Search

Multiple myeloma (MM) patients live longer due to more effective treatment, and we now see previously uncommon manifestations of MM, like extramedullary disease. We present a case of a 74-year-old man known with MM that relapsed with extramedullary manifestations at different locations. One of them as a gastric plasmacytoma (GP). He was successfully treated with chemoradiotherapy (Daratumumab, Bortezomib and Dexamethasone), which resulted in clinical response for 8 months, confirmed by biopsy and histopathology. Perforation of the GP occurred, and he underwent partial gastrectomy (Billroth II gastrojejunostomy). The patient’s disease progressed again 5 months after surgery, and he did not want any additional treatment. He accepted palliative care and died 10 months after the operation. A lack of knowledge about the characteristics and treatment of extramedullary MM exists, and prospective studies to investigate incidence, prognosis and treatment for extramedullary MM are needed for improving the poor prognosis of this manifestation.

Supplemental table 1. Bone marrow BI-505 concentration and MM-cell ICAM-1 expression

Purpose: This multicenter, first-in-human study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of BI-505, a human anti-ICAM-1 monoclonal antibody, in advanced relapsed/refractory multiple myeloma patients.Experimental Design: BI-505 was given intravenously, every 2 weeks, at escalating doses from 0.0004 to 20 mg/kg, with extension of therapy until disease progression for responding or stable patients receiving 0.09 mg/kg or higher doses.Results: A total of 35 patients were enrolled. The most common adverse events were fatigue, pyrexia, headache, and nausea. Adverse events were generally mild to moderate, and those attributed to study medication were mostly limited to the first dose and manageable with premedication and slower infusion. No maximum tolerated dose was identified. BI-505′s half-life increased with dose while clearance decreased, suggesting target-mediated clearance. The ICAM-1 epitopes on patient bone marrow myeloma were completely saturated at 10 mg/kg doses. Using the International Myeloma Working Group criteria, 7 patients on extended therapy had stable disease for more than 2 months.Conclusions: BI-505 can be safely administered at doses that saturate myeloma cell ICAM-1 receptors in patients. This study was registered at www.clinicaltrials.gov (NCT01025206). Clin Cancer Res; 21(12); 2730–6. ©2015 AACR.

Background Cardiac amyloidosis (CA) has been associated with poor outcomes. Screening studies suggest that CA is overlooked—especially in the elderly. Recent advances in treatment have brought attention to the disease, but data on temporal changes in CA epidemiology are sparse. Objectives The aim of this work was to describe all patients with CA in Denmark, examining changes in patient characteristics from 1998 to 2017. Methods All patients with any form of amyloidosis diagnosed from 1998 to 2017, as well as their comorbidities and pharmacotherapy, were identified in Danish nationwide registries. CA was defined as any diagnosis code for amyloidosis combined with a diagnosis code for heart failure, cardiomyopathy, or atrial fibrillation or a procedural code for pacemaker implantation, regardless of the order. The index date was defined as the date of meeting those criteria. Patients were divided into 5-year periods by index date. For comparison, we also included control subjects (1:4 ratio) from the general population. Results CA criteria were met by 619 patients. Comparing 1998-2002 vs 2013-2017, the median age at baseline increased from 67.4 years (interquartile range [IQR]: 53.9-75.2 years) to 72.3 years (IQR: 66.0-79.3 years). The frequency of male patients increased from 62.1% to 66.2%. The incidence of CA rose from 0.88 to 3.56 per 100,000 person-years in the Danish population aged ≥65 years, and the 2-year mortality decreased from 82.6% (IQR: 69.9%-90.5%) to 50.2% (IQR: 43.1%-56.9%). Compared with control subjects, the mortality among CA patients was significantly higher (log-rank test: P < 0.0001). Conclusions CA, as defined in this study, was increasingly diagnosed on a national scale. The increasing frequency of male patients and median age suggest that wild-type transthyretin amyloidosis is driving this increase. Greater recognition of earlier, less advanced cases might explain decreasing mortality., Central Illustration

In the phase 3 OPTIMISMM trial, pomalidomide, bortezomib, and dexamethasone (PVd) demonstrated superior efficacy vs bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma previously treated with lenalidomide, including those refractory to lenalidomide. This analysis evaluated outcomes in patients at first relapse (N = 226) by lenalidomide-refractory status, prior bortezomib exposure, and prior stem cell transplant (SCT). Second-line PVd significantly improved PFS vs Vd in lenalidomide-refractory (17.8 vs 9.5 months; P = 0.0276) and lenalidomide-nonrefractory patients (22.0 vs 12.0 months; P = 0.0491), patients with prior bortezomib (17.8 vs 12.0 months; P = 0.0068), and patients with (22.0 vs 13.8 months; P = 0.0241) or without (16.5 vs 9.5 months; P = 0.0454) prior SCT. In patients without prior bortezomib, median PFS was 20.7 vs 9.5 months (P = 0.1055). Significant improvement in overall response rate was also observed with PVd vs Vd in lenalidomide-refractory (85.9% vs 50.8%; P P

Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease.We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response.A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P = 0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy.Among patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.).

