ABSTRACT
In phase 1 of CC-92480- MM- 001 (NCT03374085), the recommended phase 2 dose (RP2D) of mezigdomide plus dexamethasone (MEZI-d) was selected at 1 mg once daily for 21/28 days. Here we report preliminary results from the MEZI-d dose-expansion cohort in patients with heavily pretreated RRMM. Key eligibility criteria were: RRMM;>=3 prior lines of therapy;disease progression <=60 days of last myeloma therapy;refractoriness to lenalidomide/pomalidomide, a proteasome inhibitor, a glucocorticoid, and an anti-CD38 monoclonal antibody. Oral mezigdomide 1 mg was given on days 1-21 of each 28-day cycle, plus weekly dexamethasone (40 mg;20 mg if >75 years of age). Primary objective was to evaluate efficacy (overall response rate [ORR]);secondary objectives included safety/tolerability and additional efficacy assessments. Pharmacodynamics was an exploratory objective. As of 16/Sep/2022, 101 patients had received MEZI-d at the RP2D. Median age was 67 (range 42-85) years, median time since initial diagnosis was 7.4 (1.1-37.0) years;39.6% of patients had plasmacytomas and 37/101 patients had high-risk cytogenetics (56/101 not evaluable). Median number of prior regimens was 6 (3-15);prior therapies included stem cell transplantation (77.2%) and anti-BCMA therapy (29.7%). All patients were refractory to last myeloma regimen and triple-class refractory. Median follow-up was 7.5 (0.5-21.9) months, with a median of 4 (1-20) cycles;10.0% of patients continued treatment;progressive disease was the main reason for discontinuation (60.4%). ORR was 40.6% for all patients. Whilst data are not mature yet, median PFS was 4.4 (95% CI 3.0-5.5) months and median duration of response was 7.6 (95% CI 5.4-9.5) months. ORR was 30.0% in patients with plasmacytomas (N = 40) and 50.0% in patients with prior anti-BCMA therapy (N = 30). Ninety-one (91.1%) patients experienced a grade 3/4 treatment-emergent adverse event (TEAE). Most frequent hematologic grade 3/4 TEAEs were neutropenia (75.2%), anaemia (35.6%), and thrombocytopenia (27.7%);34.7% of patients had grade 3/4 infections, including grade 3/4 pneumonia (15.8%) and COVID-19 (7.0%). Occurrence of other grade 3/4 non-hematologic TEAEs was generally low. Due to TEAEs, 76.2% and 29.7% of patients had mezigdomide dose interruptions and reductions, respectively;90.1% of patients discontinued mezigdomide. Mezigdomide induced substrate degradation and increases in activated and proliferating T cells in patients, including those directly refractory to pomalidomide-based therapies. MEZI-d had a manageable safety profile with encouraging efficacy in patients with triple-class refractory RRMM, including patients with prior BCMA-targeted therapies. These results strongly support the continued development of mezigdomide in MM, and especially in combination.
