Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder. SMM is distinguished from monoclonal gammopathy of undetermined significance by a much higher risk of progression to ...multiple myeloma (MM). There have been major advances in the diagnosis, prognosis, and management of SMM in the last few years. These include a revised disease definition, identification of several new prognostic factors, a classification based on underlying cytogenetic changes, and new treatment options. Importantly, a subset of patients previously considered SMM is now reclassified as MM on the basis of biomarkers identifying patients with an ≥80% risk of progression within 2 years. SMM has assumed greater significance on the basis of recent trials showing that early therapy can be potentially beneficial to patients. As a result, there is a need to accurately diagnose and risk-stratify patients with SMM, including routine incorporation of modern imaging and laboratory techniques. In this review, we outline current concepts in diagnosis and risk stratification of SMM, and provide specific recommendations on the management of SMM.
There is a need for novel therapies for relapsed or refractory multiple myeloma, and B-cell maturation antigen (BCMA) is a validated target. Teclistamab is a bispecific antibody that binds BCMA and ...CD3 to redirect T cells to multiple myeloma cells. The aim of the MajesTEC-1 study was to evaluate the safety, tolerability, and preliminary efficacy of teclistamab in patients with relapsed or refractory multiple myeloma.
This open-label, single-arm, phase 1 study enrolled patients with multiple myeloma who were relapsed, refractory, or intolerant to established therapies. Teclistamab was administered intravenously (range 0·3−19·2 μg/kg once every 2 weeks or 19·2−720 μg/kg once per week) or subcutaneously (range 80−3000 μg/kg once per week) in different cohorts, with step-up dosing for 38·4 μg/kg or higher doses. The primary objectives were to identify the recommended phase 2 dose (part one) and characterise teclistamab safety and tolerability at the recommended phase 2 dose (part two). Safety was assessed in all patients treated with at least one dose of teclistamab. Efficacy was analysed in response-evaluable patients (ie, patients who received at least one dose of teclistamab and had at least one post-baseline response evaluation). This ongoing trial is registered with ClinicalTrials.gov, NCT03145181.
Between June 8, 2017, and March 29, 2021, 219 patients were screened for study inclusion, and 157 patients (median six previous therapy lines) were enrolled and received at least one dose of teclistamab (intravenous n=84; subcutaneous n=73). 40 patients were administered the recommended phase 2 dose, identified as once per week subcutaneous administration of teclistamab at 1500 μg/kg, after 60 μg/kg and 300 μg/kg step-up doses (median follow-up 6·1 months, IQR 3·6−8·2). There were no dose-limiting toxicities at the recommended phase 2 dose in part one. In the 40 patients treated at the recommended phase 2 dose, the most common treatment-emergent adverse events were cytokine release syndrome in 28 (70%; all grade 1 or 2 events) and neutropenia in 26 (65%) patients (grade 3 or 4 in 16 40%). The overall response rate in response-evaluable patients treated at the recommended phase 2 dose (n=40) was 65% (95% CI 48−79); 58% achieved a very good partial response or better. At the recommended phase 2 dose, the median duration of response was not reached. 22 (85%) of 26 responders were alive and continuing treatment after 7·1 months’ median follow-up (IQR 5·1−9·1). At the recommended phase 2 dose, teclistamab exposure was maintained above target exposure levels, and consistent T-cell activation was reported.
Teclistamab is a novel treatment approach for relapsed or refractory multiple myeloma. At the recommended phase 2 dose, teclistamab showed promising efficacy, with durable responses that deepened over time, and was well tolerated, supporting further clinical development.
Janssen Research & Development.
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 . . .
Summary
In the phase III CASTOR trial, daratumumab, bortezomib and dexamethasone (D‐Vd) significantly extended progression‐free survival compared with bortezomib and dexamethasone (Vd) alone in ...patients with relapsed/refractory multiple myeloma (RRMM). Here, we present patient‐reported outcomes (PROs) from the CASTOR trial. PROs were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30‐item (EORTC QLQ‐C30) and the EuroQol 5‐dimensional descriptive system questionnaire. Treatment effects through Cycle 8 were measured by a repeated measures mixed‐effects model. After Cycle 8, PROs were only collected for patients in the D‐Vd group who continued on daratumumab monotherapy. Compliance rates for PRO assessments were high and similar between treatment groups. Mean changes from baseline were generally similar between treatment groups for EORTC QLQ‐C30 global health status (GHS), functioning and symptoms, and did not exceed 10 points for either treatment group. Subgroup analyses were consistent with the results observed in the overall population. There was no change in patients' health‐related quality of life for the first eight cycles of therapy; thereafter, patients treated with daratumumab over the long‐term reported improvements in GHS and pain. These results complement the significant clinical benefits observed with D‐Vd in patients with RRMM and support its use in this patient population.
Multiple myeloma Kumar, Shaji K; Rajkumar, Vincent; Kyle, Robert A ...
