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Summary: Although Janus kinase (JAK) inhibitors have demonstrated efficacy for treating autoimmune disorders and myeloproliferative neoplasms, their efficacy in treating other types of cancer has not been clearly demonstrated. We evaluated oral ruxolitinib (15 mg twice daily) with oral methylprednisolone (40 mg every other day) for multiple myeloma (MM) patients with progressive disease who had received a proteasome inhibitor, lenalidomide, glucocorticosteroids and three or more prior regimens. All of the planned 29 patients had been enrolled with follow‐up until 28 April 2022. Median lines of prior therapy were 6 (range 3–12). Cytogenetics and fluorescent in situ hybridization were evaluable in 28 patients; 9 (32%) and 17 (70%) patients showed high‐risk cytogenetics and/or 1q+, respectively. The overall response rate was 31%. The median duration of response was 13.1 (range 2.8–22.0) months. Median progression‐free survival rate was 3.4 (range 0.5–24.6) months, Overall, the treatment was well tolerated. The combination of ruxolitinib and methylprednisolone demonstrated significant clinical activity among previously heavily‐treated MM patients, and responses were achieved among patients who had high‐risk cytogenetics. This is the first clinical study to show activity of JAK inhibitors in combination with steroids for MM patients and expands the potential use of these drugs to those with cancers other than myeloproliferative neoplasms. [ABSTRACT FROM AUTHOR]

Carfilzomib, a proteasome inhibitor, is approved in the United States as a single agent, and in combination with dexamethasone or lenalidomide/dexamethasone (KRd) for relapsed or refractory multiple myeloma (MM). Under the single-agent and KRd approvals, carfilzomib is administered as a 10-minute IV infusion on days 1, 2, 8, 9, 15, and 16 of 28- day cycles (20mg/m2 [cycle 1, days 1-2]; 27mg/m2 thereafter).Thismulticenter, single-arm, phase 1/2 study, Community Harmonized Assessment of Myeloma Patients via an Integrated Oncology Network-1 (CHAMPION-1), evaluated once-weekly carfilzomib with dexamethasone in relapsed, or relapsed and refractory MM (1-3 prior therapies). Patients received carfilzomib (30-minute IVinfusion) on days 1, 8, and15 of 28-day cycles. Thephase 1 portion used a 3 1 3 dose-escalation scheme to determine the maximum tolerated dose (MTD) of carfilzomib. During phase 2, patients received carfilzomib on the same schedule at theMTD. Patients received dexamethasone (40mg) on days 1, 8, 15, and 22; dexamethasone was omitted on day 22 for cycles 91. A total of 116 patients were enrolled. The MTD was 70 mg/m2, and 104 patients (phase 1/2) received carfilzomib 70 mg/m2. At 70 mg/m2, the median number of prior regimens was 1; and 52% were bortezomib-refractory. At 70 mg/m2, the most common grade ≥3 adverse events were fatigue (11%) and hypertension (7%). Overall response rate at 70 mg/m2 was 77%. Median progression-free survival was 12.6 months. These findings merit additional evaluation of the once-weekly dosing regimen. This trial was registered at www.clinicaltrials. gov as #NCT01677858. [ABSTRACT FROM AUTHOR]

Purpose: Fatigue is a common problem among multiple myeloma (MM) patients. Armodafinil is a drug known to promote wakefulness, which is related to modafinil, a compound that improves fatigue in some cancer patients treated with chemotherapeutic agents. We investigated whether armodafinil could reduce cancer-related fatigue in MM patients. Methods: This double-blind, placebo-controlled phase 3 trial evaluated the efficacy of armodafinil in MM patients with evidence of moderate fatigue. Patients were randomized to one of two arms: treatment-only, with armodafinil given at 150 mg/daily for 56 days, or placebo-first, with placebo given on days 1-28, followed by armodafinil administered at 150 mg daily on days 29-56. Fatigue was measured on days 1 (pre-dose: baseline), 15, 28, 43, and 56 using seven separate assessments, including four patient-reported outcomes of fatigue and related quality of life measures, as well as three objective measures of cognitive function. Results: Overall toxicities were similar between treatment groups. No significant differences were observed between the placebo-first and the treatment-only arms after 28 days. Treatment with armodafinil for 28 additional days did not produce responses. Both placebo-first and treatment-only patients showed similar significant improvements in three patient-reported measures and one objective task at day 28 compared to baseline. Placebo-first patients improved on eight additional measures (one patient-reported measure, six subscales, and one objective task), suggesting a strong placebo effect in this patient population. Conclusions: Evaluation and treatment of cancer-related fatigue continues to be challenging; a clear definition of this symptom and better assessment tools are needed. [ABSTRACT FROM AUTHOR]

The article discusses a study of increased activity of circulating proteasomes in myeloma cells and efficacy of proteasome inhibitor (PI) bortezomib in anti-myeloma treatments. It discusses its enzymatic activity of circulating proteasome components in patients with hematologic disorders including acute myeloid leukemia, lymphocytic leukemias, and myelodysplastic syndrome.

Panobinostat is a histone deacetylase inhibitor that has shown synergistic preclinical anti-myeloma activity when combined with other agents, recently exhibiting synergy with the alkylating agent melphalan (Sanchez et al., Leuk Res 35(3):373-379, ). This phase 1/2 trial investigated the safety and efficacy of panobinostat in combination with melphalan for relapsed/refractory multiple myeloma patients. There were four different trial treatment schedules due to tolerability issues, with the final treatment schedule (treatment schedule D) consisting of panobinostat (15 or 20 mg) and melphalan (0.05 or 0.10 mg/kg), both administered on days 1, 3, and 5 of a 28-day cycle. A total of 40 patients were enrolled; 3 in treatment schedule A, 9 in schedule B, 7 in schedule C, and finally 21 schedule D. Patients had been treated with a median of four regimens (range, 1-16) and two prior bortezomib-containing regimens (range, 0-9). Maximum-tolerated dose was established at 20 mg panobinostat and 0.05 mg/kg melphalan in treatment schedule D. Overall, 3 patients (7.5 %) achieved ≥partial response (two very good PRs and one PR) while 23 exhibited stable disease and 14 showed progressive disease. All three responders were enrolled in cohort 2 of treatment schedule B (panobinostat 20 mg thrice weekly continuously with melphalan 0.05 mg/kg on days 1, 3, and 5). Neutropenia and thrombocytopenia were common, with 30.8 and 23.1 % of patients exhibiting ≥grade 3, respectively. Panobinostat + melphalan appears to have tolerability issues in a dosing regimen capable of producing a response. Care must be taken to balance tolerability and efficacy with this combination. [ABSTRACT FROM AUTHOR]

Bendamustine, active in multiple myeloma ( MM), is a bifunctional mechlorethamine derivative with alkylating properties. Bortezomib, approved to treat MM, is effective in combination with alkylators. The tolerability and efficacy of bendamustine plus bortezomib in relapsed/refractory MM was assessed in an open-label, dose-escalating, phase I/ II study. Patients aged ≥18 years received intravenous bendamustine 50, 70, or 90 mg/m2 (days 1 and 4) plus bortezomib 1·0 mg/m2 (days 1, 4, 8, and 11) for up to eight 28-day cycles. No dose-limiting toxicity was observed after cycle 1; bendamustine 90 mg/m2 plus bortezomib 1·0 mg/m2 was designated the maximum tolerated dose ( MTD). The most common grade 3/4 adverse events were leucopenia (58%), neutropenia (50%), lymphopenia (45%), and thrombocytopenia (30%). Primary efficacy measure was overall response rate ( ORR), which was the combined complete response ( CR), very good partial response ( VGPR), partial response ( PR), and minimal response ( MR). ORR was 48% (one CR, two VGPR, nine PR, and seven MR) for all 40 enrolled patients, 52% (16/31) at the MTD (90 mg/m2), and 42% and 46% for prior use of bortezomib ( n = 31) or alkylators ( n = 28) respectively. Bendamustine plus bortezomib was well tolerated with promising efficacy in this heavily pretreated population. [ABSTRACT FROM AUTHOR]

