The biological and clinical impact of deletions before and after large chromosomal gains in multiple myeloma.

Acquisition of a hyperdiploid (HY) karyotype or immunoglobulin heavy chain (IGH) translocations are considered key initiating events in multiple myeloma (MM). To explore if other genomic events can precede these events, we analyzed whole-genome sequencing (WGS) data from 1173 MM samples. Integrating molecular time and structural variants (SV) within early chromosomal duplications, we indeed identified pre-gain deletions in 9.4% of HY patients without IGH translocations, challenging HY as the earliest somatic event. Remarkably, these deletions affected tumor suppressor genes (TSG) and/or oncogenes in 2.4% of HY patients without IGH translocations, supporting their role in MM pathogenesis. Furthermore, our study points to post-gain deletions as novel driver mechanisms in MM. Using multi-omics approaches to investigate their biological impact, we found associations with poor clinical outcome in newly diagnosed patients and profound effects on both oncogene and TSG activity, despite the diploid gene status. Overall, this study provides novel insights into the temporal dynamics of genomic alterations in MM.

Long-term outcomes and renal responses following autologous hematopoietic stem cell transplantation for light chain deposition disease: a retrospective study on behalf of the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation.

There is little long-term outcome data on the efficacy of autologous hematopoietic stem cell transplantation (ASCT) in light chain deposition disease (LCDD). We identified 51 LCDD patients in the EBMT registry who had undergone upfront ASCT between 1995 and 2021. The median serum creatinine was 280 µmol/L and 45% required renal replacement therapy (RRT) at time of transplant. The melphalan dose was 100mg/m2 in 23%, 140mg/m2 in 55% and 200 mg/m2 in 21%. The rate of very good partial response or better improved from 41% pre-transplant to 66% at Day +100 post-ASCT. In RRT-independent patients, there was a modest improvement in renal function within the first 3 months; the median eGFR increased from 44 to 51 ml/min/1.73 m2. There was no further change between 3 and 12 months post- ASCT. No patient who was RRT-independent at ASCT became RRT dependent by Day + 100 post-ASCT. Median follow-up post-ASCT was 84 months (IQR: 46-122). At 6-years post ASCT, overall survival (OS) was 88% (95% CI: 78-98%) and PFS was 44% (95% CI: 28-60%). The 2-year cumulative incidence of relapse and non-relapse mortality (NRM) was 17% (95% CI: 6-27%) and 2% (95% CI: 0-6%), respectively. The cumulative incidence of renal transplantation at 4 years after ASCT was 27% (95% CI 13-41) with renal transplantation performed between 6.3 and 52.9 months post-ASCT (median 24.7 months). ASCT represents a feasible option for LCDD patients even if RRT dependent at time of transplant. Outcomes are favourable with low NRM and good long-term OS.

Elotuzumab, lenalidomide, bortezomib, dexamethasone, and autologous haematopoietic stem-cell transplantation for newly diagnosed multiple myeloma (GMMG-HD6): results from a randomised, phase 3 trial.

