2 (dose expansion) evaluated daratumumab at the recommended phase 2 dose (RP2D) plus lenalidomide/dexamethasone. Safety, efficacy, pharmacokinetics, immunogenicity, and accelerated daratumumab infusions were studied. In part 1 (13 patients), no dose-limiting toxicities were observed, and 16 mg/kg was selected as the R2PD. In part 2 (32 patients), median time since diagnosis was 3.2 years, with a median of 2 prior therapies (range, 1-3 prior therapies), including proteasome inhibitors (91%), alkylating agents (91%), autologous stem cell transplantation (78%), thalidomide (44%), and lenalidomide (34%); 22% of patients were refractory to the last line of therapy. Grade 3 to 4 adverse events (≥5%) included neutropenia, thrombocytopenia, and anemia. In part 2, infusion-related reactions (IRRs) occurred in 18 patients (56%); most were grade ≤2 (grade 3, 6.3%). IRRs predominantly occurred during first infusions and were more common during accelerated infusions. In part 2 (median follow-up of 15.6 months), overall response rate was 81%, with 8 stringent complete responses (25%), 3 complete responses (9%), and 9 very good partial responses (28%). Eighteen-month progression-free and overall survival rates were 72% (95% confidence interval, 51.7-85.0) and 90% (95% confidence interval, 73.1-96.8), respectively. Daratumumab plus lenalidomide/dexamethasone resulted in rapid, deep, durable responses. The combination was well tolerated and consistent with the safety profiles observed with lenalidomide/dexamethasone or daratumumab monotherapy. This trial was registered at www.clinicaltrials.gov as #NCT01615029., (© 2016 by The American Society of Hematology.)

The anti-CD38 monoclonal antibody daratumumab is well tolerated and has high single agent activity in heavily pretreated relapsed and refractory multiple myeloma (MM). However, not all patients respond, and many patients eventually develop progressive disease to daratumumab monotherapy. We therefore examined whether pretreatment expression levels of CD38 and complement-inhibitory proteins (CIPs) are associated with response and whether changes in expression of these proteins contribute to development of resistance. In a cohort of 102 patients treated with daratumumab monotherapy (16 mg/kg), we found that pretreatment levels of CD38 expression on MM cells were significantly higher in patients who achieved at least partial response (PR) compared with patients who achieved less than PR. However, cell surface expression of the CIPs, CD46, CD55, and CD59, was not associated with clinical response. In addition, CD38 expression was reduced in both bone marrow-localized and circulating MM cells, following the first daratumumab infusion. CD38 expression levels on MM cells increased again following daratumumab discontinuation. In contrast, CD55 and CD59 levels were significantly increased on MM cells only at the time of progression. All-trans retinoic acid increased CD38 levels and decreased CD55 and CD59 expression on MM cells from patients who developed daratumumab resistance, to approximately pretreatment values. This resulted in significant enhancement of daratumumab-mediated complement-dependent cytotoxicity. Together, these data demonstrate an important role for CD38 and CIP expression levels in daratumumab sensitivity and suggest that therapeutic combinations that alter CD38 and CIP expression levels should be investigated in the treatment of MM. These trials were registered at www.clinicaltrials.gov as #NCT00574288 (GEN501) and #NCT01985126 (SIRIUS)., (© 2016 by The American Society of Hematology.)

Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) may negatively influence multiple myeloma (MM) patients' health-related quality of life (HRQOL). Dose modification is the only way to minimize CIPN. To measure CIPN in daily practice, the Indication for Common Toxicity Criteria (CTC) Grading of Peripheral Neuropathy Questionnaire (ICPNQ) was developed which can be completed within five minutes by the patient. The aims of this study were to (1) perform a psychometric evaluation of the ICPNQ and (2) examine the prevalence of CIPN and its influence on HRQOL in population-based MM patients., Methods: One hundred fifty-six MM patients, diagnosed between 2000 and 2014, completed the ICPNQ, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy 20 (EORTC QLQ-CIPN20), and EORTC QLQ-C30 (65 % response)., Results: The psychometric analyses showed a Cronbach's alpha of 0.84, 0.74, and 0.61 for, respectively, the sensory, motoric, and autonomic subscales of the ICPNQ. Test-retest reliability and construct validity were good for all subscales. Overall, 65 % of patients reported grade 2-3 neuropathy according to the ICPNQ. Patients with the highest CTC grades (grade 2 with neuropathic pain and grade 3 (38 %)) according to the ICPNQ reported significantly worse scores on all EORTC QLQ-CIPN20 subscales compared to patients with lower CTC grades (p ≤ 0.002). In addition, they reported statistically significant and clinically relevant worse HRQOL scores on almost all EORTC QLQ-C30 subscales., Conclusions: CIPN is a common side effect in MM patients, which has a negative impact on HRQOL. The ICPNQ is a valid instrument to distinguish the highest CIPN CTC grades from the lower CTC grades necessary to decide on dose modifications of chemotherapy in daily clinical practice.

Background: Multiple myeloma cells uniformly overexpress CD38. We studied daratumumab, a CD38-targeting, human IgG1κ monoclonal antibody, in a phase 1-2 trial involving patients with relapsed myeloma or relapsed myeloma that was refractory to two or more prior lines of therapy., Methods: In part 1, the dose-escalation phase, we administered daratumumab at doses of 0.005 to 24 mg per kilogram of body weight. In part 2, the dose-expansion phase, 30 patients received 8 mg per kilogram of daratumumab and 42 received 16 mg per kilogram, administered once weekly (8 doses), twice monthly (8 doses), and monthly for up to 24 months. End points included safety, efficacy, and pharmacokinetics., Results: No maximum tolerated dose was identified in part 1. In part 2, the median time since diagnosis was 5.7 years. Patients had received a median of four prior treatments; 79% of the patients had disease that was refractory to the last therapy received (64% had disease refractory to proteasome inhibitors and immunomodulatory drugs and 64% had disease refractory to bortezomib and lenalidomide), and 76% had received autologous stem-cell transplants. Infusion-related reactions in part 2 were mild (71% of patients had an event of any grade, and 1% had an event of grade 3), with no dose-dependent adverse events. The most common adverse events of grade 3 or 4 (in ≥ 5% of patients) were pneumonia and thrombocytopenia. The overall response rate was 36% in the cohort that received 16 mg per kilogram (15 patients had a partial response or better, including 2 with a complete response and 2 with a very good partial response) and 10% in the cohort that received 8 mg per kilogram (3 had a partial response). In the cohort that received 16 mg per kilogram, the median progression-free survival was 5.6 months (95% confidence interval [CI], 4.2 to 8.1), and 65% (95% CI, 28 to 86) of the patients who had a response did not have progression at 12 months., Conclusions: Daratumumab monotherapy had a favorable safety profile and encouraging efficacy in patients with heavily pretreated and refractory myeloma. (Funded by Janssen Research and Development and Genmab; ClinicalTrials.gov number, NCT00574288.).