Summary The combination of pegylated liposomal doxorubicin (PLD), bortezomib and dexamethasone has shown efficacy in the treatment of multiple myeloma (MM) patients. Our earlier retrospective study suggested that modification of the doses, schedules and route of administration of these drugs appears to reduce toxicity without compromising anti-MM activity. As a result, we evaluated this modified drug combination in the frontline setting in a prospective multicentre phase II trial. Thirty-five previously untreated MM patients were enrolled. Dexamethasone IV 40 mg, bortezomib 1 mg/m2 and PLD 5 mg/m2 were administered on days 1, 4, 8 and 11 of a 4-week cycle. Patients were treated to their maximum response plus two additional cycles. The treatment regimen was discontinued after a maximum of eight cycles. Our modified schedule and dosing regimen achieved a high overall response rate of 86%, while showing a marked decrease in the incidence and severity of peripheral neuropathy, palmar-plantar erythrodysesthesia and myelosuppression compared to the standard dosing on a 3-week cycle using these drugs. This modified regimen of dexamethasone, bortezomib and PLD shows improved tolerability and safety while maintaining a high response rate when compared to standard treatment with these agents in the frontline setting. [ABSTRACT FROM AUTHOR]

Summary: Background: Non-randomised trials have reported benefits of kyphoplasty in patients with cancer and vertebral compression fractures (VCFs). We aimed to assess the efficacy and safety of balloon kyphoplasty compared with non-surgical management for patients with cancer who have painful VCFs. Methods: The Cancer Patient Fracture Evaluation (CAFE) study was a randomised controlled trial at 22 sites in Europe, the USA, Canada, and Australia. We enrolled patients aged at least 21 years who had cancer and one to three painful VCFs. Patients were randomly assigned by a computer-generated minimisation randomisation algorithm to kyphoplasty or non-surgical management (control group). Investigators and patients were not masked to treatment allocation. The primary endpoint was back-specific functional status measured by the Roland-Morris disability questionnaire (RDQ) score at 1 month. Outcomes at 1 month were analysed by modified intention to treat, including all patients with data available at baseline and at 1 month follow-up. Patients in the control group were allowed to crossover to receive kyphoplasty after 1 month. This study is registered with ClinicalTrials.gov, NCT00211237. Findings: Between May 16, 2005, and March 11, 2008, 134 patients were enrolled and randomly assigned to kyphoplasty (n=70) or non-surgical management (n=64). 65 patients in the kyphoplasty group and 52 in the control group had data available at 1 month. The mean RDQ score in the kyphoplasty group changed from 17·6 at baseline to 9·1 at 1 month (mean change −8·3 points, 95% CI −6·4 to −10·2; p<0·0001). The mean score in the control group changed from 18·2 to 18·0 (mean change 0·1 points; 95% CI −0·8 to 1·0; p=0·83). At 1 month, the kyphoplasty treatment effect for RDQ was −8·4 points (95% CI −7·6 to −9·2; p<0·0001). The most common adverse events within the first month were back pain (four of 70 in the kyphoplasty group and five of 64 in the control group) and symptomatic vertebral fracture (two and three, respectively). One patient in the kyphoplasty group had an intraoperative non-Q-wave myocardial infarction, which resolved and was attributed to anaesthesia. Another patient in this group had a new VCF, which was thought to be device related. Interpretation: For painful VCFs in patients with cancer, kyphoplasty is an effective and safe treatment that rapidly reduces pain and improves function. Funding: Medtronic Spine LLC. [Copyright &y& Elsevier]

Background: In recent years, a battery-powered bone marrow biopsy system was developed and cleared by the U.S. Food and Drug Administration to allow health care providers to access the bone marrow space quickly and efficiently. A multicenter randomized clinical trial was designed for adult patients to determine if the powered device had advantages over traditional manually-inserted needles in regard to length of procedure, patient pain, complications, user satisfaction, and pathological analysis of the specimens. Methods: Adult patients requiring marrow sampling procedures were randomized for a Manual or Powered device. Visual Analog Scale (VAS) pain scores were captured immediately following the procedure and 1 and 7 days later. Procedure time was measured and core specimens were submitted to pathology for grading. Results: Ten sites enrolled 102 patients into the study (Powered, n = 52; Manual, n = 50). Mean VAS scores for overall procedural pain were not significantly different between the arms (3.8 ± 2.8 for Powered, 3.5 ± 2.3 for Manual [p = 0.623]). A day later, more patients who underwent the Powered procedure were pain-free (67%) than those patients in the Manual group (33%; p = 0.003). One week later, there was no difference (83% for Powered patients; 76% for Manual patients.) Mean procedure time was 102.1 ± 86.4 seconds for the Powered group and 203.1 ± 149.5 seconds for the Manual group (p < 0.001). Pathology assessment was similar in specimen quality, but there was a significant difference in the specimen volume between the devices (Powered: 36.8 ± 21.2 mm³; Manual: 20.4 ± 9.0 mm³; p = 0.039). Two non-serious complications were experienced during Powered procedures (4%); but none during Manual procedures (p = 0.495). Conclusions: The results of this first trial provide evidence that the Powered device delivers larger-volume bone marrow specimens for pathology evaluation. In addition, bone marrow specimens were secured more rapidly and subjects experienced less intermediate term pain when the Powered device was employed. Further study is needed to determine if clinicians more experienced with the Powered device will be able to use it in a manner that significantly reduces needle insertion pain; and to compare a larger sample of pathology specimens obtained using the Powered device to those obtained using traditional manual biopsy needles. [ABSTRACT FROM AUTHOR]

On February 25, 2009, a panel of international experts on plasma cell dyscrasia and skeletal disease met to discuss monoclonal gammopathy of undetermined significance (MGUS). This non-malignant B-cell disorder is the most common plasma cell dyscrasia and is associated with an increased risk of developing serious B-cell disorders. Individuals with MGUS also have an increased risk of osteoporosis and osteopenia associated with an increased likelihood of developing fractures especially in the vertebral column, peripheral neuropathy and thromboembolic events. The goal of the meeting was to develop a consensus statement regarding the appropriate tests to screen, evaluate and follow-up patients with MGUS. The panel also addressed the identification and treatment of MGUS-related skeletal problems, thromboembolic events and neurological complications. The following consensus statement outlines the conclusions and marks the first time that a consensus statement for the screening and treatment of MGUS has been clearly stated. [ABSTRACT FROM AUTHOR]

Background: We conducted a single-arm, multicentre phase 2 study to evaluate bortezomib, ascorbic acid and melphalan (BAM) for patients with newly diagnosed multiple myeloma (MM). Methods: Induction consisted of up to eight 28-d cycles of bortezomib 1.0 mg/m2 on days 1, 4, 8 and 11, plus oral ascorbic acid 1 g and oral melphalan 0.1 mg/kg on days 1–4, followed by maintenance bortezomib 1.3 mg/m2 every 2 wk until progression. Results: Among 35 patients enrolled (median age 70 yr), responses occurred in 23/31 evaluable patients (74%) including five (16%) complete, three (10%) very good partial, six (19%) partial and nine (29%) minimal responses. Six patients (19%) had stable disease. Thus, disease control was achieved in 29 (94%) patients. Median times to first and best responses were 2 and 3 months (ranges 1–5 and 1–7), respectively. Median time to progression was 19 months and median overall survival has not been reached (range 2–23+ months). Grade 3 and 4 adverse events occurred in 17 and 5 patients, respectively; the most common were neutropenia, neuropathy and thrombocytopenia. Conclusions: BAM is an efficacious, well-tolerated and steroid- and immunomodulatory drug (IMiD)-free frontline treatment regimen for MM patients. [ABSTRACT FROM AUTHOR]

Bortezomib synergizes with melphalan in preclinical and early clinical studies. Updated data from our phase 1/2 study assessing the safety and efficacy of bortezomib plus melphalan in relapsed/refractory multiple myeloma (MM) are presented. Bortezomib (0.7, 1.0, or 1.3 mg/m2) on days 1, 4, 8, and 11 and oral melphalan (0.025–0.25 mg/kg) on days 1–4 of a 28-day cycle were administered. Hematologic toxicities defined the maximum tolerated dose as bortezomib 1.0 mg/m2 and melphalan 0.10 mg/kg. Because dose-limiting toxicities were attributed to the more myelosuppressive melphalan, cohorts 9 and 10 with higher bortezomib (1.3 mg/m2) and lower melphalan (0.025 and 0.10 mg/kg) doses were added. Responses occurred in 32/46 (70%) evaluable patients: two complete (4%), five near-complete (11%), 16 partial (35%), and nine minimal (20%). Complete and near-complete responses were observed only with higher bortezomib doses. Response rates were similar in patients with prior melphalan or bortezomib. Median progression-free survival was 9 months (range, 1–24), and overall survival was 32 months (range, 1–54). The most common grade 3/4 hematologic adverse events (AEs) were neutropenia (31%/0%), thrombocytopenia (25%/2%), and anemia (13%/0%). Grade 4 tumor lysis syndrome was reported in one patient. Fewer grade 3/4 hematologic AEs were reported in cohorts 9 and 10 than in cohorts receiving lower bortezomib and higher melphalan doses. In conclusion, bortezomib plus melphalan is a steroid- and immunomodulatory drug-free regimen that may provide a treatment alternative for elderly patients and patients with significant comorbidity. [ABSTRACT FROM AUTHOR]

