A Phase I Trial Evaluating the Addition of Lenalidomide to Patients with Relapsed/Refractory Multiple Myeloma Progressing on Ruxolitinib and Methylprednisolone.

BACKGROUND: Ruxolitinib (RUX), an orally administered selective Janus kinase 1/2 inhibitor, has received approval for the treatment of myelofibrosis, polycythemia vera, and graft-versus-host disease. We have previously demonstrated the anti-multiple myeloma effects of RUX alone and in combination with the immunomodulatory agent lenalidomide (LEN) and glucocorticosteroids both pre-clinically and clinically. OBJECTIVE: This study aims to evaluate whether LEN can achieve clinical activity among patients with multiple myeloma progressing on the combination of RUX and methylprednisolone (MP). METHODS: In this part of a phase I, multicenter, open-label study, we evaluated the safety and efficacy of RUX and MP for patients with multiple myeloma with progressive disease who had previously received a proteasome inhibitor, LEN, glucocorticosteroids, and at least three prior regimens; we also determined the safety and efficacy of adding LEN at the time of disease progression from the initial doublet treatment. Initially, all subjects received oral RUX 15 mg twice daily and oral MP 40 mg every other day. Those patients who developed progressive disease according to the International Myeloma Working Group criteria then received LEN 10 mg once daily on days 1-21 within a 28-day cycle in addition to RUX and MP, which were administered at the same doses these patients were receiving at the time progressive disease developed. RESULTS: Twenty-nine subjects (median age 64 years; 18 [62%] male) were enrolled in this part of the study and initially received the two-drug combination of RUX and MP. The median number of prior therapies was six (range 3-12). The overall response rate from this two-drug combination was 31% and the clinical benefit rate was 34%. The best responses were 1 very good partial response, 8 partial responses, 1 minor response, 12 stable disease, and 7 progressive disease. The median progression-free survival was 3.5 months (range  0.5-36.2 months). The median time to response was 3.0 months. The median duration of response was 12.5 months (range 2.8-36.2 months). Twenty (69%) patients who showed progressive disease had LEN added to RUX and MP; all patients had prior exposure to LEN and all but one patient was refractory to their last LEN-containing regimen. After the addition of LEN, the overall response rate was 30% and the clinical benefit rate was 40%. The best responses of patients following the addition of LEN were 2 very good partial responses, 4 partial responses, 2 minor responses, 8 stable disease, and 4 progressive disease. The median time to response was 2.6 months (range 0.7-15.0 months). The median duration of response was not reached. The median progression-free survival following the addition of LEN was 3.5 months (range 0.3-25.9 months). CONCLUSIONS: For patients with multiple myeloma, treatment with RUX and MP is effective and well tolerated, and LEN can be used to extend the benefit of this RUX-based treatment. CLINICAL TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov, NCT03110822, and is ongoing.

Fostamatinib or Thrombopoietic Receptor Agonists for the Treatment of Chronic Immune Thrombocytopenia in Adult Patients: A Real-World Assessment of Safety, Effectiveness and Cost.