In 2019 the UK Myeloma Research Alliance introduced the Myeloma Risk Profile (MRP) for prediction of outcome in patients with newly diagnosed multiple myeloma (MM), ineligible for autologous stem cell transplantation. To validate the MRP in a population-based setting we performed a study of the entire cohort of transplant ineligible MM patients above 65 years in the Danish National MM Registry. Our data confirmed the value of the MRP. In a cohort of 1,377 patients, the MRP score separated patients into three distinct risk-groups with an observed hazard ratio of 2.91 for early death in high-risk versus low-risk patients.

Contains fulltext : 229254.pdf (Publisher’s version ) (Open Access)

OBJECTIVES Multiple myeloma (MM) patients are at high risk of developing infections. The risk factors for blood stream infections (BSI) in MM patients are, however, less described. The aim of this study was to analyze the epidemiology of and risk factors for BSI in an unselected MM population. METHODS Nationwide Danish MM data of 1154 patients diagnosed from 2010 to 2013 were linked with nationwide data on blood cultures (BCs; from 2010 to 2016) to assess the peak period of having a BC taken and BC positive for pathogenic microorganisms. RESULTS The highest number of BC was taken in the period from day -30 to day +180 from date of MM diagnosis. Risk factors for having a BC sampling within the peak period were as follows: immunoparesis (HR 1.5 [1.1-2.1]; P = .007), ISS-III (HR 1.3 [1.0-1.7]; P = .035), high creatinine (HR 1.4 (1.0-2.0); P = .046), and high lactate dehydrogenase (LDH) (HR 2.8 (1.6-4.7; P

Background : The UK Myeloma Research Alliance recently introduced a new clinical prediction model for outcome in newly diagnosed multiple myeloma (MM) patients not eligible for autologous hematopoietic stem-cell transplantation (ASCT) (Lancet Haematology 2019; 6: e154-66). The score or Myeloma Risk Profile, MRP, includes WHO performance status (PS), the International Staging System (ISS), age, and C-reactive protein (CRP) as prognostic variables. First a score is calculated by the formula: Score = (PS - 2) * 0.199 + (age - 74.4) * 0.0165 + (ISS - 2) * 0.212 + (log(CRP + 1) - 2.08) * 0.0315, where PS and ISS are defined as numbers between 0-4 and 1-3, respectively, and CRP is in mg/L. Next, three risk groups are defined as 1) low risk: score < -0.256, 2) medium risk: -0.256 ≤ score ≤ -0.0283, or 3) high risk: score > -0.0283. The MRP score was generated based on two prospective clinical trial cohorts, the NRCI-Myeloma XI study (ISRCTN49407852) as training set or internal validation, and the NRCI-Myeloma IX study (Blood 2011; 118, 1231-38) as test set or external validation. Both trials investigated conventional oral alkylating agents, cyclophosphamide or melphalan, in combination with thalidomide, lenalidomide, and/or bortezomib; thus including drugs typically used in treatment of elderly MM patients. Establishment of the model included 1852 patients in the training set, and 520 patients in the test set. All patients were recruited as part of clinical trials and therefore fulfilled defined inclusion and exclusion criteria. To validate the MRP score in a population-based setting we performed a study of the entire cohort of transplant ineligible MM patients in the Danish National MM Registry. Methods : The Danish MM registry started 01 January 2005. It includes registration of all diagnosed MM patients in Denmark and given first- and second-line treatment. A data validation study has been performed (J Clin Epidemiology, 2016; 8: 583-587). At 31 December 2014, 2,926 newly diagnosed treatment demanding MM patients were registered, hereof 1,803 patients were above 65 years and found ineligible for ASCT, and constituted the patient population for this study. Results: Of 1,803 transplant in-eligible but treatment demanding newly diagnosed MM patients above 65 years 426 patients had one or more missing values for calculation of the MRP score, most often this was caused by missing ISS. Thus, 1,377 patients were evaluable with a median follow-up of 40.9 months. Patients were treated according to standard of care in Denmark during the 10-years registration period which included upfront conventional alkylating agent, mostly melphalan in 37.7%, thalidomide-based in 25.6%, bortezomib-based in 26.1%, lenalidomide based in 2.7%, and only palliative, mostly steroid-based in 7.9%. The distribution of the risk groups according to MRP was as follows: low risk 28.5%, medium-risk 25.1%, and high-risk 46.4%. Ccompared to the UK datasets we had a higher proportion of high-risk patients which undoubtedly reflects that our cohort is population based. Median survivals for the 3 risk groups are presented in Table 1 and overall survival curves illustrated in Figure 1. The model performed well in separating the patients into subgroups with different survival risks. In conclusion, our real life population-based data confirm that the MRP score is a robust and valuable risk assessment tool for elderly newly diagnosed MM patients older than 65 and not eligible for ASCT. An important advantage of the MRP score is that it is calculated from simple parameters that should be part of everyday diagnostic work-up. Disclosures Vangsted: Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Jansen: Honoraria. Plesner:Takeda: Consultancy; Oncopeptides: Consultancy; Genmab: Consultancy; AbbVie: Consultancy; Celgene: Consultancy; Janssen: Consultancy, Research Funding. Frederiksen:Novartis: Research Funding; Janssen: Research Funding; Gilead: Research Funding; Alexion: Research Funding; Abbvie: Research Funding. Abildgaard:Amgen: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Janssen: Research Funding.

