The value of quantitative immunoprecipitation mass spectrometry (QIP-MS) to identify the M-protein is being investigated in patients with monoclonal gammopathies but no data are yet available in ...high-risk smoldering myeloma (HRsMM). We have therefore investigated QIP-MS to monitor peripheral residual disease (PRD) in 62 HRsMM patients enrolled in the GEM-CESAR trial. After 24 cycles of maintenance, detecting the M-protein by MS or clonal plasma cells by NGF identified cases with a significantly shorter median PFS (mPFS; MS: not reached vs 1,4 years, p=0.001; NGF: not reached vs 2 years, p=0.0002) but reaching CR+sCR did not discriminate patients with different outcome. With NGF as a reference, the combined results of NGF and MS showed a high negative predictive value (NPV) of MS: 81% overall and 73% at treatment completion. When sequential results were considered, sustained negativity by MS or NGF was associated with a very favorable outcome with a mPFS not yet reached vs 1.66 years and 2.18 years in cases never attaining PRD or minimal residual disease (MRD) negativity, respectively. We can thus conclude that 1) the standard response categories of the IMWG do not seem to be useful for treatment monitoring in HRsMM patients, 2) MS could be used as a non-invasive, clinical valuable tool with the capacity of guiding timely bone marrow evaluations (based on its high NPV with NGF as a reference) and 3) similarly to NGF, sequential results of MS are able identify a subgroup of HRsMM patients with long-term disease control. This study was registered at www.clinicaltrials.gov (ClinicalTrials.gov identifier: NCT02415413).
Certain clinical features predict progression from smoldering to overt multiple myeloma. Patients with high-risk features who were treated with lenalidomide and dexamethasone were less likely to have ...disease progression and had a higher rate of survival than untreated patients.
Smoldering multiple myeloma is a plasma-cell proliferative disorder characterized by a monoclonal component of at least 3 g per deciliter, a level of plasma-cell infiltration into bone marrow of at least 10%, or both features.
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Currently, patients with smoldering myeloma are not treated until symptomatic disease develops.
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In the past, few drugs were effective against myeloma, and the available treatments, mainly alkylating agents, led to concerns about long-term toxicity. Attempts at early intervention with alkylating agents,
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bisphosphonates,
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antagonists of the receptor of interleukin-1β,
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or thalidomide
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failed to show a significant benefit.
Although the risk of progression to . . .
The treatment landscape for multiple myeloma has significantly evolved in the last decade. Notwithstanding, a large proportion of patients continue to relapse and novel combinations continue to be ...needed. In this phase 2 study, selinexor, a first-in-class inhibitor of exportin-1 was evaluated in combination with standard daratumumab-bortezomib-dexamethasone (DVd), for the treatment of relapsed and refractory multiple myeloma (RRMM). The aim of the trial was to assess the efficacy and safety of the combination of selinexor with DVd (S-DVd). A total of 57 patients were enrolled in the two parts of the study. Part 1 enrolled a heavily pretreated population with at least 3 prior lines of therapy and part 2 enrolled an early relapse population with at least 1 prior therapy. The primary endpoint was complete response (CR) rate in part 2 and overall response rate (ORR) in part 1. In the latter, 24 patients were treated with a median of 3 prior lines. Overall response rate (ORR) was 50% with 2 CR. Median progressionfree survival (PFS) was 7 months. In part 2, 33 patients were enrolled, with a median of 1 prior lines. ORR was 82% and CR or better was 33%. Median PFS was 24 months. In lenalidomide refractory patients, a median PFS of 22.1 months was observed. Thrombocytopenia was the most common hematological adverse event (69%; grade 3-4: 34%) and nausea, the most frequent nonhematological AE (38%; grade 3-4: 6%). 62% of the patients required dose modifications. In summary, although the primary endpoint of the study was not met, the combination of S-DVd showed encouraging clinical efficacy with a generally manageable safety profile representing a potential option for the treatment of RRMM patients.
Myelomatous plasma cells show a high heterogeneity both in their immunophenotypic characteristics as well as in their cytogenetic
features. Thus far, no extensive studies have been carried out to ...explore whether such antigenic diversity is associated with
specific genetic characteristics. We have investigated the relationship between the immunophenotypic profile at plasma cell
and both their DNA ploidy status (evaluated by flow cytometry) and specific genetic features (ascertained by fluorescence
in situ hybridization) in a large series of 915 patients with newly diagnosed multiple myeloma. The non-hyperdiploid multiple myeloma
group ( n = 454, 52%) was associated with a significantly higher frequency of positivity for CD28 and CD20 as well as a higher incidence
of CD56 − and CD117 − cases ( P < 0.001). Remarkably, 13q deletion and immunoglobulin heavy chain ( IGH ) gene rearrangements, which were significantly more common in non-hyperdiploid multiple myeloma, showed a strong association
with CD117 − cases. IGH translocation to 11q13 was associated with reactivity for CD20 ( P < 0.001), down-regulation of CD56 ( P < 0.001), and lack of expression of CD117 ( P = 0.001). By contrast, IGH translocations to other chromosome partners were almost exclusively found among CD20 − and CD117 − cases ( P < 0.001). These results suggest that genetic categories in multiple myeloma exhibit particular immunophenotypic profiles
which in turn are strongly associated with the DNA ploidy status.