Abstract: Pleiotrophin (PTN, Ptn) is an 18kDa secretory cytokine that is expressed in many human cancers, including glioblastoma. In previous experiments, interruption of the constitutive PTN signaling in human U87MG glioblastoma cells that inappropriately express endogenous Ptn reversed their rapid growth in vitro and their malignant phenotype in vivo. To seek a mechanism for the effect of the dominant-negative PTN, flow cytometry was used to compare the profiles of U87MG cells and four clones of U87MG cells that express the dominant-negative PTN (U87MG/PTN1-40 cells); here, we report that the dominant-negative PTN in U87MG cells induces tetraploidy and aneuploidy and arrests the tetraploid and aneuploid cells in the G1 phase of the cell cycle. The data suggest that PTN signaling may have a critical role in chromosomal segregation and cell cycle progression; the data suggest induction of tetraploidy and aneuploidy in U87MG glioblastoma cells may be an important mechanism that contributes to the loss of the malignant phenotype of U87MG cells. [Copyright &y& Elsevier]

We assessed the safety and efficacy of melphalan, arsenic trioxide (ATO) and ascorbic acid (AA) (MAC) combination therapy for patients with multiple myeloma (MM) who failed more than two different prior regimens. Patients received melphalan (0·1 mg/kg p.o.), ATO (0·25 mg/kg i.v.) and AA (1 g i.v) on days 1–4 of week 1, ATO and AA twice weekly during weeks 2–5 and no treatment during week 6 of cycle 1; during cycles 2–6, the schedule remained the same except ATO and AA were given twice weekly in week 1. Objective responses occurred in 31 of 65 (48%) patients, including two complete, 15 partial and 14 minor responses. Median progression-free survival and overall survival were 7 and 19 months respectively. Twenty-two patients had elevated serum creatinine levels (SCr) at baseline, and 18 of 22 (82%) showed decreased SCr levels during treatment. Specific grade 3/4 haematological (3%) or cardiac adverse events occurred infrequently. Frequent grade 3/4 non-haematological adverse events included fever/chills (15%), pain (8%) and fatigue (6%). This steroid-free regimen was effective and well tolerated in this heavily pretreated group. These results indicate that the MAC regimen is a new therapeutic option for patients with relapsed or refractory MM. [ABSTRACT FROM AUTHOR]

Abstract: Multiple myeloma (MM) is a B-cell malignancy characterized by enhanced bone loss commonly associated with a diffuse osteopenia, focal lytic lesions, pathologic fractures, hypercalcemia, and bony pain. Bone destruction in MM results from asynchronous bone turnover wherein increased osteoclastic bone resorption is not accompanied by a comparable increase in bone formation. Recent characterization of osteoclast-activating factors (OAFs), receptor activator of nuclear factor-κB (RANK) ligand (RANKL)–osteoprotegerin–RANK system, and inhibitors of Wnt signaling have provided a better understanding of myeloma bone disease in molecular level. The development of minimally invasive surgical procedures such as kyphoplasty and vertebroplasty allows myeloma patients with vertebral compression fractures to have immediate improvement in quality of life and shorter hospital stays. Monthly intravenous infusion of either pamidronate or zoledronic acid have reduced the skeletal complications among MM patients and are now a mainstay of myeloma therapy. Orally administered bisphosphonates, in contrast, have shown little ability to slow the development of skeletal complications in these patients. Although pre-clinical studies suggest nitrogen-containing bisphosphonates have potent anti-tumor effects, clinical trials will be necessary, probably at higher doses given more slowly, to establish their possible anti-tumor effects clinically. As our understanding of the pathophysiology of myeloma bone disease continues to increase, new target therapies will continue to emerge offering new and more advanced options for the management of myeloma bone disease. [Copyright &y& Elsevier]

Examines the potential of bisphosphonates in the treatment of malignant bone disease. Pharmacology of bisphosphonates; Forms of bone cancer involved in clinical trials of bisphosphonates; Types of cancers with bone metastases; Ways to prevent bone metastases.

Objectives Data regarding bone marrow (BM) sampling and cytogenetic testing rates for identification of translocation (11q13;14q32) and their changes over time in a multiple myeloma (MM) population are limited. We analyzed these metrics at a clinic specializing in the treatment of MM. Methods A total of 760 BM aspirate samples from 351 patients were collected between August 2004 and October 2021. We analyzed BM sampling statistics, cytogenetic testing frequency, and the incidence rates for the t(11;14) translocation in a single clinic specializing in the treatment of MM. Results We report that most (54.4%) patients had only 1 aspirate collected; the main reason (64.6%) for BM collection was to confirm disease progression. Less than half (47.5%) of BM samples collected for evaluation of MM disease had cytogenetic testing, but the rates have markedly increased in recent years. Our data demonstrated an incidence rate of 19.3% for t(11;14). Conclusions This report suggests that some patients may need to retest for this genetic aberration due to the possibility of false negatives and the potential benefit of identifying the t(11;14) marker for patients who may be candidates for a highly effective targeted therapy consisting of the BCL-2 inhibitor venetoclax. [ABSTRACT FROM AUTHOR]

Objectives: Isatuximab is approved for treatment of relapsed/refractory multiple myeloma (RRMM) with dexamethasone and carfilzomib or pomalidomide. Patients receiving these three‐drug regimens have exhibited more Grade ≥ 3 adverse events (AEs) compared to the two‐drug class combination of isatuximab and steroids alone. Thus, this single‐center retrospective study investigated the efficacy of isatuximab with dexamethasone and methylprednisolone (ISAdm) for RRMM patients showing only biochemical progression (BP) of their disease. Methods: Twenty‐four RRMM patients exhibiting only BP were administered isatuximab at 10 mg/kg with dexamethasone once weekly for cycle 1 of a 28‐day cycle, followed by every other week for each cycle thereafter. Starting in cycle 2, oral methylprednisolone was added every other day stopping 48 h before and starting 48 h after each dexamethasone infusion. Results: Overall response rate and clinical benefit rate were 63% and 79%, respectively. Progression free survival was 12.9 months. There were only 5 AEs of Grade ≥ 3 which included lymphocytopenia (13%), leukopenia (4%), and neutropenia (4%). No Grade ≥ 3 AE related to respiratory infection, anemia, or thrombocytopenia were reported. Conclusion: This study shows that the two‐drug class combination of ISAdm is an effective and well tolerated treatment option for RRMM patients exhibiting only BP. [ABSTRACT FROM AUTHOR]