[Background]: Maintenance therapy following autologous stem cell transplantation (ASCT) can delay disease progression and prolong survival in patients with multiple myeloma. Ixazomib is ideally suited for maintenance therapy given its convenient once-weekly oral dosing and low toxicity profile. In this study, we aimed to determine the safety and efficacy of ixazomib as maintenance therapy following ASCT. [Methods]: The phase 3, double-blind, placebo-controlled TOURMALINE-MM3 study took place in 167 clinical or hospital sites in 30 countries in Europe, the Middle East, Africa, Asia, and North and South America. Eligible participants were adults with a confirmed diagnosis of symptomatic multiple myeloma according to International Myeloma Working Group criteria who had achieved at least a partial response after undergoing standard-of-care induction therapy followed by high-dose melphalan (200 mg/m²) conditioning and single ASCT within 12 months of diagnosis. Patients were randomly assigned in a 3:2 ratio to oral ixazomib or matching placebo on days 1, 8, and 15 in 28-day cycles for 2 years following induction, high-dose therapy, and transplantation. The initial 3 mg dose was increased to 4 mg from cycle 5 if tolerated during cycles 1–4. Randomisation was stratified by induction regimen, pre-induction disease stage, and response post-transplantation. The primary endpoint was progression-free survival (PFS) by intention-to-treat analysis. Safety was assessed in all patients who received at least one dose of ixazomib or placebo, according to treatment actually received. This trial is registered with ClinicalTrials.gov, number NCT02181413, and follow-up is ongoing. [Findings]: Between July 31, 2014, and March 14, 2016, 656 patients were enrolled and randomly assigned to receive ixazomib maintenance therapy (n=395) or placebo (n=261). With a median follow-up of 31 months (IQR 27·3–35·7), we observed a 28% reduction in the risk of progression or death with ixazomib versus placebo (median PFS 26·5 months [95% CI 23·7–33·8] vs 21·3 months [18·0–24·7]; hazard ratio 0·72, 95% CI 0·58–0·89; p=0·0023). No increase in second malignancies was noted with ixazomib therapy (12 [3%] patients) compared with placebo (eight [3%] patients) at the time of this analysis. 108 (27%) of 394 patients in the ixazomib group and 51 (20%) of 259 patients in the placebo group experienced serious adverse events. During the treatment period, one patient died in the ixazomib group and none died in the placebo group. [Interpretation]: Ixazomib maintenance prolongs PFS and represents an additional option for post-transplant maintenance therapy in patients with newly diagnosed multiple myeloma, This study was sponsored by Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company.