Purpose: Cellular immunotherapy frequently fails to induce sustained remissions in patients with multiple myeloma, indicating the ability of multiple myeloma cells to evade cellular immunity. Toward a better understanding and effective therapeutic modulation of multiple myeloma immune evasion mechanisms, we here investigated the role of the tumor microenvironment in rendering multiple myeloma cells resistant to the cytotoxic machinery of T cells., Experimental Design: Using a compartment-specific, bioluminescence imaging-based assay system, we measured the lysis of luciferase-transduced multiple myeloma cells by CD4(+) or CD8(+) CTLs in the presence versus absence of adherent accessory cells of the bone marrow microenvironment. We simultaneously determined the level of CTL activation by measuring the granzyme B release in culture supernatants., Results: Bone marrow stromal cells from patients with multiple myeloma and healthy individuals, as well as vascular endothelial cells, significantly inhibited the lysis of multiple myeloma cells in a cell-cell contact-dependent manner and without substantial T-cell suppression, thus showing the induction of a cell adhesion-mediated immune resistance (CAM-IR) against CTL lysis. Further analyses revealed that adhesion to accessory cells downregulated Fas and upregulated the caspase-3 inhibitor survivin in multiple myeloma cells. Reconstitution of Fas expression with bortezomib enhanced the CTL-mediated lysis of multiple myeloma cells. Repressing survivin with the small-molecule YM155 synergized with CTLs and abrogated CAM-IR in vitro and in vivo., Conclusion: These results reveal the cell adhesion-mediated induction of apoptosis resistance as a novel immune escape mechanism and provide a rationale to improve the efficacy of cellular therapies by pharmacologic modulation of CAM-IR., (©2013 AACR.)

This systematic review of studies compared magnetic resonance imaging (MRI), (18) F-fluorodeoxyglucose positron emission tomography (FDG-PET), FDG-PET with computerized tomography (PET-CT) and CT with whole body X-Ray (WBXR) or (whole body) CT in order to provide evidence-based diagnostic guidelines in multiple myeloma bone disease. A comprehensive search of 3 bibliographic databases was performed; methodological quality was assessed using Quality Assessment of Diagnostic Accuracy Studies (QUADAS) criteria (score 1-14). Data from 32 directly comparative studies were extracted. The mean QUADAS score was 7·1 (3-11), with quality hampered mainly by a poor description of selection and execution criteria. All index tests had a higher detection rate when compared to WBXR, with up to 80% more lesions detected by the newer imaging techniques; MRI (1·12-1·82) CT (1·04-1·33), PET (1·00-1·58) and PET-CT (1·27-1·45). However, the modern imaging techniques detected fewer lesions in the skull and ribs. In a direct comparison CT and MRI performed equally with respect to detection rate and sensitivity. This systematic review supports the International Myeloma Working Group guidelines, which recommend that WBCT can replace WBXR. In our opinion, the equal performance of MRI also indicates that it is a valuable alternative. As lesions of the skull and ribs are underdiagnosed by modern imaging techniques we advise additional X-rays of these regions. The consequences of this approach are discussed., (© 2013 John Wiley & Sons Ltd.)

Donor T cells directed at hematopoietic system-specific minor histocompatibility antigens (mHags) are considered important cellular tools to induce therapeutic graft-versus-tumor (GvT) effects with low risk of graft-versus-host disease after allogeneic stem cell transplantation. To enable the clinical evaluation of the concept of mHag-based immunotherapy and subsequent broad implementation, the identification of more hematopoietic mHags with broad applicability is imperative. Here we describe novel mHag UTA2-1 with ideal characteristics for this purpose. We identified this antigen using genome-wide zygosity-genotype correlation analysis of a mHag-specific CD8(+) cytotoxic T lymphocyte (CTL) clone derived from a multiple myeloma patient who achieved a long-lasting complete remission after donor lymphocyte infusion from an human leukocyte antigen (HLA)-matched sibling. UTA2-1 is a polymorphic peptide presented by the common HLA molecule HLA-A*02:01, which is encoded by the bi-allelic hematopoietic-specific gene C12orf35. Tetramer analyses demonstrated an expansion of UTA2-1-directed T cells in patient blood samples after several donor T-cell infusions that mediated clinical GvT responses. More importantly, UTA2-1-specific CTL effectively lysed mHag(+) hematopoietic cells, including patient myeloma cells, without affecting non-hematopoietic cells. Thus, with the capacity to induce relevant immunotherapeutic CTLs, it's HLA-A*02 restriction and equally balanced phenotype frequency, UTA2-1 is a highly valuable mHag to facilitate clinical application of mHag-based immunotherapy.

