Effectiveness and infectious complications of BCMA T-cell engagers in treating multiple myeloma: Real-world evidence from Sweden.

BACKGROUND: Multiple myeloma (MM), an incurable disease characterized by frequent relapses and a need for multiple treatments, often progresses to a relapse/refractory status resistant to all available drugs and drug classes. Bispecific antibodies, specifically BCMA T-cell engagers, have emerged as effective treatments for MM, demonstrating impressive efficacy. However, these treatments can adversely affect the immune system, increasing vulnerability to infections. METHODS/RESULTS: This study evaluated the efficacy and safety of BCMA T-cell engagers in 58 Swedish patients with poor MM prognosis. The patients exhibited a 69% overall response rate, with 69% survival and 60% progression-free survival at 15 months. CONCLUSIONS: Despite the risk of infectious complications, the prognosis of MM patients can be significantly improved with vigilant monitoring and proactive management of infections. This real-world data highlight the potential of BCMA T-cell engagers in treating MM, emphasizing the need for careful patient monitoring to mitigate infection risks.

Epidemiology and clinical outcomes of light-chain amyloidosis in Sweden: A nationwide population-based study.

OBJECTIVES: This study evaluated data from six Swedish national registries to fill current evidence gaps on the epidemiology, clinical burden, and overall survival (OS) associated with light-chain (AL) amyloidosis. METHODS: Patients newly diagnosed with AL amyloidosis were identified using six linked Swedish nationwide population-based registers. For each case, individuals from the general population were selected and matched with a maximum ratio of 1:5 based on age, sex, calendar year, and county. RESULTS: 846 patients newly diagnosed with AL amyloidosis and 4227 demographically matched individuals were identified. From 2011 to 2019, annual AL amyloidosis incidence increased from 10.5 to 15.1 cases per million. At baseline, patients with AL amyloidosis had a significantly higher disease burden including higher rates of cardiac and renal failure relative to the comparison group. Among patients with AL amyloidosis, 21.5% had incident heart failure and 17.1% had incident renal failure after initial diagnosis. Median OS for patients with AL amyloidosis was 56 months versus not reached in the matched general population comparison group. CONCLUSION: The incidence of newly diagnosed AL amyloidosis in Sweden increased over time with AL amyloidosis being associated with a higher risk of cardiac/renal failure and all-cause mortality compared with the general population.

Patient Confidence and Information Preferences During the Treatment Decision-making Process: Results From a Large Multiple Myeloma Patient Survey Across 12 Countries in Europe and Israel.

BACKGROUND: The relapsing nature of multiple myeloma (MM) means that patients typically receive different and multiple lines of therapy, requiring many treatment decisions over the disease course. The aim of this study was to explore patient confidence and information preferences during the treatment decision-making process. PATIENTS AND METHODS: A multinational, cross-sectional survey enrolled patients with MM. It was co-developed and distributed by Myeloma Patients Europe across 12 countries in Europe and Israel from May 2019 to March 2020. Eligibility criteria included a self-reported diagnosis of MM and being able to recall the decision-making process at the start of their latest treatment line. RESULTS: A total of 1559 patients were included, with complete responses received from 1081 (69%) patients. The median age range was 54 to 64 years; there was an equal gender split and 57% had their latest treatment decision made within the past year. Overall, 54% of patients felt "very confident" in the latest treatment decision. Patients deemed the most important information to be safety/tolerability and treatment effectiveness, but the latter was among the least frequently received. Most patients reported that their primary physician treating MM was their main source for all types of information (range, 62%-94%), with 87% of patients reporting a "very good" or "good" relationship with them. CONCLUSION: Over half of patients felt very confident in their latest treatment decision; however, patients reported not routinely receiving important treatment effectiveness information. Addressing the discrepancies between information that patients receive and consider important may enhance confidence in decision-making.

Longitudinal minimal residual disease assessment in multiple myeloma patients in complete remission - results from the NMSG flow-MRD substudy within the EMN02/HO95 MM trial.