Extramedullary involvement (or extramedullary disease, EMD) represents an aggressive form of multiple myeloma (MM), characterized by the ability of a clone and/or subclone to thrive and grow ...independent of the bone marrow microenvironment. Several different definitions of EMD have been used in the published literature. We advocate that true EMD is restricted to soft-tissue plasmacytomas that arise due to hematogenous spread and have no contact with bony structures. Typical sites of EMD vary according to the phase of MM. At diagnosis, EMD is typically found in skin and soft tissues; at relapse, typical sites involved include liver, kidneys, lymph nodes, central nervous system (CNS), breast, pleura, and pericardium. The reported incidence of EMD varies considerably, and differences in diagnostic approach between studies are likely to contribute to this variability. In patients with newly diagnosed MM, the reported incidence ranges from 0.5% to 4.8%, while in relapsed/refractory MM the reported incidence is 3.4 to 14%. Available data demonstrate that the prognosis is poor, and considerably worse than for MM without soft-tissue plasmacytomas. Among patients with plasmacytomas, those with EMD have poorer outcomes than those with paraskeletal involvement. CNS involvement is rare, but prognosis is even more dismal than for EMD in other locations, particularly if there is leptomeningeal involvement. Available data on treatment outcomes for EMD are derived almost entirely from retrospective studies. Some agents and combinations have shown a degree of efficacy but, as would be expected, this is less than in MM patients with no extramedullary involvement. The paucity of prospective studies makes it difficult to justify strong recommendations for any treatment approach. Prospective data from patients with clearly defined EMD are important for the optimal evaluation of treatment outcomes.
Summary Treatment of multiple myeloma has substantially changed over the past decade with the introduction of several classes of new effective drugs that have greatly improved the rates and depth of ...response. Response criteria in multiple myeloma were developed to use serum and urine assessment of monoclonal proteins and bone marrow assessment (which is relatively insensitive). Given the high rates of complete response seen in patients with multiple myeloma with new treatment approaches, new response categories need to be defined that can identify responses that are deeper than those conventionally defined as complete response. Recent attempts have focused on the identification of residual tumour cells in the bone marrow using flow cytometry or gene sequencing. Furthermore, sensitive imaging techniques can be used to detect the presence of residual disease outside of the bone marrow. Combining these new methods, the International Myeloma Working Group has defined new response categories of minimal residual disease negativity, with or without imaging-based absence of extramedullary disease, to allow uniform reporting within and outside clinical trials. In this Review, we clarify several aspects of disease response assessment, along with endpoints for clinical trials, and highlight future directions for disease response assessments.
We have examined serum microRNA expression in multiple myeloma (MM) patients at diagnosis and at complete response (CR) after autologous stem-cell transplantation (ASCT), in patients with stable ...monoclonal gammopathy of undetermined significance, and in healthy controls. MicroRNAs were first profiled using TaqMan Human MicroRNA Arrays. Differentially expressed microRNAs were then validated by individual TaqMan MicroRNA assays and correlated with CR and progression-free survival (PFS) after ASCT. Supervised analysis identified a differentially expressed 14-microRNA signature. The differential expression of miR-16 (P = 0.028), miR-17 (P = 0.016), miR-19b (P = 0.009), miR-20a (P = 0.017) and miR-660 (P = 0.048) at diagnosis and CR was then confirmed by individual assays. In addition, high levels of miR-25 were related to the presence of oligoclonal bands (P = 0.002). Longer PFS after ASCT was observed in patients with high levels of miR-19b (6 vs. 1.8 years; P < 0.001) or miR-331 (8.6 vs. 2.9 years; P = 0.001). Low expression of both miR-19b and miR-331 in combination was a marker of shorter PFS (HR 5.3; P = 0.033). We have identified a serum microRNA signature with potential as a diagnostic and prognostic tool in MM.
A 58-year-old man with no significant medical history is found to have an elevated total protein concentration (8.1 g per deciliter) on a routine blood chemical study. He is asymptomatic, and his ...physical examination is normal. Serum protein electrophoresis reveals a monoclonal spike of 2.1 g per deciliter at the gamma region; immunofixation shows a monoclonal IgG kappa protein. What further evaluation is warranted, and assuming the diagnosis of monoclonal gammopathy of undetermined significance is made, how should the patient be followed?
A 58-year-old is found to have an elevated total protein concentration (8.1 g per deciliter). He is asymptomatic. Serum protein electrophoresis reveals a monoclonal spike of 2.1 g per deciliter at the gamma region. What further evaluation is warranted? How should the patient be followed?
Foreword
This
Journal
feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author's clinical recommendations.
Stage
A 58-year-old man with no significant medical history is found to have an elevated total protein concentration (8.1 g per deciliter) on a routine blood chemical study. He is asymptomatic, and his physical examination is normal. Serum protein electrophoresis reveals a monoclonal spike of 2.1 g per deciliter at the gamma region; immunofixation shows a monoclonal IgG kappa protein. What further evaluation is warranted, and assuming the diagnosis of monoclonal gammopathy of undetermined significance is made, how should the patient be followed?