INTRODUCTION: Chronic immune thrombocytopenia purpura (ITP) in adults is a serious autoimmune disease in which platelets are prematurely destroyed, leaving the patient vulnerable to bruising and bleeding. Initial treatment is with corticosteroids. In patients who become resistant or intolerant to corticosteroids, the thrombopoietic agents (TPOs), consisting of romiplostim (ROM), eltrombopag (ELT) and avatrombopag (AVA) or the spleen tyrosine kinase inhibitor fostamatinib (FOS), are appropriate next lines of therapy. In this study, the comparative safety, effectiveness and cost of care between fostamatinib vs. the TPOs was evaluated in a real-world setting. METHODS: A retrospective analysis from 17 community hematology practices across the United States was conducted to identify adult ITP patients who received one of the four agents. Data collection consisted of patient demographics, disease characteristics, as well as number and type of prior treatments. From the first day until the end of treatment, data were also collected on platelet (PLT) counts, adverse events, the use of rescue IVIG, platelet transfusions and corticosteroids. Multivariable logistic regression analysis was used to compare PLT related endpoints between agents. RESULTS: A sample of 179 ITP patients who had received at least one of the four agents was identified. This resulted in a final sample of 51, 87, 127 and 44 patients who received FOS, ELT, ROM or AVA respectively. At month six, there were no significant differences between FOS vs. the TPOs in terms of the proportion of patients with the PLT count being ≥ 30 x 103/µL, ≥ 50 x 103/µL as well as the proportion of patients whose PLTs levels doubled relative to baseline. The frequency of thromboembolic events (TEs) was 3.9% in FOS patients compared to 9.2%, 4.7% and 11.4% in the ELT, ROM and AVA groups. The mean cost per patient with FOS was $99,209 (95%CI: $59,595 to $115,074) compared to $92,341 (95:CI$68,331 to $115,519), $108,482 (95%CI: $84,782 to $132,182) and $131,050 (95%CI: $83,327 to $179,897) for ELT, ROM or AVA respectively. CONCLUSIONS: In this real-world analysis, FOS was comparable to the TPOs in maintaining PLTs at clinically beneficial levels. Given these findings, the choice of therapy should be based on overall patient safety, preexisting risk factors for TEs and cost effectiveness.

Ruxolitinib and methylprednisolone for treatment of patients with relapsed/refractory multiple myeloma.

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.

A real-world study to evaluate the safety and efficacy of three injectable neurokinin-1 receptor antagonist formulations for the prevention of chemotherapy-induced nausea and vomiting in cancer patients.

BACKGROUND: Three different injectable neurokinin-1 (NK-1) receptor antagonist formulations (CINVANTI® [C] vs. intravenous Emend® [E] vs. generic formulations of fosaprepitant [GFF]) were compared with respect to nausea and vomiting control, use of rescue therapy, and the development of infusion reactions over multiple cycles of chemotherapy. METHODS: A retrospective analysis from 17 community oncology practices across the USA was conducted on patients who received moderately or highly emetogenic chemotherapy. The co-primary endpoints were the control of chemotherapy-induced nausea and vomiting (CINV) from days 1 to 5 over all cycles and the frequency of infusion-related reactions. Propensity score weighted multivariable logistic regression analysis was used to compare complete CINV control, the use of rescue therapy, and the risk of infusion reactions between groups. RESULTS: The study enrolled 294 patients (C = 101, E = 101, GFF = 92) who received 1432 cycles of chemotherapy. Using CINVANTI® as the reference group, comparative effectiveness was suggested in CINV control over all chemotherapy cycles (odds ratio (OR): E vs. C = 1.00 [0.54 to 1.86] and GFF vs. C = 1.12 [0.54 to 2.32]). However, use of rescue therapy was significantly higher in the EMEND® group relative to CINVANTI® (OR = 2.69; 95%CI: 1.06 to 6.84). Infusion reactions were also numerically higher in the EMEND® group, but the difference did not reach statistical significance (OR = 4.35; 95%CI: 0.83 to 22.8). CONCLUSIONS: In this real-world analysis, patients receiving CINVANTI® had a reduced need for CINV rescue therapy and a numerically lower incidence of infusion reactions.

A phase 1/2 study of ixazomib in place of bortezomib or carfilzomib in a subsequent line of therapy for patients with multiple myeloma refractory to their last bortezomib or carfilzomib combination regimen.

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.

Efficacy and safety of ofatumumab and bendamustine followed by ofatumumab maintenance in patients with relapsed indolent non-Hodgkin lymphoma after prior rituximab.