Background: The overall survival of patients with Multiple Myeloma has improved due to effective, often continuous, therapy. However, knowledge on the impact of long term treatment on health-related quality of life (HRQoL) is limited. Methods: The HOVON87/NMSG18 study was a prospective, randomized, phase 3 study of newly diagnosed transplant ineligible multiple myeloma patients, comparing melphalan-prednisolone in combination with thalidomide or lenalidomide, followed by thalidomide or lenalidomide maintenance therapy (MPT-T or MPR-R). The EORTC QLQ-C30 and MY20 questionnaires were completed by patients at baseline, after 3 and 9 induction cycles and after 6 and 12 months of maintenance therapy. Linear mixed models and minimal important differences were used for between and within treatment arm HRQoL evaluation. Findings: 596 of 637 eligible patients participated in HRQoL reporting. Patients in both arms reported clinical relevant improvement in global QoL, future perspective, role and emotional functioning and the summary score, and less fatigue and pain, in general occurring after 6 to 12 months of maintenance only and independent of WHO performance at baseline. MPR-R treated patients reported clinically relevant worsening of diarrhoea and MPT-T treated patients reported a higher incidence of neuropathy. Patients who remained on lenalidomide maintenance therapy for at least 3 months reported clinically meaningful improvement in global QoL, role functioning and the summary score over time, without any clinical meaningful deteriorations. In contrast, patients on thalidomide reported clinically relevant worsening of peripheral neuropathy. Interpretation: Treatment with both thalidomide- and lenalidomide-based regimens improved HRQoL, in general reaching clinical relevance during maintenance therapy only. Clinical relevant diarrhea was reported by lenaldiomide-treated and clinical relevant PNP by thalidomide-treated patients. Trial Registration Number: The study was registered at www.trialregister.nl NTR1630. Funding Statement: Dutch Cancer Society KWF VU-2008 4246, Celgene Declaration of Interests: AW reports that the study was supported by Celgene and receives honoraria Takeda and grant from Amgen. MH reports compensation for work related to the study from NTNU Department of Cancer Research and Molecular Medicine and receives grant from Celgene Aps. MS receives personal fees from Celgene, Amgen, Janssen and Takeda. SZ receives research funding from Celgene, Janssen, Takeda and Amgen and serves on advisory board for Celgene, Janssen, Takeda and Amgen. LKN has received grants from Celgene, Janssen, Amgen and Takeda, during the conduct of the study. NA receives research funding from Celgene, Janssen, Takeda and Amgen. PS receives grants from Takeda, Karyopharma, and grants and personal fees from Celgene, Janssen-Cilag. M-DL has received personal fees from Celgene. U-HM has received lecture honoraria from Amgen, Takeda, Janssen, Mundipharma, Oncopeptides and serves on advisory board for Amgen. NvdD receives grants from Celgene, Janssen pharmaceuticals, Novatis, Amgen and BMS and serves at the advisory board for Celgene, Janssen pharmaceuticals, Novartis, Amgen, Takeda, BMS, Bayer, Servier. All other authors declare no conflicting interest. Ethics Approval Statement: The study protocol was approved by the Ethics Committee and conducted in accordance with the ethical principles of the Declaration of Helsinki and the Good Clinical Practice Guidelines. The authors obtained written informed consent from all participants.

BACKGROUND Lenalidomide (LEN), an established treatment (Tx) for newly diagnosed multiple myeloma, is routinely administered until disease progression. Therefore, patients (pts) for whom LEN is no longer an option at first relapse, including LEN-refractory pts, are a clinically relevant and growing population. Tx of these pts remains challenging, as they have been poorly represented in phase 3 clinical trials. OPTIMISMM (NCT01734928), a phase 3 trial specifically designed to address this population, demonstrated significantly improved progression-free survival (PFS) with pomalidomide (POM), bortezomib (BORT), and low-dose dexamethasone (PVd) compared with BORT and low-dose dexamethasone (Vd) in pts who received 1-3 prior regimens and were 100% LEN pretreated (70% LEN refractory) (Richardson PG, et al. Lancet Oncol. 