Background: Twice a week carfilzomib at 27 mg/m2 is approved for treatment of relapsed or refractory multiple myeloma. Phase 1/2 CHAMPION-1, the first study exploring once-weekly carfilzomib dosing, established the maximum tolerated dose at 70 mg/m2 in combination with dexamethasone. We aimed to compare progression-free survival in patients with relapsed and refractory multiple myeloma given once weekly carfilzomib or twice weekly carfilzomib.Methods: In this prespecified interim analysis of the randomised, open-label, phase 3 A.R.R.O.W. trial, we recruited patients (aged 18 years and older) with relapsed and refractory multiple myeloma previously treated with two or three treatments, including a proteasome inhibitor and immunomodulatory agent, from hospital, clinic, oncology or medical centres. Key eligibility criteria were refractory to most recent therapy (including bortezomib or ixazomib) with measurable disease, and Eastern Cooperative Oncology Group Performance Status of 0 or 1. Patients were randomly assigned (1:1) to receive carfilzomib once a week (70 mg/m2) or twice a week (27 mg/m2). The randomisation sequence was generated using a validated randomisation software and implemented using an interactive response technology system that assigned patients to treatment sequentially based on the randomisation sequence as patients were enrolled at participating clinical sites. Patients were stratified by International Staging System stage at study entry or baseline, whether or not they were refractory to bortezomib treatment, and age (block size of 4). The once weekly group received carfilzomib (30 min intravenous infusion) on days 1, 8, and 15 of all cycles (20 mg/m2 day 1 [cycle 1]; 70 mg/m2 thereafter). The twice weekly group received carfilzomib (10 min intravenous infusion) on days 1, 2, 8, 9, 15, and 16 (20 mg/m2 days 1 and 2 during cycle 1; 27 mg/m2 thereafter). All patients received dexamethasone (40 mg on days 1, 8, 15 [all cycles] and 22 [cycles 1-9 only]). Treatment continued until disease progression or unacceptable toxic effects. The primary objective was to compare progression-free survival between groups in the intention-to-treat population. Safety analysis was done in all randomly assigned patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02412878, and is no longer enrolling patients.Findings: Between September, 2015, and August, 2016, 578 patients were recruited from 118 sites. 478 patients were randomly assigned and included in the efficacy analyses (240 to receive once weekly carfilzomib; 238 to receive twice weekly carfilzomib). Median progression-free survival was higher in the once weekly group than the twice weekly group (11·2 months [95% CI 8·6-13·0] vs 7·6 months [5·8-9·2]; hazard ratio [HR] 0·69, 95% CI 0·54-0·83; p=0·0029). The incidence of grade 3 or worse adverse events was higher in the once weekly group than the twice weekly group (68% [n=161] vs 62% [n=145]); the most common events were anaemia, pneumonia, and thrombocytopenia (42 [18%] vs 42 [18%], 24 [10%] vs 16 [7%], and 17 [7%] vs 16 [7%], respectively for once weekly carfilzomib vs twice weekly carfilzomib). A lower proportion of patients had grade 3 or worse cardiac failure in the once weekly group (7 [3%]) than in the twice weekly group (10 [4%]). Treatment-related deaths occurred in five (2%) of 238 patients in the once weekly group (sepsis [n=1], death [n=1], acute lung injury [n=1], acute respiratory distress syndrome [n=1], and tumour lysis syndrome [n=1]) and in two (1%) of 235 patients in the twice weekly group (plasma cell myeloma [n=1] and congestive heart failure [n=1]). There were 58 deaths in the once weekly group and 68 deaths in the twice weekly group at the time of data cutoff.Interpretation: Once weekly carfilzomib at 70 mg/m2 significantly prolonged progression-free survival versus the twice weekly schedule. Overall safety was comparable between the groups. Once weekly carfilzomib appears safe and more effective with a convenient dosing regimen versus the twice weekly schedule for the treatment of patients with relapsed and refractory multiple myeloma.Funding: Amgen, Inc. [ABSTRACT FROM AUTHOR]

New classes of drugs including the proteasome inhibitors (PI) bortezomib and, more recently, carfilzomib and the immunomodulatory agent lenalidomide have shown improved outcomes for multiple myeloma (MM) patients during the past decade. However, most of the studies reporting outcomes for patients receiving these drugs have relied on older data sets derived from large institutions that included patients not receiving their treatment at those facilities and represented only those eligible for clinical trials or were from sites where treatment options were limited. We have analyzed data from 258 MM patients who have received treatment with at least one of three agents: bortezomib, carfilzomib, and lenalidomide in a single clinic specializing in MM with respect to their responses and other outcomes to treatment regimens including these agents. Response rates were similar between these three drugs when used for the first time and again during subsequent treatment regimens. As expected, the clinical benefit rates (CBRs) were better for patients receiving their first treatment when compared to their use in subsequent treatment regimens. The CBRs were similar during their 2nd, 3rd, and 4th treatments containing these agents. Many patients refractory to these agents showed responses to regimens containing these same drugs when used in different combinations. In addition, patients refractory to one PI often responded to the other PI. The results of this study demonstrate that novel agents can be used repeatedly in novel combinations with significant clinical benefit for patients with MM. [ABSTRACT FROM AUTHOR]

Despite recent advances made in its treatment, multiple myeloma (MM) remains an incurable B cell malignancy. Thus, the objective for treating these patients is to prolong overall survival (OS) and preserve patients' quality of life. We have analyzed data from 264 consecutive MM patients who had their initial visit between July 1, 2004 and December 1, 2014 and have received treatment in a single clinic specializing in MM. We determined their progression-free survival (PFS, OS, and 5-year OS). The PFS for frontline (n = 165 treatments), salvage (n = 980), and all treatments (n = 1145) were 13.9, 4.6, and 5.5 months, respectively. The median OS of all patients was 98 months with a 5-year survival of 74%. The results of this study show a marked improvement in OS for unselected MM patients compared with historical data. There were no significant differences in OS between patients with different International Staging System (ISS) stages. Younger patients (<65 years old) showed a longer OS. The results of this study should help physicians predict outcomes for MM patients and be encouraging for patients with this B cell malignancy. [ABSTRACT FROM AUTHOR]

• Pomalidomide is possibly a replacement drug for myeloma patients refractory to lenalidomide. • Pomalidomide achieves responses among myeloma patients refractory to lenalidomide. • Clinical activity improves for myeloma patients receiving the 4-mg pomalidomide dose. The combination of pomalidomide with dexamethasone is approved for the treatment of relapsed/refractory multiple myeloma (RRMM). This phase 2, multicenter, open-label, non-randomized study investigated pomalidomide as a replacement for lenalidomide for 45 patients with RRMM refractory to a lenalidomide-containing combination regimen containing steroids and one or more other anti-myeloma agents administered using the same schedule(s), dose(s), and drug combination. Pomalidomide was administered on days 1–21 of a 28-day cycle for ≤8 cycles at a dose of 2, 3, or 4 mg. Overall response rates (ORRs) and clinical benefit rates (CBRs) were 33% and 44%, respectively, and were higher among those who received 4 mg pomalidomide (ORR 41% and CBR 50%). Median progression-free survival and overall survival were 8 and 16 months, respectively. Adverse events were consistent with the established safety profiles for the individual agents and the replacement of lenalidomide with pomalidomide did not appear to result in greater toxicity. Overall, this study indicates that pomalidomide can be an effective and safe replacement for lenalidomide among patients with RRMM refractory to the latter immunomodulatory agent without requiring additional changes to the combination regimen. [ABSTRACT FROM AUTHOR]

Purpose: Previous studies have shown that low serum vitamin D levels have been associated with many skeletal and non-skeletal disorders. We studied the relationship between 25-hydroxyvitamin D (25D) levels and motor and sensory peripheral neuropathy (PN) among multiple myeloma (MM) patients who have been treated with bortezomib and/or thalidomide.Methods: We performed a study of 111 MM patients who had received at least one of these two agents for at least 12 weeks by correlating physical exam/neurologic assessment findings with patient self-assessment responses.Results: The median age of study patients was 66 years (range 42-89 years) and 54 % were males. 25D levels were determined, and complete history and physical and neurologic examinations were performed at the same study visit. In addition, study subjects completed questionnaires regarding symptoms related to motor and sensory PN. Overall, patients had a median serum 25D level of only 32 ng/ml; 42 % of patients were considered either 25D-deficient (<20.0 ng/mL; 16 % of patients) or 25D-insufficient (20.0-29.9 ng/mL; 26 %). Notably, we found that 25D-deficient MM patients were more likely to have severe PN (>grade 2) of both motor (p = 0.0415) and sensory (p = 0.0086) types although the overall incidence of PN was not higher in this patient population.Conclusion: These results show that the severity of peripheral neuropathy is associated with lower vitamin D levels and provides the rationale for monitoring vitamin D for myeloma patients especially those receiving drugs associated with the development of peripheral neuropathy. [ABSTRACT FROM AUTHOR]