BACKGROUND: The aim of this trial was to investigate the addition of the anti-SLAMF7 monoclonal antibody elotuzumab to lenalidomide, bortezomib, and dexamethasone (RVd) in induction and consolidation therapy as well as to lenalidomide maintenance treatment in transplant-eligible patients with newly diagnosed multiple myeloma. METHODS: GMMG-HD6 was a phase 3, randomised trial conducted at 43 main trial sites and 26 associated trial sites throughout Germany. Adult patients (aged 18-70 years) with previously untreated, symptomatic multiple myeloma, and a WHO performance status of 0-3, with 3 being allowed only if caused by myeloma disease and not by comorbid conditions, were randomly assigned 1:1:1:1 to four treatment groups. Induction therapy consisted of four 21-day cycles of RVd (lenalidomide 25 mg orally on days 1-14; bortezomib 1·3 mg/m2 subcutaneously on days 1, 4, 8, and 11]; and dexamethasone 20 mg orally on days 1, 2, 4, 5, 8, 9, 11, 12, and 15 for cycles 1-2) or, RVd induction plus elotuzumab (10 mg/kg intravenously on days 1, 8, and 15 for cycles 1-2, and on days 1 and 11 for cycles 3-4; E-RVd). Autologous haematopoietic stem-cell transplantation was followed by two 21-day cycles of either RVd consolidation (lenalidomide 25 mg orally on days 1-14; bortezomib 1·3 mg/m2 subcutaneously on days 1, 8, and 15; and dexamethasone 20 mg orally on days 1, 2, 8, 9, 15, and 16) or elotuzumab plus RVd consolidation (with elotuzumab 10 mg/kg intravenously on days 1, 8, and 15) followed by maintenance with either lenalidomide (10 mg orally on days 1-28 for cycles 1-3; thereafter, up to 15 mg orally on days 1-28; RVd/R or E-RVd/R group) or lenalidomide plus elotuzumab (10 mg/kg intravenously on days 1 and 15 for cycles 1-6, and on day 1 for cycles 7-26; RVd/E-R or E-RVd/E-R group) for 2 years. The primary endpoint was progression-free survival analysed in a modified intention-to-treat (ITT) population. Safety was analysed in all patients who received at least one dose of trial medication. This trial is registered with ClinicalTrials.gov, NCT02495922, and is completed. FINDINGS: Between June 29, 2015, and on Sept 11, 2017, 564 patients were included in the trial. The modified ITT population comprised 559 (243 [43%] females and 316 [57%] males) patients and the safety population 555 patients. After a median follow-up of 49·8 months (IQR 43·7-55·5), there was no difference in progression-free survival between the four treatment groups (adjusted log-rank p value, p=0·86), and 3-year progression-free survival rates were 69% (95% CI 61-77), 69% (61-76), 66% (58-74), and 67% (59-75) for patients treated with RVd/R, RVd/E-R, E-RVd/R, and E-RVd/E-R, respectively. Infections (grade 3 or worse) were the most frequently observed adverse event in all treatment groups (28 [20%] of 137 for RVd/R; 32 [23%] of 138 for RVd/E-R; 35 [25%] of 138 for E-RVd/R; and 48 [34%] of 142 for E-RVd/E-R). Serious adverse events (grade 3 or worse) were observed in 68 (48%) of 142 participants in the E-RVd/E-R group, 53 (39%) of 137 in the RVd/R, 53 (38%) of 138 in the RVd/E-R, and 50 (36%) of 138 in the E-RVd/R (36%) group. There were nine treatment-related deaths during the study. Two deaths (one sepsis and one toxic colitis) in the RVd/R group were considered lenalidomide-related. One death in the RVd/E-R group due to meningoencephalitis was considered lenalidomide and elotuzumab-related. Four deaths (one pulmonary embolism, one septic shock, one atypical pneumonia, and one cardiovascular failure) in the E-RVd/R group and two deaths (one sepsis and one pneumonia and pulmonary fibrosis) in the E-RVd/E-R group were considered related to lenalidomide or elotuzumab, or both. INTERPRETATION: Addition of elotuzumab to RVd induction or consolidation and lenalidomide maintenance in patients with transplant-eligible newly diagnosed multiple myeloma did not provide clinical benefit. Elotuzumab-containing therapies might be reserved for patients with relapsed or refractory multiple myeloma. FUNDING: Bristol Myers Squibb/Celgene and Chugai.

Genomic Classification and Individualized Prognosis in Multiple Myeloma.