2019;20:781-794). Here, we report the efficacy and safety of PVd in pts treated after 1 prior line of therapy (LOT) according to age, prior stem cell transplant (SCT), and in pts with high-risk cytogenetic abnormalities (HR CAs). METHODS Pts were randomized 1:1 to receive PVd or Vd in 21-day cycles. POM 4 mg/day was given on days 1-14 (PVd arm only); bortezomib (BORT) 1.3 mg/m2 was given on days 1, 4, 8, and 11 of cycles 1-8 and on days 1 and 8 of cycles 9+; and dexamethasone 20 mg/day (10 mg/day for pts aged > 75 yrs) was given on the days of and after BORT. Key eligibility criteria included ≥ 2 cycles of prior LEN, including LEN-refractory pts. The primary endpoint was PFS. RESULTS As of October 26, 2017, 226 of 559 pts enrolled in OPTIMISMM had 1 prior LOT; 100 pts were aged ≤ 65 yrs (49 PVd, 51 Vd) and 126 were aged > 65 yrs (62 PVd, 64 Vd). In pts aged ≤ 65 yrs (PVd vs Vd), the median age was 58.0 vs 59.0 yrs, 63.3% vs 47.1% were male, 55.1% vs 51.0% were LEN refractory, and 83.7% vs 72.5% had prior BORT. In pts aged > 65 yrs, the median age was 73.0 vs 71.5 yrs, 58.1% vs 51.6% were male, 59.7% vs 60.9% were LEN refractory, and 41.9% vs 46.9% had prior BORT. After 1 prior LOT, PVd vs Vd significantly improved PFS in pts aged ≤ 65 yrs (median, 22.0 vs 13.1 mos; P = .0305) and those > 65 yrs (median, 17.6 vs 9.9 mos; P = .0348) (Figure). The overall response rate (ORR) was significantly higher with PVd vs Vd across the age groups (Table). The rate of ≥ very good partial response (VGPR) was 65.3% vs 17.6% in pts aged ≤ 65 yrs and 58.1% vs 26.6% in pts aged > 65 yrs. Comparable PFS and ORR outcomes were noted for an age cutoff of ≤ 70 yrs (median PFS, 17.8 vs 13.1 mos with PVd [n = 71] vs Vd [n = 78]; ORR, 88.7% [≥ VGPR, 62.0%] vs 55.1% [≥ VGPR, 21.8%], respectively) vs > 70 yrs (median PFS, 16.5 vs 9.5 mos with PVd [n = 40] vs Vd [n = 37]; ORR, 92.5% [≥ VGPR, 60.0%] vs 54.1% [≥ VGPR, 24.3%], respectively). These PFS and ORR findings were similar to those reported in pts with and pts without prior SCT (Table). Median PFS was 22.0 mos with PVd vs 13.8 mos with Vd in pts with prior SCT (P = .0241) and 16.5 vs 9.5 mos, respectively, in pts without prior SCT (P = .0454). Pts with HR CAs (n = 32 [18 PVd, 14 Vd]), defined as having a del(17p), t(4;14), or t(14;16), had a median PFS of 14.7 mos with PVd and 9.9 mos with Vd. The most common grade 3/4 treatment-emergent adverse events (TEAEs) with PVd vs Vd were neutropenia (49.0% vs 6.3%), infections (30.6% vs 14.6%), and thrombocytopenia (26.5% vs 18.8%) in pts aged ≤ 65 yrs and neutropenia (25.8% vs 12.9%), infections (27.4% vs 16.1%), and thrombocytopenia (14.5% vs 22.6%) in pts aged > 65 yrs. CONCLUSIONS In pts with LEN-pretreated relapsed or refractory multiple myeloma at first relapse, PVd reduced the risk of progression or death by 50% in pts aged ≤ 65 yrs and by 43% in pts aged > 65 yrs vs Vd. Additionally, across age subgroups, second-line Tx with PVd vs Vd significantly improved ORR and led to deeper responses. Similar findings were observed in pts with and pts without prior SCT. PVd also benefited pts with HR CAs vs Vd. Overall, TEAEs with PVd were generally consistent with the known profiles of the constituent agents. These data in pts at first relapse continue to demonstrate that PVd is effective and safe as a second-line Tx following LEN, regardless of age, prior SCT status, and presence of HR CAs. Disclosures Dimopoulos: Sanofi Oncology: Research Funding. Weisel:GSK: Honoraria; Juno: Consultancy; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Moreau:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Anderson:Amgen, Janssen, Takeda, Celgene: Consultancy, Speakers Bureau. White:Sanofi: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria. Sonneveld:SkylineDx: Research Funding; Takeda: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria, Research Funding. Jenner:Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Dürig:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Celgene: Consultancy, Other: Travel or accommodations, Speakers Bureau. Pavic:Celgene, Janssen, Takeda, Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Casal:Celgene Corporation: Employment. Srinivasan:Celgene: Employment, Equity Ownership. Nguyen:Celgene Corporation: Employment, Equity Ownership. Biyukov:Celgene: Employment, Equity Ownership. Peluso:Celgene Corporation: Employment. Richardson:Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Yes. The triplet combination is not currently approved in the US for the treatment of multiple myeloma.