ABSTRACT
Introduction: Mucinous adenocarcinomas of the appendix are defined as epithelial neoplasms often causing cystic dilation of the appendix due to accumulation of gelatinous material. Pseudomyxoma peritonei is an extremely rare complication of appendiceal mucinous adenocarcinomas with an estimated incidence rate of one to 2 people per million per year. Here-in we present a unique case of enterocutaneous fistula formation secondary to percutaneous biopsy of an enlarging omental mass in the setting of pseudomyxoma peritonei. Case Description/Methods: A 50-year-old male with a past medical history of metastatic appendiceal mucinous adenocarcinoma presented to the ED with abdominal pain, nausea, and vomiting. The patient had previously undergone 2 debulking surgeries over the past 2 years prior to admission and has since been on FOLFOX therapy. Due to the COVID pandemic, the patient did not follow-up in the 2 years period from previous admission. A CT scan was now notable for a new enlarging omental mass despite the recent debulking surgery. Given the enlarging mass, a decision was made to pursue a percutaneous biopsy of the mass due to concern for potential new malignancy. Two weeks after the biopsy, the patient presented to our facility due to worsening erythema and drainage from the biopsy site. The patient met SIRS criteria, thus broad-spectrum antibiotics were initiated. A CT of the abdomen and pelvis with oral and IV contrast was obtained, which demonstrated a 9 cm abscess or continuation of intra-abdominal multilocular cystic lesion/ pseudomyxoma peritonei. The surgical team was consulted. Patient had 100 cc of purulent and mucinous drainage expressed from biopsy site. The patient was then placed for transfer to a hospital capable of advanced surgical management for evaluation and potential resection of fistula formation. The patient had a successful reductive surgery and intraoperative chemotherapy (Figure). Discussion(s): Given the rarity of pseudomyxoma peritonei, appropriate management is not always straightforward. A literature review yielded no previous reports of enterocutaneous fistula as a complication of percutaneous drainage in the setting of pseudomyxoma peritonei. We recommend that percutaneous drainage not be sought in individuals with this diagnosis due to potential for fistula formation.
ABSTRACT
Background: The bortezomib, lenalidomide, and dexamethasone (VRd) regimen is a standard of care for newly diagnosed multiple myeloma (NDMM). Belantamab mafodotin (belamaf) is a B-cell maturation antigen-binding antibody-drug conjugate that eliminates myeloma cells by a multimodal mechanism: direct cell kill and anti-myeloma tumor immune response. Belamaf has demonstrated deep and durable responses as a monotherapy in the DREAMM-2 study of patients (pts) with relapsed/refractory multiple myeloma (RRMM). Preclinical evidence of belamaf in combination with bortezomib or lenalidomide suggests enhanced anti-myeloma activity, providing rationale for this treatment combination. Aims: To evaluate the safety and tolerability of this combination in adult pts with transplant-ineligible (TI) NDMM and establish the recommended Phase III dose. Methods: DREAMM-9 (NCT04091126) is an ongoing Phase I, open-label, randomized study of belamaf + VRd. The belamaf dose cohorts currently being evaluated are Cohort 1 (1.9 mg/kg Q3/4W), Cohort 2 (1.4 mg/kg Q6/8W), Cohort 3 (1.9 mg/kg Q6/8W), Cohort 4 (1.0 mg/kg Q3/4W), and Cohort 5 (1.4 mg/kg Q3/4W). Belamaf is given with VRd Q3W until Cycle 8, and with Rd Q4W thereafter. After evaluation of safety data for Cohort 1, Cohorts 2-5 were opened in parallel and enrolled pts were randomized 1:1:1:1. Primary endpoint is safety. Secondary endpoints include efficacy, tolerability, and pharmacokinetics (PK). Results: As of data cutoff (07 Dec 2021), 64 pts were analyzed across all cohorts. Median age (range) was 73.0 (51- 88) years, 55% were male, 80% were white, 8% had extramedullary disease, 59% were International Staging System stage II or III, 20% had amp1q, and 17% had high-risk cytogenetics (≥1 of: t(4;14), t(14;16), del17p). The median duration of follow-up varied: Cohort 1 (17.4 months [mo]), Cohort 2 (5.9 mo), Cohort 3 (6.1 mo), Cohort 4 (4.7 mo), Cohort 5 (5.8 mo). Median number of belamaf cycles were: Cohort 1 (6), Cohort 2 (3), Cohort 3 (3.5), Cohort 4 (4.5), and Cohort 5 (5). Most common adverse events (AEs) across cohorts included thrombocytopenia (49%), constipation (43%), diarrhea (32%), and peripheral sensory neuropathy (30%). AEs related to study treatment were experienced by 61 (97%) pts. Belamaf-related grade 3/4 AEs occurred in 24 (38%) pts. Belamaf dose reductions occurred in 11 (18%) pts, with dose delays in 10 (16%) pts. Three pts experienced a fatal severe AE (unrelated to study treatment);2 due to COVID-19 infection, 1 due to pancreatic adenocarcinoma. Early deep responses were observed;67-92% pts achieved ≥very good partial response (VGPR) (Table), with median time to VGPR of 2.1-2.9 months across cohorts. Of pts with ≥VGPR, 17 were minimal residual disease (MRD) negative, 10 in Cohort 1. As of data cutoff, 8-75% of pts achieved best response of complete response (CR) or stringent CR (sCR). Grade 3 corneal exam findings were reported in 25-58% of pts;grade 3 visual acuity changes were reported in 21-75% of pts. No grade 4 corneal exam findings or visual acuity changes were reported in pts receiving belamaf Q6/8W, compared with 0-17% and 0-8%, respectively, in the Q3/4W cohorts. Belamaf PK profile was similar to that in pts with RRMM, accounting for baseline characteristics. Image: Summary/Conclusion: Belamaf + VRd demonstrated high response rates in pts with TI NDMM, with a high rate of MRD negativity indicating deep responses. No new safety signals were observed relative to DREAMM-2. Study is ongoing to evaluate the safety and efficacy of variable dose intensities of belamaf in combination with VRd.
ABSTRACT
Background: The role of upfront ASCT for NDTE MM remains under evaluation with high MRD rates following novel induction and consolidation (cons) strategies. K maintenance represents an alternative strategy to lenalidomide maintenance. The CARDAMON trial investigated K maintenance following KCd induction plus either ASCT or KCd cons. Methods: NDTE pts received 4 x KCd induction (K 20/56 mg/m2 biweekly, C 500 mg D 1,8,15, d 40mg weekly) before 1:1 randomisation to ASCT or 4 x KCd cons followed by 18 cycles K maintenance (56mg/m2 D1,8,15). Flow cytometric MRD (10-5) was assessed post induction, pre-maintenance and at 6 months maintenance. Primary endpoints were ≥VGPR post induction and 2-year PFS from randomisation. Secondary endpoints included improvements in disease response and MRD conversion following ASCT/ cons and maintenance. Results: 281 patients were registered, with 218 randomised to either ASCT or cons. The median PFS for ASCT was not yet reached vs 3.4 years for cons, with cons failing to show non-inferiority (difference in 2-year PFS 6.5%, 70% CI 1.0% to 11.1%). 196 patients received K maintenance (99 ASCT, 97 cons), 17 remain on treatment. A median of 16 cycles (1-18) were given over a median of 15.9 months (0-21.5). COVID-19 led to maintenance treatment interruptions in 41 (8 ASCT, 6 Cons) and treatment discontinuation in 15 (9 ASCT, 6 Cons). The median K dose given was 50.6mg/m2 and was similar across both arms (51.2 vs 49.4mg/m2, p=0.03). K maintenance was discontinued for PD in 14.1% (ASCT) vs 22.7% (cons), and for adverse events (AEs) in 7.1% (ASCT) vs 4.1% (cons). Most common AEs were hypertension and infections and more ≥G3 AEs were noted in ASCT vs cons (p=0.01). Patient/ clinician withdrawals from maintenance were low but occurred more in the ASCT arm (9.1% vs 1%). MRD neg patients post ASCT/ Cons had a longer PFS than MRD pos (p=0.002);with a higher MRD neg rate in the ASCT arm (53.6% vs 35.1% in Cons, p=0.01). MRD neg patients at 6 months post maintenance also had longer PFS (p=0.004 cf MRD pos patients);again with higher MRD neg rates in the ASCT arm (58.1% ASCT vs 40.5% Cons, p=0.02). There was no difference in PFS for MRD neg patients according to treatment arm from PBSCH, post-ASCT/ Cons or 6 months maintenance timepoints. Overall, 27.8% of MRD pos patients converted to MRD neg post ASCT/ Cons with more converting with ASCT (39.1% ASCT vs 16.1%, p=0.004). 23.5% of MRD pos patients converted to neg during maintenance (30.6% ASCT, 17.8%: p=0.2). Maintenance of MRD negativity over the first 6 months was similar between ASCT and Cons arms (p=0.3). There was no evidence that the timing of achievement of MRD negativity impacted PFS. Conclusions: K maintenance at 56mg/m2 weekly was deliverable and tolerable, with continued higher MRD neg rates at 6 months post-ASCT compared to post-Cons. However more ≥G3 AEs and discontinuations for AEs/ patient choice were noted for K maintenance after ASCT.