PURPOSE: Outcomes for patients with newly diagnosed multiple myeloma (NDMM) are heterogenous, with overall survival (OS) ranging from months to over 10 years. METHODS: To decipher and predict the molecular and clinical heterogeneity of NDMM, we assembled a series of 1,933 patients with available clinical, genomic, and therapeutic data. RESULTS: Leveraging a comprehensive catalog of genomic drivers, we identified 12 groups, expanding on previous gene expression-based molecular classifications. To build a model predicting individualized risk in NDMM (IRMMa), we integrated clinical, genomic, and treatment variables. To correct for time-dependent variables, including high-dose melphalan followed by autologous stem-cell transplantation (HDM-ASCT), and maintenance therapy, a multi-state model was designed. The IRMMa model accuracy was significantly higher than all comparator prognostic models, with a c-index for OS of 0.726, compared with International Staging System (ISS; 0.61), revised-ISS (0.572), and R2-ISS (0.625). Integral to model accuracy was 20 genomic features, including 1q21 gain/amp, del 1p, TP53 loss, NSD2 translocations, APOBEC mutational signatures, and copy-number signatures (reflecting the complex structural variant chromothripsis). IRMMa accuracy and superiority compared with other prognostic models were validated on 256 patients enrolled in the GMMG-HD6 (ClinicalTrials.gov identifier: NCT02495922) clinical trial. Individualized patient risks were significantly affected across the 12 genomic groups by different treatment strategies (ie, treatment variance), which was used to identify patients for whom HDM-ASCT is particularly effective versus patients for whom the impact is limited. CONCLUSION: Integrating clinical, demographic, genomic, and therapeutic data, to our knowledge, we have developed the first individualized risk-prediction model enabling personally tailored therapeutic decisions for patients with NDMM.

Stromal alterations in patients with MGUS, smoldering myeloma and multiple myeloma.

The hallmark of multiple myeloma (MM) is a clonal plasma cell infiltration in the bone marrow accompanied by myelosuppression and osteolysis. Premalignant stages like monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic stages like smoldering myeloma (SMM) can progress to multiple myeloma (MM). Mesenchymal stromal cells (MSC) are an integral component of the bone marrow microenvironment and play an important role for osteoblast differentiation and hematopoietic support. While stromal alterations have been reported in MM contributing to hematopoietic insufficiency and osteolysis, it is not clear whether alterations in MSC already occur in MGUS or SMM. In this study we analyzed MSC from MGUS, SMM and MM towards their properties and functionality and performed mRNA sequencing to find underlying molecular signatures in different disease stages. A high number of senescent cells and a reduced osteogenic differentiation capacity and hematopoietic support was already present in MGUS MSC. As shown by RNA sequencing there was a broad spectrum of differentially expressed genes including genes of the BMP/TGF-signaling pathway, detected already in MGUS and that clearly increases in SMM and MM patients. Our data may help to block these signaling pathways in the future to hinder progression to multiple myeloma.

Sequence diversity of kappa light chains from patients with AL amyloidosis and multiple myeloma.

BACKGROUND: AL amyloidosis (AL) results from the misfolding of immunoglobulin light chains (IG LCs). Aim of this study was to comprehensively analyse kappa LC sequences from AL patients in comparison with multiple myeloma (MM). OBJECTIVE: We analysed IGKV/IGKJ usage and associated organ tropism and IGKV1/D-33 in terms of mutational analysis and theoretical biochemical properties. MATERIAL AND METHODS: cDNA and bulk RNA sequencing of the LCs of AL and MM patients. RESULTS: We studied 41 AL and 83 MM patients showing that IGKV1 was most expressed among kappa AL and MM, with higher frequency in AL (80% vs. 53%, p = .002). IGKV3 was underrepresented in AL (10% vs. 30%, p = .014). IGKJ2 was more commonly used in AL than in MM (39% vs. 29%). Patients with IGKV1/D-33 were associated with heart involvement (75%, p = .024). IGKV1/D-33-segments of AL had a higher mutation count (AL = 12.0 vs. MM = 10.0). FR3 and CDR3 were most frequently mutated in both, with a median mutation count in FR3 being the highest (AL = 4.0; MM = 3.5) and one mutation hotspot (FR3 (83I)) for IGKV1/D-33/IGKJ2 was associated with cardiac involvement. CONCLUSION: This study confirmed that germline usage has an influence on AL amyloidosis risk and organ involvement.

Predictors of early morbidity and mortality in newly diagnosed multiple myeloma: data from five randomized, controlled, phase III trials in 3700 patients.