Objectives Infections pose the greatest risk of early death in patients with Multiple Myeloma. However, few studies have analyzed the risk factors for infections in Multiple Myeloma patients. The aim of this study was to analyze the risk factors infections within a population-based MM cohort. Methods Using Danish registries (from 2005 to 2013), we analyzed all ICD-10 codes for infections within the first 6 months of Multiple Myeloma diagnosis in 2557 patients. Results Pneumonia and sepsis represented 46% of infections. Multivariable regression analysis showed that risk factors for pneumonia were male gender (HR 1.4; P = 0.001), ISS II (HR 1.6; P = 0.0004) and ISSIII (HR 1.8; P = 0.0004) and elevated LDH (HR 2.6; P = 0.0008). Risk factors for sepsis were high bone marrow plasma cell % (HR 1.1; P = 0.038), ISS II (HR 1.7; P = 0.007) ISS III (HR 2.0; P = 0.002) and creatinine (HR 2.1; P = 0.002). Neither immunoparesis (hypogammaglobulinemia) nor comorbidity was significant risk factors. Conclusions Our study suggests that tumor burden and renal impairment are risk factors for pneumonia and sepsis in the early phase of Multiple Myeloma.

BACKGROUND As lenalidomide (LEN) becomes increasingly established as a standard of care in the treatment (Tx) of newly diagnosed multiple myeloma (NDMM), patients (pts) for whom LEN is no longer a Tx option, including those who have become refractory to LEN, represent a clinical reality. These pts represent the largest population with MM at first relapse in the United States and a growing population globally. To date, they have been poorly studied and remain difficult to treat. Previous trials have demonstrated a clinical benefit with pomalidomide (POM) therapy in LEN-refractory pts with relapsed or refractory MM (RRMM), including those who were heavily pretreated (median of 5 prior regimens) (San Miguel et al. Lancet Oncol 2013; Richardson et al. Blood 2014; Dimopoulos et al. Blood 2016). These studies led to the approval of POM + low-dose dexamethasone (LoDEX) in RRMM. The pomalidomide, bortezomib, and low-dose dexamethasone (PVd) regimen has shown promising activity in early-phase clinical trials in LEN-refractory pts. In the phase 3 OPTIMISMM trial, PVd showed significantly improved progression-free survival (PFS) and a manageable safety profile compared with bortezomib and low-dose dexamethasone (Vd) in intent-to-treat population of pts who received 1-3 prior regimens and were 100% LEN pretreated; 70% of pts were LEN refractory (Richardson et al. ASCO 2018 abstract 8001). Here, we present efficacy and safety results in LEN-refractory and -nonrefractory pts treated at first relapse. METHODS Pts were randomized 1:1 to receive PVd or Vd in 21-day cycles: POM 4 mg/day on days 1-14 (PVd arm only); bortezomib (BORT) 1.3 mg/m2 on days 1, 4, 8, and 11 of cycles 1-8 and on days 1 and 8 of cycles 9+; and DEX 20 mg/day (10 mg/day if aged > 75 yrs) on the days of and after BORT. Key eligibility criteria included ≥ 2 cycles of prior LEN therapy, including LEN-refractory pts. BORT-exposed pts were eligible to enroll, provided they did not have progressive disease during therapy or within 60 days of the last dose of a BORT-containing regimen with BORT dosed at 1.3 mg/m2 twice weekly. The primary endpoint was PFS. RESULTS Out of 559 pts enrolled patients, 226 were treated in the second line (2L), data cut off October 26, 2017: 111 with PVd and 115 with Vd. Median follow-up for 2L pts was 16.4 mos. Among 2L pts, 129 (57.1%) were LEN refractory (64 PVd; 65 Vd) and 97 (42.9%) were LEN nonrefractory (47 PVd; 50 Vd). In LEN-refractory pts (PVd vs Vd) median age was 68.0 vs 69.0 yrs, 57.8% vs 58.5% were male, and 56.3% vs 47.7% had prior BORT. In LEN-nonrefractory pts, median age was 66.0 vs 65.5 yrs, 63.8% vs 38% were male, and 66.0% vs 72.0% had prior BORT. Other key baseline characteristics were similar between Tx arms and subgroups. Median PFS was 17.8 mos with PVd vs 9.5 mos with Vd in LEN-refractory (HR 0.55; 95% CI, 0.33-0.94; Figure 1A) and 22.0 vs 12.0 mos in LEN-nonrefractory pts (HR 0.54; 95% CI, 0.29-1.01; Figure 1B). Response outcomes are shown in Figure 2. ORR was 85.9% with PVd vs 50.8% with Vd in LEN-refractory pts (P < .001) and 95.7% vs 60.0% in LEN-nonrefractory pts (P < .001). In 2L LEN-refractory pts, the most common grade 3 or 4 treatment-emergent adverse events (TEAEs) with PVd vs Vd were neutropenia (35.9% vs 12.9%), thrombocytopenia (17.2% vs 22.6%), and anemia (17.2% vs 8.1%). Grade 3 or 4 infections occurred in 29.7% vs 21.0% of pts. In 2L LEN-nonrefractory pts, the most common grade 3 or 4 TEAEs were neutropenia (36.2% vs 6.3%) and thrombocytopenia (23.4% vs 18.8%). Grade 3 or 4 infections occurred in 27.7% vs 8.3% of pts. In 2L LEN-refractory pts, median Tx duration of PVd vs Vd was 9.7 vs 6.1 mos. In 2L LEN-nonrefractory pts, median Tx duration of Pvd vs Vd was 13.6 vs 6.6 mos. CONCLUSIONS To date, OPTIMISMM is the only phase 3 trial to address Tx of pts with RRMM following LEN exposure in early lines and the first to report data in LEN-refractory pts after first relapse. PVd reduced the risk of progression and death by 45% and 46% vs Vd in LEN-refractory and -nonrefractory pts, respectively. Further, in both subgroups, 2L Tx with PVd significantly improved ORR and led to deeper responses compared with Vd. AEs with PVd therapy were generally consistent with the known AEs of POM, BORT, and DEX. These data further demonstrate that PVd is effective and tolerable in pts for whom LEN is no longer a Tx option, including LEN-refractory pts, supporting its use as 2L therapy in RRMM. Disclosures Dimopoulos: Celgene: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria. Weisel:Amgen, Celgene, Janssen, and Sanofi: Research Funding; Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria; Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moreau:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Anderson:Celgene: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau. White:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. San-Miguel:Celgene: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; Roche: Honoraria; BMS: Honoraria; Novartis: Honoraria. Sonneveld:Amgen: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Jenner:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau. Dürig:Janssen: Consultancy, Honoraria; Celgene: Honoraria; Roche: Honoraria, Speakers Bureau. Pavic:AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Salomo:Cilag: Consultancy; Janssen: Consultancy. Yu:Celgene: Employment, Equity Ownership. Nguyen:Celgene Corporation: Employment. Bensmaine:Celgene: Equity Ownership. Peluso:Celgene Corporation: Employment, Equity Ownership. Zaki:Celgene Corporation: Employment, Equity Ownership. Richardson:BMS: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees.