BACKGROUND: Multiple myeloma remains an incurable disease with multiple relapses due to residual myeloma cells in the bone marrow of patients after therapy. Presence of small number of cancer cells in the body after cancer treatment, called minimal residual disease, has been shown to be prognostic for progression-free and overall survival. However, for multiple myeloma, it is unclear whether patients attaining minimal residual disease negativity may be candidates for treatment discontinuation. We investigated, if longitudinal flow cytometry-based monitoring of minimal residual disease (flow-MRD) may predict disease progression earlier and with higher sensitivity compared to biochemical assessments. METHODS: Patients from the Nordic countries with newly diagnosed multiple myeloma enrolled in the European-Myeloma-Network-02/Hovon-95 (EMN02/HO95) trial and undergoing bone marrow aspiration confirmation of complete response, were eligible for this Nordic Myeloma Study Group (NMSG) substudy. Longitdudinal flow-MRD assessment of bone marrow samples was performed to identify and enumerate residual malignant plasma cells until observed clinical progression. RESULTS: Minimal residual disease dynamics were compared to biochemically assessed changes in serum free light chain and M-component. Among 20 patients, reaching complete response or stringent complete response during the observation period, and with ≥3 sequential flow-MRD assessments analysed over time, increasing levels of minimal residual disease in the bone marrow were observed in six cases, preceding biochemically assessed disease and clinical progression by 5.5 months and 12.6 months (mean values), respectively. Mean malignant plasma cells doubling time for the six patients was 1.8 months (95% CI, 1.4-2.3 months). Minimal malignant plasma cells detection limit was 4 × 10-5. CONCLUSIONS: Flow-MRD is a sensitive method for longitudinal monitoring of minimal residual disease dynamics in multiple myeloma patients in complete response. Increasing minimal residual disease levels precedes biochemically assessed changes and is an early indicator of subsequent clinical progression. TRIAL REGISTRATION: NCT01208766.

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.

Germline variants at SOHLH2 influence multiple myeloma risk.

Multiple myeloma (MM) is caused by the uncontrolled, clonal expansion of plasma cells. While there is epidemiological evidence for inherited susceptibility, the molecular basis remains incompletely understood. We report a genome-wide association study totalling 5,320 cases and 422,289 controls from four Nordic populations, and find a novel MM risk variant at SOHLH2 at 13q13.3 (risk allele frequency = 3.5%; odds ratio = 1.38; P = 2.2 × 10-14). This gene encodes a transcription factor involved in gametogenesis that is normally only weakly expressed in plasma cells. The association is represented by 14 variants in linkage disequilibrium. Among these, rs75712673 maps to a genomic region with open chromatin in plasma cells, and upregulates SOHLH2 in this cell type. Moreover, rs75712673 influences transcriptional activity in luciferase assays, and shows a chromatin looping interaction with the SOHLH2 promoter. Our work provides novel insight into MM susceptibility.

Treatment of relapsed and refractory multiple myeloma: recommendations from the International Myeloma Working Group.

This Policy Review presents the International Myeloma Working Group's clinical practice recommendations for the treatment of relapsed and refractory multiple myeloma. Based on the results of phase 2 and phase 3 trials, these recommendations are proposed for the treatment of patients with relapsed and refractory disease who have received one previous line of therapy, and for patients with relapsed and refractory multiple myeloma who have received two or more previous lines of therapy. These recommendations integrate the issue of drug access in both low-income and middle-income countries and in high-income countries to help guide real-world practice and thus improve patient outcomes.

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.

Melflufen plus dexamethasone in relapsed/refractory multiple myeloma: long-term survival follow-up from the Phase II study O-12-M1.

An updated survival analysis was conducted for the Phase II study O-12-M1 of melphalan flufenamide (melflufen) plus dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM) with two or more prior lines of therapy (including bortezomib and lenalidomide). Partial response or better was seen in 31%. After a 46-month median overall survival (OS) follow-up, melflufen plus dexamethasone had a median OS of 20·7 months (75th percentile OS, 47·5 months). The median time-to-next treatment for melflufen plus dexamethasone was 7·9 months. In summary, melflufen plus dexamethasone resulted in sustained long-term clinical benefit in patients with RRMM.