Background: Skeletal complications are a major clinical manifestation of multiple myeloma. These complications are caused by soluble factors that stimulate osteoclasts to resorb bone. Bisphosphonates such as pamidronate inhibit osteoclastic activity and reduce bone resorption. Methods: Patients with stage III multiple myeloma and at least one lytic lesion received either placebo or pamidronate (90 mg) as a four-hour intravenous infusion given every four weeks for nine cycles in addition to antimyeloma therapy. The patients were stratified according to whether they were receiving first-line (stratum 1) or second-line (stratum 2) antimyeloma chemotherapy at entry into the study. Skeletal events (pathologic fracture, irradiation of or surgery on bone, and spinal cord compression), hypercalcemia (symptoms or a serum calcium concentration >12 mg per deciliter [3.0 mmol per liter]), bone pain, analgesic-drug use, performance status, and quality of life were assessed monthly. Results: Among 392 treated patients, the efficacy of treatment could be evaluated in 196 who received pamidronate and 181 who received placebo. The proportion of patients who had any skeletal events was significantly lower in the pamidronate group (24 percent) than in the placebo group (41 percent, P<0.001), and the reduction was evident in both stratum 1 (P = 0.04) and stratum 2 (P = 0.004). The patients who received pamidronate had significant decreases in bone pain and no deterioration in performance status and quality of life. Pamidronate was well tolerated. Conclusions: Monthly infusions of pamidronate provide significant protection against skeletal complications and improve the quality of life of patients with stage III multiple myeloma. (N Engl J Med 1996;334:488-93.) [ABSTRACT FROM AUTHOR]

• sBCMA is elevated in B-cell malignancies such as CLL. • Addition of sBCMA to CLL prognostic scores improved the ability to predict TTFT and OS. • sBCMA is a promising new biomarker for CLL. B-Cell maturation antigen (BCMA) is a cell membrane receptor expressed on mature B lymphocytes, with elevated serum levels found among patients with B-cell malignancies, including chronic lymphocytic leukemia (CLL). Serum BCMA (sBCMA) levels were measured in 331 untreated, newly diagnosed CLL patients using an enzyme-linked immunosorbent assay with a polyclonal anti-BCMA antibody. Elevated sBCMA levels were found among patients with CLL compared with age- and sex-matched healthy controls and those with more active CLL based on prognostic factors. The relationships between sBCMA, time to first treatment (TTFT), overall survival (OS) and multiple prognostic factors were compared using Mann–Whitney and Kruskal–Wallis tests. The median sBCMA level in the CLL cohort (48.6 ng/mL) was significantly higher (p < 0.001) compared with those of age- and sex-matched healthy subjects (n = 100; 37.8 ng/mL). Serum BCMA correlated with TTFT (hazard ratio [HR] = 2.9, 95% confidence interval 2.0–4.2, p < 0.001) and OS (HR = 2.5, 95% confidence interval: 1.5–4.0, p < 0.001). Multiple models were used to test the predictive effects of sBCMA, sex, CLL International Prognostic Index (CLL-IPI) and International Prognostic Score for early-stage CLL (IPS-E) on TTFT and OS. The addition of sBCMA to CLL-IPI and IPS-E improved their prognostic ability to predict TTFT and OS. Thus, sBCMA is a new promising prognostic biomarker for CLL. [ABSTRACT FROM AUTHOR]

• Replacement of bortezomib or carfilzomib with ixazomib in RRMM was investigated • Patients continued use of the same drugs, dose, and frequency of non-PI regimen components. • Ixazomib was well tolerated but not efficacious and was unable to overcome PI resistance. Identifying effective combination regimens is a high priority in multiple myeloma (MM), as most patients eventually become refractory to their current treatments. In this study, we investigated whether the proteasome inhibitor (PI) ixazomib could delay disease progression among patients who failed regimens containing another PI, bortezomib or carfilzomib. This phase 1/2, multicenter, open-label, nonrandomized study enrolled patients who were refractory to a previous regimen containing bortezomib or carfilzomib. Patients continued the other anti-MM drugs in the regimen at the same doses and frequencies. Patients with combination regimens with unknown maximum tolerated dose (MTD) of ixazomib were enrolled in phase 1, with ixazomib starting at 3 mg and then dose escalated to 4 mg. Patients on regimens with a known ixazomib MTD were enrolled in phase 2. Primary endpoints were overall response rate (ORR), clinical benefit rate (CBR), adverse events (AEs), and determination of maximum tolerated dose (MTD). Of the 46 patients enrolled, 39 were evaluable for efficacy. ORR and CBR were 12.8% and 17.9%, respectively. Ixazomib appeared to be well tolerated as a replacement for carfilzomib and bortezomib, with 23.9% of patients experiencing at least one grade ≥3 serious adverse event (SAE) and 37.0% experiencing at least one grade ≥3 AE. The most common grade ≥3 AEs were hyponatremia (8.7%), anemia (8.7%), dyspnea (8.7%), thrombocytopenia (6.5%), dehydration (4.3%), and pneumonia (4.3%). The results indicate that ixazomib is not an effective replacement for bortezomib or carfilzomib for patients with MM who have previously relapsed on other bortezomib/carfilzomib-containing regimens. [ABSTRACT FROM AUTHOR]

High-risk multiple myeloma (MM) continues to have a poor prognosis and remains a therapeutic challenge. This phase 2 study evaluated the efficacy and safety of elotuzumab in combination with pomalidomide, carfilzomib, and low-dose dexamethasone for patients with high-risk relapsed/refractory (RR)MM (NCT03104270). Of 13 enrolled patients, 11 were evaluable for efficacy. Overall response rate and clinical benefit rate were 45.4% and 54.5%, respectively. Deep responses were observed including two complete responses. The novel quadruplet combination was overall well-tolerated, with clinically manageable adverse events. Common adverse events of ≥ grade 3 included lymphopenia (15%), anemia (15%), sepsis (15%), pneumonia (15%), and hypophosphatemia (15%). The novel combination showed promising efficacy and was well tolerated in this heavily pretreated MM population. Even though the study was terminated early prior to completion of enrollment, the results indicate that this may be a promising therapeutic approach for high-risk RRMM patients, which warrants further study. [ABSTRACT FROM AUTHOR]

Abstract: The development of the plasma cell tumor (PCT) model was the first widely accepted in vivo model of multiple myeloma (MM). Potter and colleagues used this chemically induced PCT model to study the pathophysiology of malignant plasma cells and also used it to screen anti-MM agents. Two decades later the C57BL/KaLwRij mouse strain was found to spontaneously develop MM. Testing of pamidronate using this endogenously arising MM model revealed significant reductions in MM-associated bone disease, which was subsequently confirmed in human trials in MM patients. Transgenic models have also been developed in which the MM is localized in the bone marrow causing lytic bone lesions. Experiments in a transgenic model showed that a new oral proteasome inhibitor was effective at reducing MM burden. A clinical trial later confirmed this observation and validated the model. The xenograft model has been used to grow human MM in immunocompromised mice. The xenograft models of MM have been very useful in optimizing drug schedules and doses, which have helped in the treatments given to MM patients. However, in vivo models have been criticized for having a low clinical predictive power of new chemical entities (NCEs). Despite this, the knowledge gained from in vivo models of MM has without a doubt benefited MM patients. [Copyright &y& Elsevier]

The Clinical Response and Efficacy Study of Bortezomib in the Treatment of Relapsing Multiple Myeloma (CREST) demonstrated substantial activity with two dose levels of bortezomib (1·0 and 1·3 mg/m2), alone or with dexamethasone, in relapsed or refractory multiple myeloma. We present updated survival analyses after prolonged follow-up (median >5 years). One- and 5-year survival rates were 82% and 32%, respectively, in the 1·0 mg/m2 group ( n = 28), and 81% and 45%, respectively, in the 1·3 mg/m2 group ( n = 26). Notable survival, response, and time-to-progression data suggest that a bortezomib starting dose of 1·3 mg/m2 is preferred. If bortezomib dose reduction is required, the 1·0 mg/m2 dose still offers patients a substantial survival benefit. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) patients with smoldering (S) disease are defined by a lack of CRAB/SLiM criteria but may transform into disease requiring treatment. The International Myeloma Working Group risk stratification model for SMM uses serum M‐protein, serum‐free light chain ratio, and bone marrow plasma cell percentage. We investigated whether baseline serum B‐cell maturation antigen (sBCMA) levels are predictive of disease progression among 65 patients with SMM. A receiver operating characteristic curve was used to establish a definition for high‐risk baseline sBCMA. Mantel Byar analysis was used to examine whether high‐risk sBCMA was correlated with shorter time to transformation, and a time‐dependent cox proportional hazard was used to determine whether it is independent of other risk factors. A z test for proportions was used to compare the percentage of patients that progressed among high‐risk versus low‐risk sBCMA patients. A baseline sBCMA level ≥137.5 mg/ml was found to be the optimal cutoff between high‐ and low‐risk SMM patients. Patients with high‐risk sBCMA levels had a shorter time to transformation (P =.000332). sBCMA was also higher at the time of transformation than baseline levels (P =.0116). sBCMA was the only variable found to be significantly predictive of time to transformation and additionally was found to be independent of other risk factors. In this study, we have shown for the first time that sBCMA levels predict transformation of SMM to active disease and that these levels increase at the time of transformation. These results are consistent with other studies showing that active MM patients undergoing therapy with higher baseline sBCMA levels are more likely to progress early and its levels increase at the time of disease progression. [ABSTRACT FROM AUTHOR]