Nature reviews. Disease primers,
07/2017, Letnik:
3
Journal Article
Recenzirano
Multiple myeloma is a malignancy of terminally differentiated plasma cells, and patients typically present with bone marrow infiltration of clonal plasma cells and monoclonal protein in the serum ...and/or urine. The diagnosis of multiple myeloma is made when clear end-organ damage attributable to the plasma cell proliferative disorder or when findings that suggest a high likelihood of their development are present. Distinguishing symptomatic multiple myeloma that requires treatment from the precursor stages of monoclonal gammopathy of undetermined significance and smouldering multiple myeloma is important, as observation is the standard for those conditions. Much progress has been made over the past decade in the understanding of disease biology and individualized treatment approaches. Several new classes of drugs, such as proteasome inhibitors and immunomodulatory drugs, have joined the traditional armamentarium (corticosteroids, alkylating agents and anthracyclines) and, along with high-dose therapy and autologous haemopoietic stem cell transplantation, have led to deeper and durable clinical responses. Indeed, an increasing proportion of patients are achieving lasting remissions, raising the possibility of cure for this disease. Success will probably depend on using combinations of effective agents and treating patients in the early stages of disease, such as patients with smouldering multiple myeloma.
Summary
Relapsed/refractory multiple myeloma (RRMM) is known to have a high burden of disease and complications associated with refractoriness to prior lines of therapy. Severe pain and fatigue ...symptoms and impairments in physical and emotional functioning have been strongly linked to reduced health‐related quality of life (HRQoL) in patients with RRMM. Assessment of patient reported‐outcome measures from the pivotal, Phase II HORIZON study (OP‐106; NCT02963493) in patients with RRMM (n = 64) demonstrated that melphalan flufenamide (melflufen) plus dexamethasone treatment preserved HRQoL. Patients had clinically meaningful improvements, even after eight treatment cycles, in relevant scales such as global health status/QoL, physical functioning, emotional functioning, pain, and fatigue. Patients with triple‐class–refractory disease (n = 50) displayed similar improvements. Patient‐reported outcome deterioration was delayed for a substantial amount of time in patients who experienced a response to melflufen plus dexamethasone treatment relative to patients who did not experience a response. These findings support the notion that treatment with melflufen plus dexamethasone may sustain or improve HRQoL over time in patients with RRMM, including in patients with triple‐class–refractory disease for whom outcomes are generally worse. The clinical benefits observed in patients from the HORIZON trial are encouraging and supportive of translation into real‐world practice.
Multiple myeloma (MM) is a heterogeneous disease with certain genetic features eg, t(4;14), del17p associated with worse outcome. The introduction of thalidomide, lenalidomide, and bortezomib has ...dramatically improved the outlook for patients with MM, but their relative benefit (or harm) for different genetic patient subgroups remains unclear. Unfortunately, the small number of patients in each subgroup frequently limits the analysis of high-risk patients enrolled in clinical trials. Strategies that result in survival of high-risk genetic subgroups approximating that of patients lacking high-risk features are said to overcome the poor prognostic impact of these high-risk features. This outcome has been difficult to achieve, and studies in this regard have so far been limited by inadequate sample size. In contrast, strategies that compare the survival of high-risk genetic subgroups randomized to different treatment arms can identify approaches that improve survival. This type of analysis is clinically useful, even if the absolute gains do not improve outcomes to levels seen in patients without high-risk cytogenetics. Reviewing available data in high-risk MM from this perspective, it appears that bortezomib has frequently been associated with improved survival, whereas thalidomide maintenance has sometimes been associated with a shorter survival.
Summary
Immunoparesis is the suppression of normal polyclonal immunoglobulins and is present in most patients with newly diagnosed multiple myeloma (MM). The association of immunoparesis at ...diagnosis, and particularly its recovery along with treatment, with survival in patients ineligible for autologous stem‐cell transplantation (ASCT) has not been well established. This retrospective study evaluated the impact of immunoparesis in 431 patients diagnosed with MM, ineligible for ASCT, with a median overall survival of 36 months 95% confidence interval (CI): 31–40. Immunoparesis was present in 81.2% of patients at diagnosis and was associated with a trend to a worse overall response rate (ORR: 84.8% vs. 74.9%; OR 1.88 (95% CI: 0.97–3.63), shorter progression‐free survival (PFS) 22.0 vs. 18.2 months; hazard ratio (HR) 0.775; 95%CI: 0.590–1.018; p = 0.066, and overall survival (OS) (45.9 vs. 34.2 months; HR 0.746; 95% CI: 0.551–1.010; p = 0.057). Twenty‐four per cent of patients who had immunoparesis at diagnosis recovered polyclonal immunoglobulins in the follow‐up period. Interestingly, these patients had a better ORR (96.3% vs. 68.2%; OR 12.29 (95% CI: 3.77–40.06), PFS (HR 0.703; 95CI%: 0.526–0.941; p = 0.018) and OS (HR 0.678; 95 CI%: 0.503–0.913; p = 0.011) than patients who did not recover it. In summary, restoring a healthy immune system along with first‐line treatment in patients with MM, not receiving ASCT, is associated with better outcomes.
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