Early morbidity and mortality affect patient outcomes in multiple myeloma. Thus, we dissected the incidence and causes of morbidity/mortality during induction therapy (IT) for newly diagnosed multiple myeloma (NDMM), and developed/validated a predictive risk score. We evaluated 3700 transplant-eligible NDMM patients treated in 2005-2020 with novel agent-based triplet/quadruplet IT. Primary endpoints were severe infections, death, or a combination of both. Patients were divided in a training (n = 1333) and three validation cohorts (n = 2367). During IT, 11.8%, 1.8%, and 12.5% of patients in the training cohort experienced severe infections, death, or both, respectively. Four major, baseline risk factors for severe infection/death were identified: low platelet count (<150/nL), ISS III, higher WHO performance status (>1), and age (>60 years). A risk score (1 risk factor=1 point) stratified patients in low (39.5%; 0 points), intermediate (41.9%; 1 point), and high (18.6%; ≥2 points) risk. The risk for severe infection/death increased from 7.7% vs. 11.5% vs. 23.3% in the low- vs. intermediate- vs. high-risk groups (p < 0.001). The risk score was independently validated in three trials incorporating quadruplet IT with an anti-CD38 antibody. Our analyses established a robust and easy-to-use score to identify NDMM patients at risk of severe infection/death, covering the latest quadruplet induction therapies. Trial registrations: HOVON-65/GMMG-HD4: EudraCT No. 2004-000944-26. GMMG-MM5: EudraCT No. 2010-019173-16. GMMG-HD6: NCT02495922. EMN02/HOVON-95: NCT01208766. GMMG-HD7: NCT03617731.

An early post-transplant relapse prediction score in multiple myeloma: a large cohort study from the chronic malignancies working party of EBMT.

Early relapse (ER) following Autologous Hematopoietic Cell Transplantation (AHCT) confers a poor prognosis. We therefore developed a novel scoring system to predict ER. A total of 14,367 AHCT-1 patients were transplanted between 2014 and 2019, and were conditioned with Melphalan 200 mg/m2 (Mel200) (n = 7228; 2014-2017) (training cohort); Mel200 (n = 5616; 2018-2019) or Mel140 (n = 1523; 2018-2019) (validation cohorts). PFS-12 and the Cumulative Incidence of Relapse at 12 months were 84.1% and 14.7% (training Mel200), 87.2% and 11.6% (validation Mel200), and 80.3% and 16.9% (validation Mel140), respectively. The points in the risk score were: 0, 1,2 for ISS stages I, II, and III; Disease status: 0 (CR/VGPR); 1 (PR); 2 (SD/MR); 4 (Relapse/Progression); and 1 for Karnofsky ≤ 70. The distribution of scores: 0 (24%), 1 (33.9%), 2 (29.6 %), 3 (9.5%), and ≥4 (2.7%). The score separated PFS-12, with the lowest risk group (n = 1752) having a PFS-12 of 91.7% and the highest risk group (n = 195) 57.1%. This also applied in cytogenetically high-risk patients. If the pre-score baseline risks are 15% (standard risk) and 25% (high-risk), a score of ≥4 confers calculated risks of 38% and 54%, respectively. This novel EBMT ER score, therefore, allows for the identification of five discrete prognostic groups.

Impact of newly diagnosed extramedullary myeloma on outcome after first autograft followed by maintenance: A CMWP-EBMT study.

BACKGROUND: No adequate data exist on the impact of multiple myeloma (MM) with extramedullary disease (EMD) after autograft and maintenance therapy. METHODS: We identified 808 patients with newly diagnosed MM who received first autograft, of whom 107 had EMD (83 paraskeletal and 24 organ involvement), and who had been reported to the EBMT registry December 2018. Distribution according to type of involvement was similar between the treatment groups (p = .69). For EMD, 46 (40%) received thalidomide, 59 (51%) lenalidomide, and 11 (10%) bortezomib. RESULTS: The median follow-up from maintenance start was 44 months. Three-year progression-free survival (PFS) was 52% (48%-57%) for no EMD, 56% (44%-69%) for paraskeletal involvement, and 45% (22%-68%) for organ involvement (p = .146). Early PFS (within first year) appeared to be significantly worse for organ involvement (hazard ratio, 3.40), while no significant influence was found after first year from maintenance start. Three-year overall survival (OS) was 81% (77%-84%), 88% (80%-96%), and 68% (47%-89%; p = .064), respectively. With thalidomide as reference, lenalidomide was significantly associated with better PFS and OS, whereas bortezomib appeared to improve outcome specifically in EMD. CONCLUSION: Lenalidomide maintenance is standard of care for MM without EMD, whereas extramedullary organ involvement remains a significant risk factor for worse outcome, especially for early events after maintenance start.

