The choice of serum-free light chain analysis method could potentially have clinical consequences for myeloma patients.

Multiple myeloma (MM) is a disease, that at times poses diagnostic and monitoring challenges. Over the last decades laboratory methods have been expanded with serum free light chain (FLC) analysis. Alerted by two index cases with clinical impact due to failure of the FLC analysis to indicate a disease progression, we aimed to identify any clinical consequences due to known differences between FLC analysis methods. We applied two FLC analysis methods (Freelite Binding Site [FBS] and N-Latex Siemens [NLS]) on all patients with MM and monoclonal gammopathy of uncertain significance diagnosed/followed up at Södra Älvsborg Hematology Unit, from April to December 2022. From a total of 123 patients with malignant plasma cell disorder, we identified five cases (4.1%) where solely the FBS method, as opposed to NLS, urine and serum electrophoresis, could support diagnosis or detect progression. The consequences of this discrepancy included not only change of diagnosis or delayed therapy but also change of treatment. Our findings indicate that a stronger awareness of the potential weaknesses of different FLC methods is needed, which calls for a closer collaboration between clinical chemists and hematologists.

Regional differences in treatment and outcome for myeloma patients in Sweden: A population based Swedish myeloma register study.

BACKGROUND: We wanted to evaluate if health care for multiple myeloma (MM) patients is equal in different regions of Sweden. AIM: To study differences in survival for MM depending on health care region and early use of modern treatment. METHODS AND RESULTS: Data from the Swedish Myeloma Register from patients diagnosed between 2008 and 2017 was used. Cohorts were defined by the six healthcare regions (labeled A-F) in Sweden and modern initial treatment was defined as including certain drug combinations. To adjust for time to treatment bias, survival analyses were performed also for patients alive 6 months after diagnosis. In all treated MM patients (n = 5326), we observed a superior overall survival (OS) for region A compared to all other regions (p < .01 for all respectively). After adjusting for time to treatment there was also a superior survival in the region with highest use of modern initial treatment (region A) compared to the regions defined in the study as having intermediate and low use (p < .01 for both). In patients receiving autologous stem cell transplantation (ASCT) a superior survival was observed for region A compared to all regions besides region B. Similar results were seen when adjusting for a time to treatment bias. In patients not receiving ASCT, 75 years or older and adjusted for time to treatment bias, a difference was noted only between region A and E (log rank p = .04, HR 1.2, CI 1.00-1.44, p = .06). In multivariate analyses including age, international staging system stage and time period of diagnosis, differences in survival remained for patients receiving ASCT between region A versus C, D, E and F (p = .01, p < .01, p < .01, p = .03). CONCLUSION: We observed a superior survival in region A for patients receiving ASCT. Explanations may be higher usage of modern initial treatment or regional residual confounding. For patients not receiving ASCT, 75 years or older, differences in survival could be adjusted for.

Serum metabolomic profiling correlated with ISS and clinical outcome for multiple myeloma patients treated with high-dose melphalan and autologous stem cell transplantation.

The metabolome, which is the final down-stream global product of metabolic processes in organisms, is not sufficiently described in multiple myeloma (MM) patients. The aim of this study was, therefore, to study the serum metabolomic profile using proton nuclear magnetic resonance (1H-NMR) spectroscopy, and its relationship to clinical characteristics and patient outcome. Serum samples, which were taken at diagnosis, from 201 MM patients who underwent high-dose melphalan followed by autologous stem cell transplantation as the first-line therapy, were analyzed. We found that the metabolomic profile differed between patients with different MM International Staging System (ISS) stages. The profile revealed increased levels of cholesterol, phospholipids, high-density lipoprotein, low-density lipoprotein, apolipoproteins A1 and A2, valine, and leucine in ISS I patients compared with ISS III patients. The metabolomic profile also differed between patients with IgA and IgG paraproteins, predominantly because of higher levels of high- and low-density lipoprotein subfractions in IgA patients. The exact pathway of metabolism leading to accumulation of these metabolites is still elusive, but this study indicates an area of interest for further investigation in the search for new therapy targets and prognostic markers for this disease.

Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial.