Venetoclax is a BCL-2 inhibitor currently indicated for use in treating hematologic malignancies with recommended doses ranging from 400 to 600 mg/day. Although currently not FDA-approved to treat multiple myeloma (MM) patients, there is a growing number of reports indicating its efficacy as a salvage therapy for these patients, especially for those with the t(11;14) chromosomal marker. These studies, however, have also indicated that venetoclax given at doses ≥ 400 mg/day can cause serious adverse events (SAEs) especially when administered with bortezomib, commonly related to infections. The purpose of this single-center retrospective study was to determine the efficacy of low dose venetoclax (defined as ≤ 250 mg/day) in combination with low dose bortezomib (defined as 1.0 mg/m2 per dose), daratumumab, and dexamethasone (Dvvd) as a salvage therapy for relapsed/refractory myeloma (RRMM) patients. Twenty-two RRMM patients were given venetoclax orally at doses ranging from 100 to 250 mg daily using this four-drug regimen. While the low doses resulted in reduced venetoclax efficacy among those lacking t(11;14) (overall response rate [ORR] = 31%), those harboring the t(11;14) marker exhibited an ORR of 80%. Notably, this response was without frequent infection-related SAEs as reported in previous studies. Together, the results of this study demonstrate that treatment of t(11;14) positive RRMM patients with Dvvd is both effective and well-tolerated. [ABSTRACT FROM AUTHOR]

The purpose of this single-center retrospective study was to determine the incidence of decreased blood phosphorus levels and hypophosphatemia among multiple myeloma (MM) patients treated with elotuzumab. Hypophosphatemia, which is defined as a serum phosphorus concentration < 2.5 mg/dL, leads to complications ranging from muscle weakness and disorientation to seizures and heart failure. A total of 23 MM patients receiving care in a clinic specializing in treatment of MM from July 2018 to March 2020 and treated with an elotuzumab-containing therapy were evaluated, and 9 were investigated for this study. Elotuzumab was given at 10 mg/kg weekly for the first two treatment cycles (28 days/cycle), followed by 10 mg/kg every other week for all subsequent cycles. Four different elotuzumab combination therapies were administered: 1) elotuzumab and dexamethasone 2) elotuzumab, lenalidomide and dexamethasone 3) elotuzumab, pomalidomide and dexamethasone and 4) elotuzumab, carfilzomib, pomalidomide, and dexamethasone. Phosphorous levels were determined at a median of every 13 days at intervals ranging from once weekly to once monthly until a phosphate supplement was prescribed to the patient or when elotuzumab treatment was discontinued. We found that regardless of elotuzumab combination therapy, all patients treated showed decreased phosphorus levels after initiating elotuzumab treatment with reductions ranging from 12.5% to 44.1% below baseline. Six participants (67%) demonstrated an average serum phosphorus at or below 2.5 mg/dL after starting elotuzumab therapy. This retrospective study suggests that hypophosphatemia commonly occurs among MM patients receiving elotuzumab-containing therapies. [ABSTRACT FROM AUTHOR]

Summary: The serum B‐cell maturation antigen (sBCMA) has been identified as a novel serum biomarker for patients with multiple myeloma. However, no study has yet established a reference range for sBCMA levels. Its levels were determined in 196 healthy subjects and showed a right‐tailed distribution with a median value of 37·51 ng/ml with a standard deviation of 22·54 ng/ml (range 18·78–180·39 ng/ml). Partitioning of subgroup reference ranges was considered but determined to be irrelevant. A non‐parametric method using the median ± 2 standard deviations suggests using a universal reference interval of <82·59 ng/ml. [ABSTRACT FROM AUTHOR]

Summary: Multiple myeloma (MM) tumour cells evade host immunity through a variety of mechanisms, which may potentially include the programmed cell death ligand‐1 (PD‐L1):programmed cell death protein‐1 (PD‐1) axis. This interaction contributes to the immunosuppressive bone marrow (BM) microenvironment, ultimately leading to reduced effector cell function. PD‐L1 is overexpressed in MMBM and is associated with the resistance to immune‐based approaches for treating MM. Ruxolitinib (RUX), an inhibitor of the Janus kinase (JAK) family of protein tyrosine kinases, is approved for myeloproliferative diseases. We investigated the effects of RUX alone or in combination with anti‐MM agents on the expression of PD‐L1 and T‐cell cytotoxicity in MM. We showed that the expression of the PD‐L1 gene was markedly increased in BM mononuclear cells from patients with MM with progressive disease versus those in complete remission. Furthermore, RUX treatment resulted in a concentration‐dependent reduction of PD‐L1 gene expression in the MM tumour cells cultured alone or co‐cultured with stromal cells compared with untreated cells. The results also demonstrated that RUX increased MM cell apoptosis in the presence of interleukin‐2‐stimulated T cells to a similar degree as the treatment with anti‐PD‐1 or anti‐PD‐L1 antibodies. In summary, these results indicate that RUX can block PD‐L1 expression resulting in augmentation of anti‐MM effects of T cells. [ABSTRACT FROM AUTHOR]

Summary: Serum B‐cell maturation antigen (sBCMA) is a novel biomarker for B‐cell malignancies. A normal reference range (<82·59 ng/ml) has been recently established but the impact of achieving normal levels to outcomes for patients receiving treatment for B‐cell malignancies has not been studied. We first found that among multiple myeloma (MM) patients starting a new treatment, those who begin treatment within normal sBCMA limits (<82·59 ng/ml) have improved progression‐free survival (PFS; P = 0·0398) and overall survival (OS; P = 0·0217) than those who do not. Furthermore, among patients who begin treatment with elevated (≥82·59 ng/ml) sBCMA levels, we assessed the relationship of a decrease in sBCMA to the normal range to OS and found that those who normalize sBCMA demonstrated improved OS (P = 0·0078). Normalizing patients also experienced a markedly improved overall response rate (P < 0·0001). Moreover, all patients who achieved complete remission (CR) showed normalization of sBCMA, and time to normalization (median 0·9 months) was faster than time to CR (5·0 months; P = 0·0036) for these patients. These results suggest that normalization of sBCMA may be an accurate predictor of OS for MM patients during treatment and predict for a higher likelihood of response. [ABSTRACT FROM AUTHOR]

A 52-year-old African-American woman with a prior history of monoclonal gammopathy of undetermined significance (MGUS) developed infiltrating ductal carcinoma of the left breast. Following a mastectomy, she underwent reconstruction with a silicone gel breast implant. Three years later, her MGUS had progressed to active multiple myeloma (MM). She had a minimal response after two different regimens of bortezomib-based treatments and monthly zoledronic acid, and was placed on maintenance therapy with bortezomib, intravenous dexamethasone, and oral methylprednisolone, as well as ongoing monthly zoledronic acid. After 1 year of this maintenance therapy, during which her myeloma markers remained unchanged, she had her silicone implant replaced with saline. Despite no change in her myeloma treatment, her laboratory values began to steadily improve following removal of the silicone implant. Her M-protein decreased from 2.14 to 0.83 g/dL and her IgG levels from 3,330 to 1,210 mg/dL following replacement of her silicone implant with saline. To our knowledge, this is the first report in which removal of silicone implants improved the clinical status of a patient with MM following a year of maintenance therapy during which the patient's myeloma laboratory values remained unchanged. Further studies are warranted to determine if silicone breast implant removal can, in fact, improve MM patients' disease status. [ABSTRACT FROM AUTHOR]