Widespread amyloidogenicity potential of multiple myeloma patient-derived immunoglobulin light chains.

BACKGROUND: In a range of human disorders such as multiple myeloma (MM), immunoglobulin light chains (IgLCs) can be produced at very high concentrations. This can lead to pathological aggregation and deposition of IgLCs in different tissues, which in turn leads to severe and potentially fatal organ damage. However, IgLCs can also be highly soluble and non-toxic. It is generally thought that the cause for this differential solubility behaviour is solely found within the IgLC amino acid sequences, and a variety of individual sequence-related biophysical properties (e.g. thermal stability, dimerisation) have been proposed in different studies as major determinants of the aggregation in vivo. Here, we investigate biophysical properties underlying IgLC amyloidogenicity. RESULTS: We introduce a novel and systematic workflow, Thermodynamic and Aggregation Fingerprinting (ThAgg-Fip), for detailed biophysical characterisation, and apply it to nine different MM patient-derived IgLCs. Our set of pathogenic IgLCs spans the entire range of values in those parameters previously proposed to define in vivo amyloidogenicity; however, none actually forms amyloid in patients. Even more surprisingly, we were able to show that all our IgLCs are able to form amyloid fibrils readily in vitro under the influence of proteolytic cleavage by co-purified cathepsins. CONCLUSIONS: We show that (I) in vivo aggregation behaviour is unlikely to be mechanistically linked to any single biophysical or biochemical parameter and (II) amyloidogenic potential is widespread in IgLC sequences and is not confined to those sequences that form amyloid fibrils in patients. Our findings suggest that protein sequence, environmental conditions and presence and action of proteases all determine the ability of light chains to form amyloid fibrils in patients.

A phase I first-in-man study to investigate the pharmacokinetics and safety of liposomal dexamethasone in patients with progressive multiple myeloma.

Despite the introduction of multiple new drugs and combination therapies, conventional dexamethasone remains a cornerstone in the treatment of multiple myeloma (MM). Its application is, however, limited by frequent adverse effects of which the increased infection rate may have the strongest clinical impact. The efficacy-safety ratio of dexamethasone in MM may be increased by encapsulation in long-circulating PEG-liposomes, thereby both enhancing drug delivery to MM lesions and reducing systemic corticosteroid exposure. We evaluated the preliminary safety and feasibility of a single intravenous (i.v.) infusion of pegylated liposomal dexamethasone phosphate (Dex-PL) in heavily pretreated relapsing or progressive symptomatic MM patients within a phase I open-label non-comparative interventional trial at two dose levels. In the 7 patients that were enrolled (prior to having to close the study prematurely due to slow recruitment), Dex-PL was found to be well tolerated and, as compared to conventional dexamethasone, no new or unexpected adverse events were detected. Pharmacokinetic analysis showed high and persisting concentrations of dexamethasone in the circulation for over a week after i.v. administration, likely caused by the long-circulation half-life of the liposomes that retain dexamethasone as the inactive phosphate prodrug form, something which could significantly limit systemic exposure to the active parent drug. Thus, despite the limitations of this small first-in-man trial, Dex-PL seems safe and well tolerated without severe side effects. Follow-up studies are needed to confirm this in a larger patient cohort and to evaluate if i.v. Dex-PL can provide a safer and more efficacious dexamethasone treatment option for MM.

Addition of isatuximab to lenalidomide, bortezomib, and dexamethasone as induction therapy for newly diagnosed, transplantation-eligible patients with multiple myeloma (GMMG-HD7): part 1 of an open-label, multicentre, randomised, active-controlled, phase 3 trial.