BACKGROUND: Panobinostat is a potent oral pan-deacetylase inhibitor that in preclinical studies has synergistic anti-myeloma activity when combined with bortezomib and dexamethasone. We aimed to compare panobinostat, bortezomib, and dexamethasone with placebo, bortezomib, and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma. METHODS: PANORAMA1 is a multicentre, randomised, placebo-controlled, double-blind phase 3 trial of patients with relapsed or relapsed and refractory multiple myeloma who have received between one and three previous treatment regimens. Patients were randomly assigned (1:1) via an interactive web-based and voice response system, stratified by number of previous treatment lines and by previous use of bortezomib, to receive 21 day cycles of placebo or panobinostat (20 mg; on days 1, 3, 5, 8, 10, 12, orally), both in combination with bortezomib (1·3 mg/m(2) on days 1, 4, 8, 11, intravenously) and dexamethasone (20 mg on days 1, 2, 4, 5, 8, 9, 11, 12, orally). Patients, physicians, and the investigators who did the data analysis were masked to treatment allocation; crossover was not permitted. The primary endpoint was progression-free survival (in accordance with modified European Group for Blood and Marrow Transplantation criteria and based on investigators' assessment) and was analysed by intention to treat. The study is ongoing, but no longer recruiting, and is registered at ClinicalTrials.gov, number NCT01023308. FINDINGS: 768 patients were enrolled between Jan 21, 2010, and Feb 29, 2012, with 387 randomly assigned to panobinostat, bortezomib, and dexamethasone and 381 to placebo, bortezomib, and dexamethasone. Median follow-up was 6·47 months (IQR 1·81-13·47) in the panobinostat group and 5·59 months (2·14-11·30) in the placebo group. Median progression-free survival was significantly longer in the panobinostat group than in the placebo group (11·99 months [95% CI 10·33-12·94] vs 8·08 months [7·56-9·23]; hazard ratio [HR] 0·63, 95% CI 0·52-0·76; p<0·0001). Overall survival data are not yet mature, although at the time of this analysis, median overall survival was 33·64 months (95% CI 31·34-not estimable) for the panobinostat group and 30·39 months (26·87-not estimable) for the placebo group (HR 0·87, 95% CI 0·69-1·10; p=0·26). The proportion of patients achieving an overall response did not differ between treatment groups (235 [60·7%, 95% CI 55·7-65·6] for panobinostat vs 208 [54·6%, 49·4-59·7] for placebo; p=0·09); however, the proportion of patients with a complete or near complete response was significantly higher in the panobinostat group than in the placebo group (107 [27·6%, 95% CI 23·2-32·4] vs 60 [15·7%, 12·2-19·8]; p=0·00006). Minimal responses were noted in 23 (6%) patients in the panobinostat group and in 42 (11%) in the placebo group. Median duration of response (partial response or better) was 13·14 months (95% CI 11·76-14·92) in the panobinostat group and 10·87 months (9·23-11·76) in the placebo group, and median time to response (partial response or better) was 1·51 months (1·41-1·64) in the panobinostat group and 2·00 months (1·61-2·79) in the placebo group. Serious adverse events were reported in 228 (60%) of 381 patients in the panobinostat group and 157 (42%) of 377 patients in the placebo group. Common grade 3-4 laboratory abnormalities and adverse events (irrespective of association with study drug) included thrombocytopenia (256 [67%] in the panobinostat group vs 118 [31%] in the placebo group), lymphopenia (202 [53%] vs 150 [40%]), diarrhoea (97 [26%] vs 30 [8%]), asthenia or fatigue (91 [24%] vs 45 [12%]), and peripheral neuropathy (67 [18%] vs 55 [15%]). INTERPRETATION: Our results suggest that panobinostat could be a useful addition to the treatment armamentarium for patients with relapsed or relapsed and refractory multiple myeloma. Longer follow up will be necessary to determine whether there is any effect on overall survival. FUNDING: Novartis Pharmaceuticals.

Melphalan 100 mg/m2 with stem cell support as first relapse treatment is safe and effective for myeloma patients with long remission after autologous stem cell transplantation.

INTRODUCTION: Today, a number of therapeutic options are available as the patient with myeloma relapses from initial treatment with high-dose melphalan and autologous stem cell transplantation (ASCT). For patients who experience a durable response to primary ASCT, retreatment with high-dose melphalan is recommended by many current guidelines. Yet, toxicity is an important aspect in the choice of relapse treatment, and a second ASCT in this setting could be associated with enhanced toxicity. As the goal for the treatment for relapsed myeloma should be disease control while maintaining quality of life, lower doses of melphalan might be preferable. METHODS AND OBJECTIVES: In this retrospective study, we account for the outcome of 66 patients with myeloma in first systemic relapse after ASCT, who were treated with intermediate-dose melphalan, 100 mg/m2, and stem cell support (MEL 100). The aim was to evaluate this treatment in relation to prior response duration after initial ASCT and with respect to response rate, toxicity and survival. RESULTS: The overall response rate was 62%. There was limited, mostly haematological, toxicity, and no treatment-related mortality was observed. The median progression-free survival (PFS) was 8.5 months, and the median overall survival was 24 months. Patients with time to progression of 34 months or more (n=17; ≥75th percentile) after initial ASCT had a median PFS of 12.5 months after MEL 100. CONCLUSION: For patients with a long-lasting response after ASCT, MEL 100 could be a therapeutic option with low toxicity and with efficacy comparable to newer immunomodulatory drugs.