In indolent non-Hodgkin's lymphoma (iNHL), patients treated with rituximab, alone or in combination with various chemotherapeutic agents eventually relapse. This study evaluated the combination of ofatumumab and bendamustine, followed by maintenance ofatumumab in patients with relapsed iNHL with prior sensitivity to rituximab. Among the 49 patients enrolled, 24.5% achieved a complete response (CR) and 42.9% achieved a partial response (PR), with an overall response rate of 67.3% at the end of the induction therapy. Additionally, six patients with PR during induction phase achieved CR during the maintenance phase. Treatment-related adverse event was observed in 95.9% patients. The most common hematologic and biochemical abnormalities were decrease in lymphocytes (85.7%) and increase in glucose (91.8%), respectively. Overall, 42.9% progressed and 14.3% died during the study. Thus, ofatumumab in combination with bendamustine, followed by ofatumumab maintenance, was effective in the treatment of patients with iNHL with a manageable safety profile (NCT01294579).

Safety of BTZ retreatment for patients with low-grade peripheral neuropathy during the initial treatment.

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.

Where does magnetic resonance imaging stand in the diagnosis of knee injuries?

BACKGROUND: The aim of this study was to determine the diagnostic value of magnetic resonance imaging (MRI) in the diagnosis of knee injuries. MATERIALS AND METHODS: Ninety-eight consecutive patients were enrolled in the study. In all patients, MRI and arthroscopy were performed and the results were compared. RESULTS: MRI was most sensitive in the detection of medial meniscus injuries, and the highest specificity and negative predictive value (NPV) were found in the detection of posterior cruciate ligament injuries. CONCLUSION: MRI is a valuable tool, and according to its high NPV, normal MRI can prevent unnecessary arthroscopic interventions.

Ultrasound guided platelet-rich plasma injection for the treatment of rotator cuff tendinopathy.

BACKGROUND: Degenerative changes and inflammation in the rotator cuff (RC) are the most important causes of shoulder pain. The aim of the present study was to determine the effectiveness of platelet-rich plasma (PRP) in patients with chronic RC tendinopathy. MATERIALS AND METHODS: This study was an open-label study performed at Kashani Hospital between April 2012 and June 2014. Patients with a <1 cm partial tearing of the bursal side of RC with no or little response to conservative management were included. PRP injection was done using ultrasonography guide via posterior subacromial approach. Demographic data were obtained in all patient before the study, and shoulder function was evaluated using Constant shoulder score (CSS) before and 3 months after PRP injection. RESULTS: A total number of 17 patients were enrolled. The mean of CSS before and after intervention was 37.05 ± 11.03 and 61.76 ± 14.75, respectively (P < 0.001). There was no statistically significant correlation between the pain score before the study and the improvement in CSS (P = 0.45, r = 0.03). Significant relation was observed between the individuals' age and improvement of CSS (P = 0.02, r = -0.49). There was no significant difference in CSS improvement between genders (P = 0.23). CONCLUSION: Single injection of PRP is effective to reduce pain and improve range of motion in patients with bursal side partial tearing of RC who failed to respond to conservative treatments.

Scaphoid nonunion fracture and results of the modified Matti-Russe technique.

BACKGROUND: The best treatment for scaphoid nonunion fractures is still controversial. The main aim of this study was to determine the results of the modified Matti-Russe method of surgery on scaphoid nonunion. MATERIALS AND METHODS: In this prospective interventional study, 30 patients with nonunion scaphoid fracture recruited from clinics of the Isfahan University of Medical Sciences between October 2007 and March 2011 underwent the modified Matti-Russe method of surgery. Union rate was evaluated four and six months after the procedure. Mayo wrist score (MWS) was calculated for the subjects six months after surgery. RESULTS: Mean age of the subjects was 25.9 ± 7.8 years, ranging from 16 to 35 years. Twenty-seven (90%) were men, and three (10%) were women. Four and six months after surgery, 10 (33%) and 26 (86.7%) subjects had a united fracture. Mean MWS was 75.0 ± 8.8 in all the subjects, ranging from 54 to 90 six months after surgery. Three subjects (10%) were grouped as excellent, 9 (30%) good, 16 (53.3%) satisfactory, and 3 (6.7%) poor. CONCLUSION: A fracture or nonunion of the scaphoid bone can be a complex and troubling injury, but the modified Matti-Russe method showed satisfactory results six months after surgery.

Management of scaphoid nonunion with avascular necrosis using 1,2 intercompartmental supraretinacular arterial bone graft.