Autoimmune disease is associated with a lower risk of progression in monoclonal gammopathy of undetermined significance.

OBJECTIVES AND METHODS: We conducted a population-based study including 19 303 individuals diagnosed with MGUS in Sweden from 1985 to 2013, with the aim to determine whether a prior history of autoimmune disease, a well-described risk factor for MGUS is a risk factor for progression of MGUS to multiple myeloma (MM) or lymphoproliferative diseases (LPs). Using the nationwide Swedish Patient registry, we identified MGUS cases with versus without an autoimmune disease present at the time of MGUS diagnosis and estimated their risk of progression. RESULTS: A total of 5612 (29.1%) MGUS cases had preceding autoimmune diseases. Using Cox proportional hazards models, we found the risk of progression from MGUS to MM (HR = 0.83, 95% CI 0.73-0.94) and LPs (HR = 0.84, 95% CI 0.75-0.94) to be significantly lower in MGUS cases with prior autoimmune disease (compared to MGUS cases without). CONCLUSIONS: In this large population-based study, a history of autoimmune disease was associated with a reduced risk of progression from MGUS to MM/other LPs. Potential underlying reason is that MGUS caused by chronic antigen stimulation is biologically less likely to undergo the genetic events that trigger progression. Our results may have implications in clinical counseling for patients with MGUS and underlying autoimmune disease.

A preseason booster prolongs the increase of allergen specific IgG4 levels, after basic allergen intralymphatic immunotherapy, against grass pollen seasonal allergy.

BACKGROUND: Allergen specific IgG4 levels have been monitored as a surrogate marker for the tolerance inducing effect of subcutaneous immunotherapy (SCIT) in many studies. Its accuracy at group level has been well established, but IgG4 has not yet found its place in the daily care of immunotherapy patients. METHODS: Intralymphatic immunotherapy (ILIT) is a novel route for allergy vaccination against pollen allergy, where an ultrasound-guided injection of 1000 SQ-U Alutard is given directly into a groin lymph node. The suggested standard dosing so far has been one injection with 4 weeks in-between. In total 3000 SQ-U with the treatment completed in 2 months. IgG4 was measured with Immulite technique and rhinoconjunctivitis symptoms were estimated with daily online questionnaires. Mann-Whitney U-test and Wilcoxon Signed Rank test were applied for comparisons between groups and within groups, respectively. RESULTS: The present study demonstrates that a single, preseason ILIT booster of 1000 SQ-U Alutard 5-grasses®, re-increases the allergen specific timothy-IgG4 levels, in patients already treated with ILIT before the previous pollen season. It also shows the feasibility of the ILIT-route for allergy vaccination of rhinitis patients, with or without concomitant asthma, with low degree of side effects and reconfirms high and sustained patient satisfaction. CONCLUSIONS: It is tempting to suggest that the allergen specific IgG4 levels can be used to build an intuitive algorithm for future clinical guidance of ILIT patients.Trial registration Is Intralymphatic Allergen Immunotherapy Effective and Safe?, ClinicalTrials.gov Identifier NCT04210193. Registered 24 December 2019-Retrospectively registered, https://clinicaltrials.gov/ct2/show/study/NCT04210193?term=NCT04210193&draw=2&rank=1.

Melflufen plus dexamethasone in relapsed and refractory multiple myeloma (O-12-M1): a multicentre, international, open-label, phase 1-2 study.