Summary Bone loss in multiple myeloma (MM) is caused by an uncoupling of bone formation to resorption trigged by malignant plasma cells. Increasing evidence indicates that the bone remodelling compartment (BRC) canopy, which normally covers the remodelling sites, is important for coupled bone remodelling. Loss of this canopy has been associated with bone loss. This study addresses whether the bone remodelling in MM is improved by high-dose therapy. Bone marrow biopsies obtained from 20 MM patients, before and after first-line treatment with high-dose melphalan followed by autologous stem cell transplantation, and from 20 control patients with monoclonal gammopathy of undetermined significance were histomorphometrically investigated. This investigation confirmed that MM patients exhibited uncoupled bone formation to resorption and reduced canopy coverage. More importantly, this study revealed that a good response to anti-myeloma treatment increased the extent of formative bone surfaces with canopy, and reduced the extent of eroded surfaces without canopy, reverting the uncoupled bone remodelling, while improving canopy coverage. The association between improved coupling and the canopy coverage supports the notion that canopies are critical for the coupling of bone formation to resorption. Furthermore, this study supports the observation that systemic bone disease in MM can be reversed in MM patients responding to anti-myeloma treatment.

Purpose: This multicenter, first-in-human study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of BI-505, a human anti-ICAM-1 monoclonal antibody, in advanced relapsed/refractory multiple myeloma patients. Experimental Design: BI-505 was given intravenously, every 2 weeks, at escalating doses from 0.0004 to 20 mg/kg, with extension of therapy until disease progression for responding or stable patients receiving 0.09 mg/kg or higher doses. Results: A total of 35 patients were enrolled. The most common adverse events were fatigue, pyrexia, headache, and nausea. Adverse events were generally mild to moderate, and those attributed to study medication were mostly limited to the first dose and manageable with premedication and slower infusion. No maximum tolerated dose was identified. BI-505′s half-life increased with dose while clearance decreased, suggesting target-mediated clearance. The ICAM-1 epitopes on patient bone marrow myeloma were completely saturated at 10 mg/kg doses. Using the International Myeloma Working Group criteria, 7 patients on extended therapy had stable disease for more than 2 months. Conclusions: BI-505 can be safely administered at doses that saturate myeloma cell ICAM-1 receptors in patients. This study was registered at www.clinicaltrials.gov (NCT01025206). Clin Cancer Res; 21(12); 2730–6. ©2015 AACR.

The combination of melphalan, prednisone, and thalidomide (MPT) is considered standard therapy for newly diagnosed patients with multiple myeloma who are ineligible for stem cell transplantation. Long-term treatment with thalidomide is hampered by neurotoxicity. Melphalan, prednisone, and lenalidomide, followed by lenalidomide maintenance therapy, showed promising results without severe neuropathy emerging. We randomly assigned 668 patients between nine 4-week cycles of MPT followed by thalidomide maintenance until disease progression or unacceptable toxicity (MPT-T) and the same MP regimen with thalidomide being replaced by lenalidomide (MPR-R). This multicenter, open-label, randomized phase 3 trial was undertaken by Dutch-Belgium Cooperative Trial Group for Hematology Oncology and the Nordic Myeloma Study Group (the HOVON87/NMSG18 trial). The primary end point was progression-free survival (PFS). A total of 318 patients were randomly assigned to receive MPT-T, and 319 received MPR-R. After a median follow-up of 36 months, PFS with MPT-T was 20 months (95% confidence interval [CI], 18-23 months) vs 23 months (95% CI, 19-27 months) with MPR-R (hazard ratio, 0.87; 95% CI, 0.72-1.04; P = .12). Response rates were similar, with at least a very good partial response of 47% and 45%, respectively. Hematologic toxicity was more pronounced with MPR-R, especially grades 3 and 4 neutropenia: 64% vs 27%. Neuropathy of at least grade 3 was significantly higher in the MPT-T arm: 16% vs 2% in MPR-R, resulting in a significant shorter duration of maintenance therapy (5 vs 17 months in MPR-R), irrespective of age. MPR-R has no advantage over MPT-T concerning efficacy. The toxicity profile differed with clinically significant neuropathy during thalidomide maintenance vs myelosuppression with MPR.