Combination of carfilzomib with dexamethasone (Kd) is approved for use in relapsed and/or refractory multiple myeloma (RRMM), with carfilzomib administered twice weekly at 56 mg/m2 (Kd56 BIW) or once weekly at 70 mg/m2 (Kd70 QW). Post hoc cross‐trial comparisons were performed to compare efficacy and safety profiles of Kd70 QW vs Kd56 BIW dosing schedules using data from three trials of patients with RRMM: A.R.R.O.W., CHAMPION‐1, and ENDEAVOR. To select for comparable patient populations, side‐by‐side efficacy and safety comparisons were performed in subgroups of patients with 2‐3 prior lines of therapy who were not refractory to bortezomib. The overall response rate (ORR) was 69.9% (95% confidence interval [CI], 61.7‐77.2) for Kd70 QW and 72.4% (95% CI, 65.9‐78.2) for Kd56 BIW. Median progression‐free survival (PFS) was 12.1 months (95% CI, 8.4‐14.3) for Kd70 QW and 14.5 months (95% CI, 10.2—not evaluable) for Kd56 BIW. Frequency of grade ≥ 3 adverse events (AEs) was 67.6% for Kd70 QW and 85.3% for Kd56 BIW. Regression analyses (adjusting for prognostic factors) of all patients in the trials who received Kd70 QW vs Kd56 BIW estimated a PFS hazard ratio of 0.91 (95% CI, 0.69‐1.19; P =.47) and an ORR odds ratio of 1.12 (95% CI, 0.74‐1.69; P =.61). These results suggest that Kd70 QW has a comparable efficacy profile compared with Kd56 BIW and represents a convenient and well‐tolerated treatment for patients with RRMM. [ABSTRACT FROM AUTHOR]

Summary: Monocytes polarize into pro‐inflammatory macrophage‐1 (M1) or alternative macrophage‐2 (M2) states with distinct phenotypes and physiological functions. M2 cells promote tumour growth and metastasis whereas M1 macrophages show anti‐tumour effects. We found that M2 cells were increased whereas M1 cells were decreased in bone marrow (BM) from multiple myeloma (MM) patients with progressive disease (PD) compared to those in complete remission (CR). Gene expression of Tribbles homolog 1 (TRIB1) protein kinase, an inducer of M2 polarization, was increased in BM from MM patients with PD compared to those in CR. Ruxolitinib (RUX) is an inhibitor of the Janus kinase family of protein tyrosine kinases (JAKs) and is effective for treating patients with myeloproliferative disorders. RUX markedly reduces both M2 polarization and TRIB1 gene expression in MM both in vitro and in vivo in human MM xenografts in severe combined immunodeficient mice. RUX also downregulates the expression of CXCL12, CXCR4, MUC1, and CD44 in MM cells and monocytes co‐cultured with MM tumour cells; overexpression of these genes is associated with resistance of MM cells to the immunomodulatory agent lenalidomide. These results provide the rationale for evaluation of JAK inhibitors, including MM BM in combination with lenalidomide, for the treatment of MM patients. [ABSTRACT FROM AUTHOR]

This study identifies a potential effective therapeutic approach and treatment option for RRMM patients with t(11;14) with prior exposure to anti-CD38 medications and should lead to more extensive evaluation of this combination therapy regardless of time from prior exposure to a CD38 antibody as part of another treatment regimen. Keywords: anti-CD38; daratumumab; multiple myeloma; venetoclax EN anti-CD38 daratumumab multiple myeloma venetoclax 222 223 2 01/19/23 20230201 NES 230201 NOVELTY STATEMENT What is the new aspect of your work? Regardless of the time elapsed from previous anti-CD38 monoclonal antibody (mAb) exposure in another regimen, retreatment with anti-CD38 mAb therapy combined with venetoclax is effective for relapsed/refractory multiple myeloma (RRMM) patients with t(11;14). [Extracted from the article]

The Janus kinase (JAK) pathway has been shown to play key roles in the growth and resistance to drugs that develop in multiple myeloma (MM) patients. The anti-MM effects of the selective JAK1 inhibitor INCB052793 (INCB) alone and in combination with anti-MM agents were evaluated in vitro and in vivo. Significant inhibition of cell viability of primary MM cells obtained fresh from MM patients, and the MM cell lines RPMI8226 and U266, was observed with single agent INCB and was enhanced in combination with other anti-MM agents including proteasome inhibitors and glucocorticosteroids. Single-agent INCB resulted in decrease in tumor growth of the MM xenograft LAGκ-1A growing in severe combined immunodeficient mice. Mice dosed with INCB (30 mg/kg) showed significant reductions in tumor volume on days 28, 35, 42, 49, 56, and 63. Similarly, INCB at 10 mg/kg showed anti-tumor effects on days 56 and 63. Tumor-bearing mice receiving combinations of INCB with carfilzomib, bortezomib, dexamethasone, or lenalidomide showed significantly smaller tumors when compared to vehicle control and mice treated with single agents. These results provide further support for the clinical evaluation of INCB052793 alone and in combination treatment for MM patients. [ABSTRACT FROM AUTHOR]

Immunomodulatory drugs including thalidomide, lenalidomide ( LEN) and pomalidomide ( POM), are effective for treating multiple myeloma ( MM). POM has shown enhanced efficacy with dexamethasone ( DEX). Pegylated liposomal doxorubicin ( PLD) with bortezomib is US Food and Drug Administration-approved for treating MM. PLD with LEN or thalidomide has shown efficacy for MM patients. LEN with DEX, PLD and bortezomib achieves high response rates. We evaluated the combination of POM with DEX 40 mg and PLD 5 mg/m2 with the latter two drugs administered on days 1, 4, 8 and 11 on a 28-day cycle for the treatment of relapsed/refractory MM patients. During Phase 1, the maximum tolerated dose of POM was 4 mg, and was used in Phase 2, which also required patients to be refractory to LEN. However, neutropenia ≥ grade 3 was observed in 10/17 (59%) patients, and the dose was lowered to 3 mg. Median PFS was 5·4 months (range, 0·3-29·0 + months). Overall response rates for patients in Phase 2 were 39% and 31% among subjects receiving POM at 3 mg and 4 mg, respectively, and clinical benefit rates were 51% and 44%, respectively. POM, PLD and DEX is a treatment option for relapsed/refractory MM patients including those who are refractory to LEN. [ABSTRACT FROM AUTHOR]

Objective: Neuropathy is an important complication that may limit treatment options for patients with multiple myeloma. Previous studies have focused on treatment efficacy and have shown that retreatment with bortezomib (BTZ) is an effective treatment option. The goal of this study was to focus on the clinical manifestations of peripheral neuropathy (PN) and to retrospectively compare the incidence and severity of PN between the initial BTZ regimen and upon retreatment. Furthermore, this study evaluated how certain factors affect BIPN, which will help determine what conditions should be considered prior to retreatment.Methods: Charts were reviewed from 93 patients who were retreated with a BTZ-containing regimen after previously being treated with this drug.Results: Among the patients who developed PN, most patients in the study had low-grade neuropathy during the initial BTZ treatment (n = 52, 68%). The results showed no evidence of cumulative toxicity, and there was no significant difference in the incidence and severity of PN upon retreatment. Factors such as the presence of baseline PN, number of prior treatments, dose of BTZ, and comorbidities did not increase the severity of PN upon retreatment. The lapse of time between the two regimens also did not affect the severity of PN.Conclusion: The results suggest that retreatment with BTZ may be a feasible option, without additional risks of PN, for MM patients even with peripheral neuropathy during their initial treatment with this drug. [ABSTRACT FROM AUTHOR]

Oprozomib (OPZ or ONYX 0912) is an irreversible, orally administered proteasome inhibitor (PI) and an analog of carfilzomib. We set out to determine the anti-angiogenic effect of OPZ using the choriollantoic membrane/feather bud (CAM/FB) model and its anti-MM effects using MM xenograft models (LAGκ-1A, LAGλ-1). OPZ significantly reduced blood vessel formation, endothelial gene and protein expression using the CAM/FB assay. In vivo , we determined the anti-MM effects of OPZ, dexamethasone (Dex) and pomalidomide (Pom) and showed that the combinations of two drugs (OPZ + Dex or OPZ + Pom) showed marked anti-MM effects when compared to monotherapy. Pom + Dex and the triplicate combination (OPZ + Pom + Dex) showed more anti-MM effects when compared to the doublets of either OPZ + Dex or OPZ + Pom; continued treatment with all three drugs (OPZ + Pom + Dex) was superior when compared to Pom + Dex, in both MM xenograft models tested. These studies show that OPZ has anti-angiogenic effects, and that the combination of OPZ, Dex and Pom produces greater anti-MM effects in vivo when compared to any of the doublet combinations. These studies provide further support for clinical trials evaluating OPZ in combination with Pom and Dex. [ABSTRACT FROM AUTHOR]