BACKGROUND: Multiple myeloma is an incurable haematological malignancy, representing over 10% of haematological cancers in the USA. We did a phase 1-2 study of melflufen and dexamethasone in patients with relapsed and refractory multiple myeloma to determine the maximum tolerated dose of melflufen and to investigate its safety and efficacy. METHODS: We did a multicentre, international, dose-confirmation and dose-expansion, open-label, phase 1-2 study in seven centres in the USA and Europe. Eligible patients were aged 18 years or older, had relapsed and refractory multiple myeloma, had received two or more previous lines of therapy (including lenalidomide and bortezomib), were refractory to their last line of therapy, and had an Eastern Cooperative Oncology Group performance status of 2 or less. In phase 1, patients received an intravenous infusion of melflufen at 15 mg, 25 mg, 40 mg, or 55 mg for 30 min on day 1 in 21-day cycles plus oral dexamethasone 40 mg weekly and did not receive melflufen as a single agent. Melflufen was also tested in a single-agent cohort late in phase 2 in a small number of patients at the maximum tolerated dose identified in phase 1. In phase 2, patients were enrolled at the maximum tolerated dose in the melflufen plus dexamethasone in the combination cohort.. The phase 1 primary objective was to determine the maximum tolerated dose. The phase 2 primary objective was to evaluate overall response rate and clinical benefit rate. This primary analysis was done per protocol, in the all-treated and efficacy-evaluable population (defined as patients who received at least two doses of melflufen and who had a response assessment after baseline). The single-agent melflufen cohort was closed on October 6, 2016, as per the recommendation by the data safety monitoring committee on the basis of interim data suggesting greater activity in the melflufen plus dexamethasone cohort. The study is completed but survival follow-up is ongoing. This study is registered with ClinicalTrials.gov, NCT01897714. FINDINGS: Patients were enrolled between July 4, 2013, and Dec 31, 2016: 23 patients in phase 1 and 58 in phase 2, including six patients from phase 1 treated at the maximum tolerated dose of melflufen 40 mg plus weekly dexamethasone. In phase 2, 45 patients were given a combination of melflufen plus dexamethasone and 13 patients were given single-agent melflufen. In phase 1, the established maximum tolerated dose was 40 mg of melflufen in combination with dexamethasone. No dose-limiting toxicities were observed in the first three dose cohorts (15 mg, 25 mg, and 40 mg). The highest dose cohort tested (55 mg) exceeded the maximum tolerated dose because four of six patients experienced grade 4 neutropenia with grade 4 thrombocytopenia also occurring in three of these patients; therefore, the planned highest dose of 70 mg was not tested. In phase 2, patients treated with combination therapy achieved an overall response rate of 31% (14 of 45 patients; 95% CI 18-47) and clinical benefit rate of 49% (22 of 45; 34-64) in the all-treated population, and 41% (14 of 34; 25-59) and 65% (22 of 34; 47-80) in the efficacy-evaluable population. In the phase 2 single-agent cohort, the overall response rate was 8% (one of 13 patients; 0·2-36·0) and the clinical benefit rate was 23% (three of 13; 5-54). Among the 45 patients given melflufen plus dexamethasone during phase 2, the most common grade 3-4 adverse events were clinically manageable thrombocytopenia (28 [62%] patients) and neutropenia (26 [58%]), and non-haematological toxicity was infrequent. 24 serious adverse events were reported in 17 (38%) of 45 patients, most commonly pneumonia (five [11%]). The most common grade 3-4 adverse events that occurred in the phase 2 single-agent cohort of 13 patients were neutropenia (nine [69%]) and thrombocytopenia (eight [62%]). Nine patients experienced serious adverse events in the single-agent cohort, most commonly thrombocytopenia (two [15%]). There were three deaths from adverse events within 30 days of treatment that were possibly related to treatment: one in the 25 mg cohort in phase 1 (due to bacteraemia) and two in the phase 2 combination cohort (one due to neutropenic sepsis and one due to Escherichia coli sepsis), each in the setting of progressive disease. INTERPRETATION: These data show that melflufen is active in patients with relapsed and refractory multiple myeloma and tolerable in most patients. These results show the feasibility of this regimen and support the initiation of additional clinical studies of melflufen in multiple myeloma, both in combination with dexamethasone as well as in triplet regimens with additional classes of drugs. FUNDING: Oncopeptides AB.

Health-related quality of life in transplant ineligible newly diagnosed multiple myeloma patients treated with either thalidomide or lenalidomide-based regimen until progression: a prospective, open-label, multicenter, randomized, phase 3 study.