Several risk scores for disease progression in Smoldering Multiple Myeloma (SMM) patients have been proposed, however, all have been developed using single center registries. To examine risk factors for time to progression (TTP) to Multiple Myeloma (MM) for SMM we analyzed a nationwide population-based cohort of 321 newly diagnosed SMM patients registered within the Danish Multiple Myeloma Registry between 2005 and 2014. Significant univariable risk factors for TTP were selected for multivariable Cox regression analyses. We found that both an M-protein ≥ 30g/l and immunoparesis significantly influenced TTP (HR 2.7, 95%CI(1.5;4.7), p=0.001, and HR 3.3, 95%CI(1.4;7.8), p=0.002 respectively). High free light chain (FLC) ratio did not significantly influence TTP in our cohort. Therefore, our data do not support the recent IMWG proposal of identifying patients with FLC ratio above 100 as having ultra-high risk of transformation to MM. Using only immunoparesis and M-protein ≥ 30g/l, we created a scoring system to identify low, intermediate and high risk SMM. This first population-based study of SMM patients confirms that an M-protein ≥ 30g/l and immunoparesis remain important risk factors for progression to MM. This article is protected by copyright. All rights reserved.

also remained sensitive to conventional myeloma chemotherapeutics (melphalan, doxorubicin and vincristine). Further analysis of the N-BP-resistant cells revealed an increased activity of the N-BP-specific target enzyme farnesyl pyrophosphate synthase, without upregulation of its gene transcription. Our results suggest that continuous exposure of myeloma cells to alendronate leads to the development of N-BP resistance. This is associated with an increased activity of farnesyl pyrophosphate synthase and does not evolve from defective apoptotic pathways. Importantly, the antitumour effects of conventional myeloma chemotherapeutics are preserved in the N-BP-resistant myeloma cells.

Background: Quantification of free monoclonal light chains in urine [Bence Jones proteins (BJPs)] is used to diagnose multiple myeloma and to evaluate response to treatment. We have developed and evaluated an optimized approach for quantification of BJPs.Methods: High-resolution gel electrophoresis of unconcentrated urine and albumin calibrators was carried out on Sebia’s Hydrasys instrument with Hydragel HR agarose gels. After staining with acid violet, the gels were scanned densitometrically. The staining intensities of BJP bands relative to the staining intensities of albumin solutions were used to determine the BJP concentrations. Results for patient samples were compared with conventional agarose gel electrophoresis on concentrated samples.Results: The relationships between staining intensity and the protein concentrations of albumin and BJPs were linear up to protein concentrations of ∼2000 mg/L. The detection limit was ∼20 mg/L. The interassay imprecision (CV) was ∼8% (n = 23, duplicate analysis), and the results (y) showed a close positive relationship to the comparison method: slope = 0.82 (confidence interval, 0.75-0.88); y-intercept = 34 (−14 to 81) mg/L; n = 29; r2 = 0.96.Conclusions: Agarose gel electrophoresis of unconcentrated urine samples together with a series of albumin calibrators followed by acid violet staining and densitometric scanning is sufficiently reproducible and sensitive to quantify clinically relevant BJPs.

Although amino-bisphosphonates (N-BPs) induce apoptosis of myeloma cells in vitro, most in-vivo studies fail to demonstrate a corresponding antitumour effect. This discrepancy might reflect the development of resistance to the antitumour effects of N-BP in myeloma cells when they are exposed to N-BP for a prolonged time. To test this hypothesis, two N-BP-sensitive human myeloma cell lines were continuously exposed to increasing concentrations of the N-BP alendronate for 6 weeks. During this treatment period, 10 out of 10 sublines developed reduced apoptotic and antiproliferative responses to alendronate treatment. This de novo alendronate resistance was accompanied by resistance to another N-BP (zoledronate) but not to an inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase or Fas ligand. Importantly, N-BP-resistant myeloma cells also remained sensitive to conventional myeloma chemotherapeutics (melphalan, doxorubicin and vincristine). Further analysis of the N-BP-resistant cells revealed an increased activity of the N-BP-specific target enzyme farnesyl pyrophosphate synthase, without upregulation of its gene transcription. Our results suggest that continuous exposure of myeloma cells to alendronate leads to the development of N-BP resistance. This is associated with an increased activity of farnesyl pyrophosphate synthase and does not evolve from defective apoptotic pathways. Importantly, the antitumour effects of conventional myeloma chemotherapeutics are preserved in the N-BP-resistant myeloma cells.

A 32-year-old man was admitted to the hospital because of oedema and 8 kg of gained weight. The oedema decreased spontaneously over weeks and there was no evidence for a nephrotic syndrome; however, the blood tests revealed a moderate pancytopenia. The patient practiced excessive physical activity at work and in his spare time, and kept a very thorough training and weight diary. Owing to a high intake of energy and protein drinks he tried to optimise his physical performance and kept a normal body mass index at 23.7. A bone marrow biopsy showed gelatinous bone marrow transformation, normally seen in critically ill patients or those with severe malnutrition. In this case, the cause is presumed to be excessive physical activity/overtraining in combination with relatively insufficient nutrition.