BACKGROUND: Anti-CD38 monoclonal antibodies have consistently shown increased efficacy when added to standard of care for patients with multiple myeloma. We aimed to assess the efficacy of isatuximab in addition to lenalidomide, bortezomib, and dexamethasone in patients with newly diagnosed transplantation-eligible multiple myeloma. METHODS: This open-label, multicentre, randomised, active-controlled, phase 3 trial was done at 67 academic and oncology practice centres in Germany. This study is ongoing and divided into two parts; herein, we report results from part 1. Eligible patients were aged 18-70 years; had a confirmed diagnosis of untreated multiple myeloma requiring systemic treatment and a WHO performance status of 0-2; and were eligible for induction therapy, high-dose melphalan and autologous haematopoietic stem-cell transplantation, and maintenance treatment. Patients were randomly assigned (1:1) to receive three 42-day cycles of induction therapy either with isatuximab plus lenalidomide, bortezomib, and dexamethasone (isatuximab group) or lenalidomide, bortezomib, and dexamethasone alone (control group) using a web-based system and permuted blocks. Patients in both groups received lenalidomide (25 mg orally on days 1-14 and 22-35), bortezomib (1·3 mg/m2 subcutaneously on days 1, 4, 8, 11, 22, 25, 29, and 32), and dexamethasone (20 mg orally on days 1-2, 4-5, 8-9, 11-12, 15, 22-23, 25-26, 29-30, and 32-33). Isatuximab was given as 10 mg/kg intravenously on days 1, 8, 15, 22, and 29 of cycle 1 and on days 1, 15, and 29 of cycles 2 and 3. The primary endpoint was minimal residual disease (MRD) negativity assessed by flow cytometry, in the intention-to-treat (ITT) population. This study is registered with ClinicalTrials.gov, NCT03617731. FINDINGS: Between Oct 23, 2018, and Sep 22, 2020, 660 patients were included in the ITT analysis (331 in the isatuximab group and 329 in the control group). 654 (99%) patients were White, two were African, one was Arabic, and three were Asian. 250 (38%) were women and 410 (62%) were men. The median age was 59 years (IQR 54-64). MRD negativity after induction therapy was reached in 166 (50%) patients in the isatuximab group versus 117 (36%) in the control group (OR 1·82 [95% CI 1·33-2·48]; p=0·00017). Median follow-up time from start to end of induction therapy was 125 days (IQR 125-131) versus 125 days (125-132). At least one grade 3 or 4 adverse event occurred in 208 (63%) of 330 patients versus 199 (61%) of 328 patients. Neutropenia of grade 3 or 4 occurred in 77 (23%) versus 23 (7%) patients and infections of grade 3 or 4 occurred in 40 (12%) versus 32 (10%) patients. Among 12 deaths during induction therapy, one death due to septic shock in the isatuximab group and four deaths (one cardiac decompensation, one hepatic and renal failure, one cardiac arrest, and one drug-induced enteritis) in the control group were considered treatment-related. INTERPRETATION: Addition of isatuximab to lenalidomide, bortezomib, and dexamethasone for induction therapy improved rates of MRD negativity with no new safety signals in patients with newly diagnosed transplantation-eligible multiple myeloma. FUNDING: Sanofi and Bristol Myers Squibb (Celgene).

Opportunities for Participation in Randomized Controlled Trials for Patients with Multiple Myeloma: Trial Access Depends on Restrictive Eligibility Criteria and Patient Expectations.

Randomized controlled trials (RCT) are the driver of therapeutic innovations. However, it has been frequently shown that less than 5% of adult cancer patients enroll in clinical trials, although 70% of patients are considered as being willing to participate. Barriers to trial participation have been extensively studied. Although there is evidence that trial participation correlates with improved survival and reduced mortality, the rate of participation has not changed substantially. We provide retrospective data from a single-center analysis of 411 patients with multiple myeloma (MM) who were treated at the University Hospital Duesseldorf in Germany between January 2014 and December 2016. Each patient was analyzed for the real-world possibility of participating in a clinical study, based on the inclusion and exclusion (I/E) criteria and the recruiting period of open studies. The overall rate of study participation was 19%. A total of 53% of NDMM patients were eligible for first-line studies (GMMG-HD6, LenaMain). Of these, 80% consented to enrolment (42% of all). In contrast, only 38% of the RRMM population was eligible (GMMG-Relapse, Castor, Tourmaline, Admyre). Of these, only 22% (7% of all) consented. This was confirmed by virtual analysis, showing that only 29% of all RRMM patients would have been eligible for six internationally recruiting trials leading to later drug approval. The majority of cases were rendered ineligible by only one I/E criterion. The most common criteria were study-specific (prior therapies or refractory disease to a specific drug), kidney disease, and previous malignancy, followed by internal, neurologic, and infectious disease. In summary, this single-center analysis showed that I/E criteria permit study participation for most NNDM patients, with a dramatic decrease in the RRMM population. This is aggravated by the fact that the willingness for study participation also significantly declines in RRMM. Thus, addressing patient expectations and priorities seems to be the most promising approach to increasing patient enrollment in clinical trials.