The Clinical Problem
Monoclonal gammopathy of undetermined significance (MGUS) is defined by the presence of a monoclonal . . .
Summary Background New treatment options are needed for patients with multiple myeloma that is refractory to proteasome inhibitors and immunomodulatory drugs. We assessed daratumumab, a novel ...CD38-targeted monoclonal antibody, in patients with refractory multiple myeloma. Methods In this open-label, multicentre, phase 2 trial done in Canada, Spain, and the USA, patients (age ≥18 years) with multiple myeloma who were previously treated with at least three lines of therapy (including proteasome inhibitors and immunomodulatory drugs), or were refractory to both proteasome inhibitors and immunomodulatory drugs, were randomly allocated in a 1:1 ratio to receive intravenous daratumumab 8 mg/kg or 16 mg/kg in part 1 stage 1 of the study, to decide the dose for further assessment in part 2. Patients received 8 mg/kg every 4 weeks, or 16 mg/kg per week for 8 weeks (cycles 1 and 2), then every 2 weeks for 16 weeks (cycles 3–6), and then every 4 weeks thereafter (cycle 7 and higher). The allocation schedule was computer-generated and randomisation, with permuted blocks, was done centrally with an interactive web response system. In part 1 stage 2 and part 2, patients received 16 mg/kg dosed as in part 1 stage 1. The primary endpoint was overall response rate (partial response PR + very good PR + complete response CR + stringent CR). All patients who received at least one dose of daratumumab were included in the analysis. The trial is registered with ClinicalTrials.gov , number NCT01985126. Findings The study is ongoing. In part 1 stage 1 of the study, 18 patients were randomly allocated to the 8 mg/kg group and 16 to the 16 mg/kg group. Findings are reported for the 106 patients who received daratumumab 16 mg/kg in parts 1 and 2. Patients received a median of five previous lines of therapy (range 2–14). 85 (80%) patients had previously received autologous stem cell transplantation, 101 (95%) were refractory to the most recent proteasome inhibitors and immunomodulatory drugs used, and 103 (97%) were refractory to the last line of therapy. Overall responses were noted in 31 patients (29·2%, 95% CI 20·8–38·9)—three (2·8%, 0·6–8·0) had a stringent CR, ten (9·4%, 4·6–16·7) had a very good PR, and 18 (17·0%, 10·4–25·5) had a PR. The median time to first response was 1·0 month (range 0·9–5·6). Median duration of response was 7·4 months (95% CI 5·5–not estimable) and progression-free survival was 3·7 months (95% CI 2·8–4·6). The 12-month overall survival was 64·8% (95% CI 51·2–75·5) and, at a subsequent cutoff, median overall survival was 17·5 months (95% CI 13·7–not estimable). Daratumumab was well tolerated; fatigue (42 40% patients) and anaemia (35 33%) of any grade were the most common adverse events. No drug-related adverse events led to treatment discontinuation. Interpretation Daratumumab monotherapy showed encouraging efficacy in heavily pretreated and refractory patients with multiple myeloma, with a favourable safety profile in this population of patients. Funding Janssen Research & Development.
Achieving and maintaining a high-quality response is the treatment goal for patients with newly diagnosed multiple myeloma (NDMM). The phase 3 PETHEMA/GEM2012 study, in 458 patients aged ≤65 years ...with NDMM, is evaluating bortezomib (subcutaneous) + lenalidomide + dexamethasone (VRD) for 6 cycles followed by autologous stem cell transplant (ASCT) conditioned with IV busulfan + melphalan vs melphalan and posttransplant consolidation with 2 cycles of VRD. We present grouped response analysis of induction, transplant, and consolidation. Responses deepened over time; in patients who initiated cycle 6 of induction (n = 426), the rates of a very good partial response or better were 55.6% by cycle 3, 63.8% by cycle 4, 68.3% by cycle 5, and 70.4% after induction. The complete response rate of 33.4% after induction in the intent-to-treat (ITT) population, which was similar in the 92 patients with high-risk cytogenetics (34.8%), also deepened with further treatment (44.1% after ASCT and 50.2% after consolidation). Rates of undetectable minimal residual disease (median 3 × 10−6 sensitivity) in the ITT population also increased from induction (28.8%) to transplant (42.1%) and consolidation (45.2%). The most common grade ≥3 treatment-emergent adverse events during induction were neutropenia (12.9%) and infection (9.2%). Grade ≥2 peripheral neuropathy (grouped term) during induction was 17.0%, with a low frequency of grade 3 (3.7%) and grade 4 (0.2%) events. VRD is an effective and well-tolerated regimen for induction in NDMM with deepening response throughout induction and over the course of treatment. This trial was registered at www.clinicaltrials.gov as #NCT01916252 and EudraCT as #2012-005683-10.
•VRD was effective and well tolerated before ASCT; 33.4% complete response/28.8% minimal residual disease–negative after 6 induction cycles.•Responses deepened with VRD throughout induction and over the course of treatment with few discontinuations due to toxicity.
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