ABSTRACT
Introduction: COVID-19 created a huge impact across the globe with no partiality. Majority of the cities in India is affected. India was in good shape a few months back and now, it is affected badly. There may be various causes to this situation and by seeing the current number of cases, soon India is going to take the first place in COVID-19. It is important to study various factors around the current and future state of COVID-19 in India. Aim: The objective of this research paper is to explore the current state of COVID-19 pandemic of India and the USA and understand how the COVID-19 spread is severe in India. The secondary aim of the research is to predict the confirmed cases and death rates for the forthcoming days for the USA and India as well and conclude India’s future state in COVID-19. Sample, Technique and Methods: For this research, we have used the data from 20 January 2020 to 13 October 2020 from the World Health Organization. To forecast the COVID-19 cumulative confirmed and death cases for the United States America and India, we have used FORECAST.ETS function in Microsoft Excel. The prediction calculated till 31 December 2020. Results: By 31 Oct 2020, the forecasted cumulative cases would be 8569864 in the USA and India, it would be 8288117 approximately. By 27 Nov 2020, the forecasted cumulative cases would be 9930000 in the USA and India, it would be 9941491 approximately. By 31 Dec 2020, the forecasted cumulative cases would be 11642764 in the USA and India, it would be 12023517 approximately. So, by the last week of November, India will have more COVID-19 cases than the USA and hence India will take first place globally. Conclusion: Along with the guidelines and advisory from WHO, the government of India and the department of health is taking various initiatives to control the COVID-19 spread and maintain the lower number of COVID-19 cases. However, the number of confirmed and death rates are increasing in an uncontrolled manner in the Indian sub-continent. It is not a good symptom to see that India will take over the USA’s position in COVID-19. Unless there is an initiative which can control the spread, it is not going to be easy for India by considering the population and the forthcoming winter session. © IJCRR.
ABSTRACT
Aim: The objective of this research is to explore the current state of COVID-19 pandemic at the United States of America and understand how the COVID-19 spread across various states in the county and the possible influencers to the highest number of positive cases and mortality rates. The secondary aim of the research is to predict the confirmed cases and death rates for the forthcoming days for the USA. Sample, Technique and Methods: For this research, we have used the data from 20 January 2020 to 17 July 2020. For forecasting the number of COVID-19 cases for the United States America, we have used FORECAST.ETS function in Microsoft Excel. The prediction calculated till 31 August 2020. Results: From the forecasting analysis for the United States of America, by the end of August, as on 31 August 2020, the number of cumulative confirmed cases may reach up to 6419049 (64.2 lakhs). If the situation is good, it can be controlled at 5888853(58.8 lakhs), and it may go up to 6949245(69.4 lakhs) if the scenario goes bad. By 31 August 2020, the number of cumulative death cases may go up to 166945 in the typical scenario, and however, it may reach up to 202566 if the COVID-19 situation goes wrong due to various reasons. Conclusion: There are numerous combined initiatives from the government authorities to control, treat and prevent COVID-19 at the United States of America. But still, the number of confirmed and death rates are increasing in an uncontrolled manner since it is identified in the USA. Various countries have managed the COVID-19 situation better. The USA needs to interact and learn the best practices from the nations who were able to control better. Forecasting is a powerful tool in the pandemic management which needs to be formulated strategically. © 2020, Radiance Research Academy. All rights reserved.