18F-FDG-PET/CT in relapsed multiple myeloma: Are prognostic thresholds different from first-line therapy?

PURPOSE: While 18F-FDG PET/CT yields valuable prognostic information for patients in first-line therapy of multiple myeloma (MM), its prognostic relevance in relapse is not established. Available studies of relapsed MM describe prognostic thresholds for frequently used PET/CT parameters that are significantly higher than those identified in the first-line setting. The purpose of this study was to evaluate the prognostic role of PET/CT in relapsed MM, based on parameters used in the first-line setting. METHODS: Our retrospective study included 36 patients with MM who had received autologous or allogeneic stem cell transplantation, suffered at least one relapse, and underwent FDG-PET/CT at relapse. Number of focal bone lesions (FL), maximal standardised uptake value (SUVmax), and presence of PET-positive extramedullary lesions (EMD) were analysed. RESULTS: For the number of FLs, the prognostic value was demonstrated with a cut-off of > 3 (median OS 3.8 months vs. not reached, p = 0.003). Median OS of patients with SUVmax ≤ 4 was not reached, while it was 3.9 months in patients with SUVmax > 4 (p = 0.014). Presence of EMD was a significant prognostic parameter too, with median OS of 3.6 months versus not reached (p = 0.004). The above-mentioned parameters showed prognostic significance for PFS as well. Combination of higher ISS stage and PET/CT parameters identified patients with particularly short OS (3.7 months vs. not reached, p < 0.001) and PFS (3.6 vs. 11.7 months p < 0.001). CONCLUSION: The PET/CT parameters SUVmax > 4, nFL > 3, and presence of EMD identify patients with poor prognosis not only in the first-line setting but also in relapsed MM.

Oral ixazomib-dexamethasone vs oral pomalidomide-dexamethasone for lenalidomide-refractory, proteasome inhibitor-exposed multiple myeloma: a randomized Phase 2 trial.

Multiple myeloma (MM) patients typically receive several lines of combination therapy and first-line treatment commonly includes lenalidomide. As patients age, they become less tolerant to treatment, requiring convenient/tolerable/lenalidomide-free options. Carfilzomib and/or bortezomib-exposed/intolerant, lenalidomide-refractory MM patients with ≥2 prior lines of therapy were randomized 3:2 to ixazomib-dexamethasone (ixa-dex) (n = 73) or pomalidomide-dexamethasone (pom-dex) (n = 49) until progression/toxicity. Median progression-free survival (mPFS) was 7.1 vs 4.8 months with ixa-dex vs pom-dex (HR 0.847, 95% CI 0.535-1.341, P = 0.477; median follow-up: 15.3 vs 17.3 months); there was no statistically significant difference between arms. In patients with 2 and ≥3 prior lines of therapy, respectively, mPFS was 11.0 vs 5.7 months (HR 1.083, 95% CI 0.547-2.144) and 5.7 vs 3.7 months (HR 0.686, 95% CI 0.368-1.279). Among ixa-dex vs pom-dex patients, 69% vs 81% had Grade ≥3 treatment-emergent adverse events (TEAEs), 51% vs 53% had serious TEAEs, 39% vs 36% had TEAEs leading to drug discontinuation, 44% vs 32% had TEAEs leading to dose reduction, and 13% vs 13% died on study. Quality of life was similar between arms and maintained during treatment. Ixa-dex represents an important lenalidomide-free, oral option for this heavily pretreated, lenalidomide-refractory, proteasome inhibitor-exposed population.Trial registration: ClinicalTrials.gov number, NCT03170882.