Immunosuppressed patients are known to have an increased incidence of skin cancer. Patients with multiple myeloma ( MM) show impaired immune function. In the past, because of poor survival, the incidence of specific secondary primary malignancies such as skin cancer among these patients was difficult to establish. With more effective MM therapies that have emerged in recent years, these patients are living markedly longer, and therefore, it becomes of increasing importance to determine whether their risk of developing other medical problems such as skin cancer is increased. We performed a retrospective cohort study of 205 myeloma patients and 193 age-, race-, and gender-matched control subjects to assess the incidence of skin cancers among patients with MM and determine the specific types of and risk factors for skin cancer. We found that there is an increased occurrence of skin cancer among patients with MM compared to control subjects (26.8% vs. 16.1% in controls; P = 0.009). Among specific types of skin cancer, the proportion of patients with squamous cell carcinoma ( SCC) was higher than controls ( P = 0.016). In addition to MM diagnosis, older age and Caucasian ethnicity were predictors of skin cancer of any type. Furthermore, older age was also a predictor of SCC. [ABSTRACT FROM AUTHOR]

Interferon-α (IFNα) has been prescribed to effectively treat multiple myeloma (MM) and other malignancies for decades. Its use has waned in recent years, however, due to significant toxicity and a narrow therapeutic index (TI). We sought to improve IFNα’s TI by, first, attaching it to an anti-CD38 antibody, thereby directly targeting it to MM cells, and, second, by introducing an attenuating mutation into the IFNα portion of the fusion protein rendering it relatively inactive on normal, CD38 negative cells. This anti-CD38-IFNα(attenuated) immunocytokine, or CD38-Attenukine™, exhibits 10,000-fold increased specificity for CD38 positive cells in vitro compared to native IFNα and, significantly, is ~6,000-fold less toxic to normal bone marrow cells in vitro than native IFNα. Moreover, the attenuating mutation significantly decreases IFNα biomarker activity in cynomolgus macaques indicating that this approach may yield a better safety profile in humans than native IFNα or a non-attenuated IFNα immunocytokine. In human xenograft MM tumor models, anti-CD38-IFNα(attenuated) exerts potent anti-tumor activity in mice, inducing complete tumor regression in most cases. Furthermore, anti-CD38-IFNα(attenuated) is more efficacious than standard MM treatments (lenalidomide, bortezomib, dexamethasone) and exhibits strong synergy with lenalidomide and with bortezomib in xenograft models. Our findings suggest that tumor-targeted attenuated cytokines such as IFNα can promote robust tumor killing while minimizing systemic toxicity. [ABSTRACT FROM AUTHOR]

Multiple myeloma ( MM) is characterized by the enhanced production of the same monoclonal immunoglobulin (M-Ig or M protein). Techniques such as serum protein electrophoresis and nephelometry are routinely used to quantify levels of this protein in the serum of MM patients. However, these methods are not without their shortcomings and problems accurately quantifying M proteins remain. Precise quantification of the types and levels of M-Ig present is critical to monitoring patient response to therapy. In this study, we investigated the ability of the HevyLite ( HLC) immunoassay to correlate with clinical status based on levels of involved and uninvolved antibodies. In our cohort of MM patients, we observed that significantly higher ratios and greater differences of involved HLC levels compared to uninvolved HLC levels correlated with a worse clinical status. Similarly, higher absolute levels of involved HLC antibodies and lower levels of uninvolved HLC antibodies also correlated with a worse clinical status and a shorter progression-free survival. These findings suggest that the HLC assay is a useful and a promising tool for determining the clinical status and survival time for patients with multiple myeloma. [ABSTRACT FROM AUTHOR]

Background: Immunomodulatory drugs (IMiDs) and proteasome inhibitors have dramatically changed management of multiple myeloma (MM). While MM remains incurable, consolidation and maintenance therapy aimed at improving duration of response can potentially improve survival outcomes. A majority of randomized controlled trials (RCTs) have demonstrated benefit of IMiD-based maintenance therapy in delaying disease progression; however, whether this therapy can lead to improved survival remains controversial. Methods: PubMed and abstract databases of major hematology and/or oncology meetings were searched for RCTs that studied maintenance therapy with IMiDs in MM. A meta-analysis was conducted to systematically evaluate the impact of IMiD-based maintenance therapy on survival outcomes and serious adverse events associated with the therapy. All statistical tests were two-sided. Results: Eighteen phase 3 RCTs enrolling 7730 patients were included. IMiD-based maintenance therapy statistically significantly prolonged progression-free survival (PFS; hazard ratio (HR) = 0.62, 95% confidence interval (CI) = 0.57 to 0.67, P < .001) but failed to improve overall survival (OS; HR = 0.93, 95% CI = 0.85 to 1.01, P = .082). Stratified analyses demonstrated that both thalidomide and lenalidomide provided PFS but not OS benefit in transplantation as well as nontransplantation settings. IMiD-based maintenance therapy in MM led to a higher risk of grade 3-4 thromboembolism (risk ratio = 2.52, 95% CI = 1.41 to 4.52, P = .002). Thalidomide maintenance therapy increased the risk of peripheral neuropathy; lenalidomide maintenance therapy increased the risks of myelosuppression and second primary hematological malignancies. Conclusions: Thalidomide- or lenalidomide-based maintenance therapy improves PFS but not OS in MM and increases risks of grade 3-4 adverse events, including thromboembolism, peripheral neuropathy, neutropenia, and infection. [ABSTRACT FROM AUTHOR]

A series of pyrimidine hydroxamic acids with a sulfide substituent at the second position and a sulfonamide substituent at the fourth position have been synthesized and evaluated for their activity against human myeloma cell line RPMI 8226. Several compounds exhibited significant anti-cancer potency. It was found that representative compound 6a selectively killed cancerous but not normal cells. Moreover, compound 6a was effective in causing apoptosis in RPMI 8226 cells and exhibited promising HDAC-inhibitory activities. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy and safety of elotuzumab and dexamethasone (Ed) for relapsed or refractory multiple myeloma (RRMM) patients. Method: This retrospective study evaluated the efficacy and safety of Ed treatment for 21 RRMM patients, 11 of whom were considered lenalidomide-refractory, and all of whom had progressed on at least 1 prior steroid-containing regimen. We also evaluated the efficacy of adding lenalidomide to a subset of patients following progression from Ed. Results: The overall response rate (ORR) and clinical benefit rate (CBR) of Ed were 10% and 19%, respectively. An additional 52% of patients demonstrated stable disease as their best response. The median PFS was 1.8 months on Ed for all patients. Fifteen patients received ERd following progression on Ed, and 60% of these patients were lenalidomide-refractory. The ORR and CBR were 20% and 33%, respectively, and the median PFS was 3.4 months. Conclusion: Our results suggest that some patients can benefit from Ed without an accompanying immunomodulatory agent and that efficacy can be achieved with the addition of lenalidomide at the time of progression. No new safety signals were detected, except for thrombocytopenia in 1 patient on Ed. [ABSTRACT FROM AUTHOR]

Proteasome inhibition is an effective treatment strategy for multiple myeloma. With improving survival, attention is increasingly focusing on ease of administration and toxicity profile. Ixazomib is an investigational, orally bioavailable 20S proteasome inhibitor. Sixty patients with relapsed and/or refractory multiple myeloma were enrolled on this phase 1 trial to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) of single-agent, oral ixazomib given weekly for 3 of 4 weeks. Upon MTD determination, patients were enrolled to 4 different cohorts based on relapsed/refractory status and prior bortezomib and carfilzomib exposure. The MTD was determined to be 2.97 mg/m2. Doselimiting toxicities were grade 3 nausea, vomiting, and diarrhea in 2 patients, and grade 3 skin rash in 1 patient. Common drug-related adverse events were thrombocytopenia (43%), diarrhea (38%), nausea (38%), fatigue (37%), and vomiting (35%). The observed rate of peripheral neuropathy was 20%, with only 1 grade 3 event reported. Nine (18%) patients achieved a partial response or better, including 8 of 30 (27%) evaluable patients treated at the MTD. Pharmacokinetic studies suggested a long terminal half-life of 3.6 to 11.3 days, supporting once-weekly dosing. [ABSTRACT FROM AUTHOR]