BACKGROUND: 1,2 ICSRA, introduced by Aidembery et al., is a well-established technique, with up to 100% union rate among different studies. The purpose of our study was to evaluate the outcome of scaphoid nonunion undergoing 1,2 ICSRA bone graft in Iran. MATERIALS AND METHODS: All participants who presented sequentially over a period of 24 months between 2010 and 2013 with nonunion scaphoid fracture with AVN in proximal pole were included in the study. Anteroposterior and lateral view plain radiographs of carpal bones were obtained for diagnosis of nonunion, and a diagnosis of avascular necrosis was made by MRI of the scaphoid. Subjects underwent 1,2 ICSRA bone graft surgery. Patients were assessed based on radiographs and the Mayo Wrist Score (MWS) questionnaire on before and after surgery. Data were analyzed using SPSS ver. 18 by paired t test. RESULTS: Overall, 16 patients (100% male) were included in the study. Mean age of subjects was 27.50 ± 5.86 (18 to 38). Mean Mayo score was 36.63 ± 8.92 and 83.75 ± 9.22 before and 6 month after surgery, respectively, and the difference was statistically significant (P < 0.001). after 8 weeks, 10 (62.5%) had union, and after 12 weeks, all subjects had union. Nine (56.25%) of our patients had excellent functional outcome, 5 (31.25%) had good and 2 (12.5%) had satisfactory functional outcome. CONCLUSION: 1,2 ICSRA is a proper pedicle of vascularized bone graft due to the ease of visibility and dissection. The functional results and union rates were satisfactory in our study.

Randomized phase II study of carboplatin and etoposide with or without obatoclax mesylate in extensive-stage small cell lung cancer.

OBJECTIVE: This randomized phase II study assessed the efficacy and safety of obatoclax mesylate, a small-molecule Bcl-2 inhibitor, added to carboplatin/etoposide chemotherapy as initial treatment for extensive-stage small-cell lung cancer (ES-SCLC). MATERIALS AND METHODS: Chemotherapy-naïve subjects with ES-SCLC and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2 received carboplatin/etoposide with (CbEOb) or without (CbE) obatoclax for up to six cycles. Responders to CbEOb could receive maintenance obatoclax until disease progression. The primary endpoint was objective response rate (ORR). RESULTS: 155 subjects (median age 62, 58% male, 10% ECOG PS 2) were treated with CbEOb (n=77) or CbE (n=78); 65% and 59% of subjects, respectively, completed six cycles. ORR was 62% with CbEOb versus 53% with CbE (1-sided p=0.143). Clinical benefit (ORR+ stable disease) trended better with CbEOb (81% versus 68%; p=0.054). Median progression-free survival (PFS) and overall survival (OS) were 5.8 months (95% confidence interval [CI]: 5.3-6.5) and 10.5 months (8.9-13.8) with CbEOb and 5.2 months (95% CI: 4.1-5.7) and 9.8 months (7.2-11.2) with CbE. Median OS was 10.5 months (95% CI: 8.9-13.8) and 9.8 months (7.2-11.2) with a nonsignificant hazard ratio for OS, 0.823; 1-sided p=0.121. Grade 3/4 adverse events (AEs) were primarily hematologic and similar in frequency between treatment arms. Obatoclax-related somnolence and euphoria were grade 1/2, transient, and did not require treatment discontinuation. CONCLUSION: Obatoclax was well tolerated when added to carboplatin/etoposide in first-line treatment of ES-SCLC, but failed to significantly improve ORR, PFS, or OS.

Hour glass constriction in advanced carpal tunnel syndrome.