De Novo Sequencing of Antibody Light Chain Proteoforms from Patients with Multiple Myeloma.

In multiple myeloma diseases, monoclonal immunoglobulin light chains (LCs) are abundantly produced, with, as a consequence in some cases, the formation of deposits affecting various organs, such as the kidney, while in other cases remaining soluble up to concentrations of several g·L-1 in plasma. The exact factors crucial for the solubility of LCs are poorly understood, but it can be hypothesized that their amino acid sequence plays an important role. Determining the precise sequences of patient-derived LCs is therefore highly desirable. We establish here a novel de novo sequencing workflow for patient-derived LCs, based on the combination of bottom-up and top-down proteomics without database search. PEAKS is used for the de novo sequencing of peptides that are further assembled into full length LC sequences using ALPS. Top-down proteomics provides the molecular masses of proteoforms and allows the exact determination of the amino acid sequence including all posttranslational modifications. This pipeline is then used for the complete de novo sequencing of LCs extracted from the urine of 10 patients with multiple myeloma. We show that for the bottom-up part, digestions with trypsin and Nepenthes digestive fluid are sufficient to produce overlapping peptides able to generate the best sequence candidates. Top-down proteomics is absolutely required to achieve 100% final sequence coverage and characterize clinical samples containing several LCs. Our work highlights an unexpected range of modifications.

Selective elimination of immunosuppressive T cells in patients with multiple myeloma.

Elimination of suppressive T cells may enable and enhance cancer immunotherapy. Here, we demonstrate that the cell membrane protein SLAMF7 was highly expressed on immunosuppressive CD8+CD28-CD57+ Tregs in multiple myeloma (MM). SLAMF7 expression associated with T cell exhaustion surface markers and exhaustion-related transcription factor signatures. T cells from patients with a high frequency of SLAMF7+CD8+ T cells exhibited decreased immunoreactivity towards the MART-1aa26-35*A27L antigen. A monoclonal anti-SLAMF7 antibody (elotuzumab) specifically depleted SLAMF7+CD8+ T cells in vitro and in vivo via macrophage-mediated antibody-dependent cellular phagocytosis (ADCP). Anti-SLAMF7 treatment of MM patients depleted suppressive T cells in peripheral blood. These data highlight SLAMF7 as a marker for suppressive CD8+ Treg and suggest that anti-SLAMF7 antibodies can be used to boost anti-tumoral immune responses in cancer patients.

Salvage autologous transplant and lenalidomide maintenance vs. lenalidomide/dexamethasone for relapsed multiple myeloma: the randomized GMMG phase III trial ReLApsE.

The role of salvage high-dose chemotherapy and autologous stem cell transplantation (sHDCT/ASCT) for relapsed and/or refractory multiple myeloma (RRMM) in the era of continuous novel agent treatment has not been defined. This randomized, open-label, phase III, multicenter trial randomized patients with 1st-3rd relapse of multiple myeloma (MM) to a transplant arm (n = 139) consisting of 3 Rd (lenalidomide 25 mg, day 1-21; dexamethasone 40 mg, day 1, 8, 15, and 22; 4-week cycles) reinduction cycles, sHDCT (melphalan 200 mg/m2), ASCT, and lenalidomide maintenance (10 mg/day) or to a control arm (n = 138) of continuous Rd. Median PFS was 20.7 months in the transplant and 18.8 months in the control arm (HR 0.87; 95% CI 0.65-1.16; p = 0.34). Median OS was not reached in the transplant and 62.7 months in the control arm (HR 0.81; 95% CI 0.52-1.28; p = 0.37). Forty-one patients (29%) did not receive the assigned sHDCT/ASCT mainly due to early disease progression, adverse events, and withdrawal of consent. Multivariate landmark analyses from the time of sHDCT showed superior PFS and OS (p = 0.0087/0.0057) in patients who received sHDCT/ASCT. Incorporation of sHDCT/ASCT into relapse treatment with Rd was feasible in 71% of patients and did not significantly prolong PFS and OS on ITT analysis while patients who received sHDCT/ASCT may have benefitted.