To prospectively evaluate allogeneic stem cell transplantation (allo-SCT) for myeloma as part of first-line therapy, a donor versus no-donor analysis was performed of patients treated in the HOVON-50 study, a study that was originally designed to examine thalidomide combined with intensive therapy. Two hundred sixty patients having received an autologous-SCT fulfilled the criteria to be included, 138 patients without an HLA-identical sibling donor and 122 patients with a donor. After a median follow-up of 77 months, complete remission, progression-free survival (PFS), and overall survival were not significantly different between the 2 groups. PFS at 6 years was 28% for patients with a donor versus 22% for patients without a donor (P = .19) and overall survival at 6 years from high-dose melphalan was 55%, irrespective of having a donor (P = .68). Cumulative incidence of nonrelapse mortality at 6 years after autologous-SCT was 16% in the donor group versus 3% in the no-donor group (P < .001). However, PFS was significantly prolonged in the 99 patients who actually proceeded to allo-SCT compared with the 115 patients who continued maintenance or received a second high-dose melphalan, but the difference did not translate into a prolonged survival benefit. These results do not support a general application of allo-SCT in all myeloma patients as part of first-line therapy.

To improve the outcome of allogeneic stem cell transplantation (allo-SCT) in multiple myeloma as part of first-line treatment, we prospectively investigated the feasibility and efficacy of lenalidomide maintenance. Patients started maintenance 1 to 6 months after nonmyeloablative allo-SCT. Lenalidomide was dosed 10 mg on days 1 to 21 of a 28-day schedule for a total of 24 cycles. Peripheral blood samples were taken to evaluate immune modulating effects. Thirty-five eligible patients were enrolled, and 30 started with lenalidomide. After 2 cycles, 14 patients (47%) had to stop treatment, mainly because of the development of acute graft versus host disease (GVHD). In total, 13 patients (43%) stopped treatment because of development of GVHD, 5 patients (17%) because of other adverse events, and 5 patients (17%) because of progression. Responses improved in 37% of patients, and the estimated 1-year progression-free survival from start of maintenance was 69% (90% confidence interval, 53%-81%). Lenalidomide increased the frequency of human leukocyte antigen-DR(+) T cells and regulatory T cells, without correlation with clinical parameters. In conclusion, lenalidomide maintenance 10 mg daily after nonmyeloablative allo-SCT with unmanipulated graft in multiple myeloma patients is not feasible, mainly because of the induction of acute GVHD. This trial was registered at www.trialregister.nl as #NTR1645.

For relapsed multiple myeloma (MM) patients, allo-SCT is a possible treatment option, but recent data obtained using a nonmyeloablative (NMA) conditioning regimen are scarce. We retrospectively collected data from 38 relapsed MM patients who received a NMA allo-SCT from October 2001 to January 2008. In total, 18 patients (48%) were transplanted using a matched unrelated donor. The median follow-up is 2.3 years. In 16 patients (42%) the response improved and eight patients (21%) were rapidly progressive within 6 months after allo-SCT. In total, 15 patients (39%) were in CR after allo-SCT. The median PFS was 1.4 years (range, 0.1-4.9), and having a CR after allo-SCT or having chronic GVHD resulted in longer PFS. Median OS was 3.1 years (range, 0.2-7.2) and again having a CR after allo-SCT or chronic GVHD was associated with a better OS. Six patients (16%) have died from treatment-related diseases. These results indicate that NMA allo-SCT is a treatment option in relapsed MM patients and that results may be improved by strategies that enhance the CR rate after allo-SCT.