Data on the impact of long term treatment with immunomodulatory drugs (IMiD) on health-related quality of life (HRQoL) is limited. The HOVON-87/NMSG18 study was a randomized, phase 3 study in newly diagnosed transplant ineligible patients with multiple myeloma, comparing melphalan-prednisolone in combination with thalidomide or lenalidomide, followed by maintenance therapy until progression (MPT-T or MPR-R). The EORTC QLQ-C30 and MY20 questionnaires were completed at baseline, after three and nine induction cycles and six and 12 months of maintenance therapy. Linear mixed models and minimal important differences were used for evaluation. 596 patients participated in HRQoL reporting. Patients reported clinically relevant improvement in global quality of life (QoL), future perspective and role and emotional functioning, and less fatigue and pain in both arms. The latter being of large effect size. In general, improvement occurred after 6-12 months of maintenance only and was independent of the World Health Organisation performance at baseline. Patients treated with MPR-R reported clinically relevant worsening of diarrhea, and patients treated with MPT-T reported a higher incidence of neuropathy. Patients who remained on lenalidomide maintenance therapy for at least three months reported clinically meaningful improvement in global QoL and role functioning at six months, remaining stable thereafter. There were no clinically meaningful deteriorations, but patients on thalidomide reported clinically relevant worsening in neuropathy. In general, HRQoL improves both during induction and maintenance therapy with immunomodulatory drugs. The side effect profile of treatment did not negatively affect global QoL, but it was, however, clinically relevant for the patients. (Clinicaltrials.gov identifier: NTR1630).

Outcome and characteristics of non-measurable myeloma: A cohort study with population-based data from the Swedish Myeloma Registry.

OBJECTIVE: We describe survival in patients with oligo- and non-secretory multiple myeloma (MM). We refer to the whole group as non-measurable MM and compare it with secretory MM. METHODS: Oligo-secretory MM was defined as M protein in serum <10 g/L and M protein in urine <200 measured as mg/day, mg/liter or mg/mmol creatinine. If patients had no M protein, they were defined as non-secretory. The groups were also subdivided by Free Light Chains (SFLC) level and ratio. RESULTS: Out of 4325 patients with symptomatic MM in the Swedish Myeloma Registry during 2008-2016 eligible for the study, 389 patients (9%) had non-measurable MM. Out of these, 253 patients (6%) had oligo-secretory and 136 (3%) had non-secretory MM. Median survival for secretory MM was 42.7 months, non-measurable MM 40.2 months, oligo-secretory MM 38.6 months, and non-secretory MM 44.6 months. Difference in overall observed survival was non-significant for all groups when compared with secretory MM. Within non-secretory MM, stem cell transplantation (SCT), 95% being auto-SCT, was significant for superior survival in multivariate analysis (HR 0.048. P = .0015). CONCLUSION: In this population-based study, we found no difference in survival between oligo- or non-secretory MM when compared with secretory MM. SCT appears to be important also for patients with non-secretory disease.

Cryotherapy as prophylaxis against oral mucositis after high-dose melphalan and autologous stem cell transplantation for myeloma: a randomised, open-label, phase 3, non-inferiority trial.

The conditioning therapy used in connection with haematopoietic stem cell transplantation (HSCT) can induce painful oral mucositis, which has negative impacts on patient quality of life and survival, as well as on health-care costs. While cooling of the oral mucosa (cryotherapy) is regarded as standard prophylaxis against oral mucositis, the long duration of the treatment affects compliance owing to side effects. In this prospective, randomised trial, 94 patients (62 males/32 females; median age 59 years, range 34-69) with a diagnosis of myeloma who were undergoing autologous HSCT were randomised 1:1 to receive cryotherapy for 7 h (N = 46) or 2 h (N = 48). Oral mucositis was evaluated prospectively. No significant difference was observed with respect to the proportion of patients who showed grades 3 and 4 toxicity according to the WHO scale (2.1 and 4.3% for 2 and 7 h, respectively; 95% CI -0.09 to 0.049; p = 0.98) as between the groups. Two hours of cryotherapy was as effective as 7 h in terms of protecting against severe oral mucositis in connection with autologous HSCT for myeloma. This trial is registered with ClinicalTrials.gov (NCT03704597).