BACKGROUND: Compressive neuropathy of median nerve is relatively common but development of an hourglass like constriction is a rare phenomenon. The purpose of this study is to show morphologic changes of median nerve in advances carpal tunnel syndrome. METHODS: Eighty patients with thenar atrophy, anesthesia and paresthesia of first, second and third finger and severe changes of EMG-NCV were chosen for surgery. All the cases were operated by classic approach. RESULTS: At ten cases, nerve was constricted in point and in six patients' area constriction was seen. Internal and external neurolysis was performed in all the cases. In two of them because of the wide and severe constriction, resection and end-to-end repair was performed. All the patients have been examined periodically. Mean follow-up was 12 month (8-40). According to grading, pain degree (from 8-9 pre operation to 3-4 post operation) and two point discrimination (from the mean of 14 mm (13-20 mm) to 8 mm (6-10 mm)) decreased. Grip power was increased from the mean of 10 kg to 21 kg. In 15 cases return of sensation, and in 13 cases improvement of opposition power was seen. CONCLUSION: We recommend epineurolysis for mild to moderate constriction and also end-to-end repair may be needed if extensive and severe constriction was found. It means that if we manage mild to moderate constriction sooner, it can prevent the need for further surgical procedure because of sever constriction.

Translation and cultural adaptation of the oxford hip score for Iranian population.

INTRODUCTION: In recent years, outcome assessment related to orthopedic surgeries has increasingly focused on patient-reported questionnaires. The Oxford Hip Score (OHS), self-administered questionnaire, is a reliable, valid, and responsive instrument for assessing hip in patients undergoing Arthroplasty. METHODS: The study involved 105 adult Persian-speaking patients admitted for primary Total Hip Arthroplasty in two hospitals in Isfahan in Iran from September 2009 until April 2011. All of them filled out their scales (Persian OHS, WOMAC, and SF12) in preoperative examination. RESULTS: Mean scores of OHS in first administrations was 42.7 ± 12.7. The Persian OHS overall score demonstrated high reproducibility (ICC,0.93, P < 0.001) and internal consistency (CA, 0.94). PersianOHS had high correlations with WOMAC total score (r = 0.86), function score (r = 0.86), and pain score (r = 0.79), the relationship between the Persian OHS and the WOMAC stiffness subscale was somewhat lower (r = 0.69). The correlation coefficient between the Persian OHS and the PCS of the SF-12 in our study was moderate (r = 0.58). Persian OHS had low correlation with MCS of the SF-12 (r = 0.40). DISCUSSION: Persian OHS had high correlations with WOMAC total score, function score, and pain score. It had moderate correlation with PCS of the SF-12 and low correlation with MCS of the SF-12. CONCLUSIONS: Our study demonstrated the trans-cultural adaptation and validation of the Persian OHS is a reliable and practicable instrument for assessment of function and pain in Iranian patients with hip osteoarthritis.

Zoledronic acid markedly improves bone mineral density for patients with monoclonal gammopathy of undetermined significance and bone loss.

PURPOSE: Patients with monoclonal gammopathy of undetermined significance (MGUS) have increased rates of bone resorption, osteopenia, osteoporosis, and risk of fractures. This study was undertaken to determine the efficacy and safety of zoledronic acid for patients with MGUS and enhanced bone loss. EXPERIMENTAL DESIGN: In this phase II open-label study, 54 patients with MGUS and osteopenia or osteoporosis were administered zoledronic acid 4 mg i.v. at 0, 6, and 12 months. The primary efficacy end point was bone mineral density, assessed using a dual-energy X-ray absorptiometry scan in the lumbar (L)-spine done at screening and at 13 months (1 month after the final zoledronic acid infusion). RESULTS: At study end for all patients (N = 54), L-spine T-scores improved by a median of +0.27 (range, -0.38 to +3.91), corresponding to a median increase in bone mineral density of +15.0% (range, -18.0% to +1,140.0%; P < 0.0001). Hip T-scores improved by a median of +0.10 (range, -2.40 to +2.03), corresponding to a median increase of +6.0% (range, -350.0% to +165.0%). During the study, no new fractures, osteonecrosis of the jaw, or significant renal adverse events were reported. CONCLUSIONS: Zoledronic acid administered i.v. at a dosage of 4 mg every 6 months for three doses total was well-tolerated and substantially improved bone mineral density for patients with MGUS and bone loss. Zoledronic acid may be effective for the prevention of new fractures in this high-risk population.