Background and Methods: To obtain efficacy and safety data on lenalidomide treatment outside of clinical trials, we analyzed the clinical data of 114 patients with refractory or relapsed multiple myeloma treated with lenalidomide on a compassionate use basis. The recommended treatment consisted of lenalidomide 25 mg given on days 1-21 of a 28-day cycle, in combination with dexamethasone. A median of 3 previous lines of therapy were given, including thalidomide in 91%. Most patients were treated until progression or intolerable toxicity., Results: The median number of cycles was 7 (range, 1-21+ cycles) with a maximum response after a median of 3 cycles (range, 1-10 cycles). The overall response rate was 69%, including complete response in 6%, very good partial response in 19%, and partial response in 44%. The response rate was not influenced by previous thalidomide and/or bortezomib treatment. The median time to progression (TTP) was 9 months and the median overall survival (OS) was 22 months. A significantly longer TTP was observed in patients who previously underwent allogeneic stem cell transplantation (12.5 months vs. 8 months; P = .036). Overall survival was significantly affected by performance status (P < .0001). Lenalidomide toxicity was predominantly hematologic (37%; Common Toxicity Criteria > or = 3) and the incidence of venous thrombotic events was low (5%) using the recommended prophylaxis., Conclusion: This analysis confirms that, outside clinical prospective trials, treatment with lenalidomide is highly effective and feasible in heavily pretreated patients with multiple myeloma.

The phase 3 trial HOVON-50 was designed to evaluate the effect of thalidomide during induction treatment and as maintenance in patients with multiple myeloma who were transplant candidates. A total of 556 patients was randomly assigned to arm A: 3 cycles of vincristine, adriamycin, and dexamethasone, or to arm B: thalidomide 200 mg orally, days 1 to 28 plus adriamycin and dexamethasone. After induction therapy and stem cell mobilization, patients were to receive high-dose melphalan, 200 mg/m(2), followed by maintenance with alpha-interferon (arm A) or thalidomide 50 mg daily (arm B). Thalidomide significantly improved overall response rate as well as quality of the response before and after high dose melphalan. Best overall response rate on protocol was 88% and 79% (P = .005), at least very good partial remission 66% and 54% (P = .005), and complete remission 31% and 23% (P = .04), respectively, in favor of the thalidomide arm. Thalidomide also significantly improved event-free survival from median 22 months to 34 months (P < .001), and prolonged progression free from median 25 months to 34 months (P < .001). Median survival was longer in the thalidomide arm, 73 versus 60 months; however, this difference was not significant (P = .77). Patients randomized to thalidomide had strongly reduced survival after relapse. This trial was registered on www.controlled-trials.com as ISRCTN06413384.

Much progress has been made in the treatment of patients with multiple myeloma (MM). The introduction of new drugs such as thalidomide, bortezomib and lenalidomide has created more possibilities for patients than many years before. In addition, autologous peripheral blood stem cell transplantation after high-dose melphalan has become the standard of care for younger patients. Allogeneic stem cell transplantation is an experimental option for those younger patients with a human leucocyte antigen identical donor. Because of these rapid developments and many treatment options we need good quality clinical studies that can guide us in what to do in everyday practice. This review will focus on those studies that have changed the treatment guidelines for patients with MM.

Recent literature suggests that after non-myeloablative allogeneic (NMA) stem cell transplantation (SCT), the incidence of extramedullary (EM) relapse in multiple myeloma (MM) patients is increased and that these relapses have a poor prognosis. However, numbers on incidence and treatment outcome are scarce. We collected data from 54 relapsed MM patients from a total group of 172 treated with sequential autologous and allogeneic NMA SCT at seven transplantation centres. There were 43 (79.6%) systemic relapses, including 6 with concurrent EM localisation. Five patients had a local EM relapse only. Six patients relapsed with only bone involvement. Patients with deletion of chromosome 13 had a higher incidence of EM relapse (30.8 versus 5.6%, P=0.06). EM relapses were treated with donor lymphocyte infusion, radiotherapy, or chemotherapy, especially with novel agents. The response rate was 45.5%, which was not different when compared to patients without EM disease (54.1%). Overall survival and progression-free survival were not significantly different in patients with EM disease, when compared to those without EM disease. In conclusion, the incidence of relapse with EM disease following allogeneic NMA SCT was 20.4%. There was no negative impact of EM relapse on response rate, overall survival and progression-free survival.