B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches.

Despite considerable advances in the treatment of multiple myeloma (MM) in the last decade, a substantial proportion of patients do not respond to current therapies or have a short duration of response. Furthermore, these treatments can have notable morbidity and are not uniformly tolerated in all patients. As there is no cure for MM, patients eventually become resistant to therapies, leading to development of relapsed/refractory MM. Therefore, an unmet need exists for MM treatments with novel mechanisms of action that can provide durable responses, evade resistance to prior therapies, and/or are better tolerated. B-cell maturation antigen (BCMA) is preferentially expressed by mature B lymphocytes, and its overexpression and activation are associated with MM in preclinical models and humans, supporting its potential utility as a therapeutic target for MM. Moreover, the use of BCMA as a biomarker for MM is supported by its prognostic value, correlation with clinical status, and its ability to be used in traditionally difficult-to-monitor patient populations. Here, we review three common treatment modalities used to target BCMA in the treatment of MM: bispecific antibody constructs, antibody-drug conjugates, and chimeric antigen receptor (CAR)-modified T-cell therapy. We provide an overview of preliminary clinical data from trials using these therapies, including the BiTE® (bispecific T-cell engager) immuno-oncology therapy AMG 420, the antibody-drug conjugate GSK2857916, and several CAR T-cell therapeutic agents including bb2121, NIH CAR-BCMA, and LCAR-B38M. Notable antimyeloma activity and high minimal residual disease negativity rates have been observed with several of these treatments. These clinical data outline the potential for BCMA-targeted therapies to improve the treatment landscape for MM. Importantly, clinical results to date suggest that these therapies may hold promise for deep and durable responses and support further investigation in earlier lines of treatment, including newly diagnosed MM

The impact of disease control measures on the spread of COVID-19 in the province of Sindh, Pakistan

The province of Sindh reported the first COVID-19 case in Pakistan on 26(th) February 2020. The Government of Sindh has employed numerous control measures to limit its spread. However, for low-and middle-income countries such as Pakistan, the management protocols for controlling a pandemic are not always as definitive as they would be in other developed nations. Given the dire socio-economic conditions of Sindh, continuation of province-wise lockdowns may inadvertently cause a potential economic breakdown. By using a data driven SEIR modelling framework, this paper describes the evolution of the epidemic projections because of government control measures. The data from reported COVID-19 prevalence and google mobility is used to parameterize the model at different time points. These time points correspond to the government’s call for advice on the prerequisite actions required to curtail the spread of COVID-19 in Sindh. Our model predicted the epidemic peak to occur by 18(th) June 2020 with approximately 3500 reported cases at that peak, this projection correlated with the actual recorded peak during the first wave of the disease in Sindh. The impact of the governmental control actions and religious ceremonies on the epidemic profile during this first wave of COVID-19 are clearly reflected in the model outcomes through variations in the epidemic peaks. We also report these variations by displaying the trajectory of the epidemics had the control measures been guided differently; the epidemic peak may have occurred as early as the end of May 2020 with approximately 5000 reported cases per day had there been no control measures and as late as August 2020 with only around 2000 cases at the peak had the lockdown continued, nearly flattening the epidemic curve

Post-Transplant Outcomes in High-Risk Compared with Non-High-Risk Multiple Myeloma: A CIBMTR Analysis.

Conventional cytogenetics and interphase fluorescence in situ hybridization (FISH) identify high-risk multiple myeloma (HRM) populations characterized by poor outcomes. We analyzed these differences among HRM versus non-HRM populations after upfront autologous hematopoietic cell transplantation (autoHCT). Between 2008 and 2012, 715 patients with multiple myeloma identified by FISH and/or cytogenetic data with upfront autoHCT were identified in the Center for International Blood and Marrow Transplant Research database. HRM was defined as del17p, t(4;14), t(14;16), hypodiploidy (-Y) or chromosome 1 p and 1q abnormalities; all others were non-HRM. Among 125 HRM patients (17.5%), induction with bortezomib and immunomodulatory agents (imids) was higher compared with non-HRM (56% versus 43%, P \u3c .001) with similar pretransplant complete response (CR) rates (14% versus 16%, P .1). At day 100 post-transplant, at least a very good partial response was 59% in HRM and 61% in non-HRM (P = .6). More HRM patients received post-transplant therapy with bortezomib and imids (26% versus 12%, P = .004). Three-year post-transplant progression-free (PFS) and overall survival (OS) rates in HRM versus non-HRM were 37% versus 49% (P \u3c .001) and 72% versus 85% (P \u3c .001), respectively. At 3 years, PFS for HRM patients with and without post-transplant therapy was 46% (95% confidence interval [CI], 33 to 59) versus 14% (95% CI, 4 to 29) and in non-HRM patients with and without post-transplant therapy 55% (95% CI, 49 to 62) versus 39% (95% CI, 32 to 47); rates of OS for HRM patients with and without post-transplant therapy were 81% (95% CI, 70 to 90) versus 48% (95% CI, 30 to 65) compared with 88% (95% CI, 84 to 92) and 79% (95% CI, 73 to 85) in non-HRM patients with and without post-transplant therapy, respectively. Among patients receiving post-transplant therapy, there was no difference in OS between HRM and non-HRM (P = .08). In addition to HRM, higher stage, less than a CR pretransplant, lack of post-transplant therapy, and African American race were associated with worse OS. In conclusion, we show HRM patients achieve similar day 100 post-transplant responses compared with non-HRM patients, but these responses are not sustained. Post-transplant therapy appeared to improve the poor outcomes of HRM

The anti-myeloma activity of a novel purine scaffold HSP90 inhibitor PU-H71 is via inhibition of both HSP90A and HSP90B1

<p>Abstract</p> <p>Background</p> <p>Heat shock protein 90 (HSP90) inhibitors have emerged as a promising class of anti-cancer drugs in both solid and hematologic malignancies. The HSP90 family includes the cytosolic HSP90 (HSP90AA1), the ER paralogue gp96 (HSP90B1) and the mitochondrial member TRAP1 (HSP90L). We evaluated the <it>in vitro </it>anti-tumor activity and mechanism of action of PU-H71, a novel purine scaffold HSP90 inhibitor in human multiple myeloma cell lines.</p> <p>Methods</p> <p>Multiple human myeloma cell lines including cells that are resistant to corticosteroids and bortezimab were treated with PU-H71, followed by analysis of cell viability, cell cycle progression and apoptosis, by flow cytometry and caspase 3 immunoblot. Induction of unfolded protein response was studied by XBP-1 s immunoblot. The role of gp96 was further assessed by small hairpin RNA knockdown of gp96 before treatment with PU-H71.</p> <p>Results</p> <p>PU-H71 has potent <it>in vitro </it>anti-myeloma activity in both drug-sensitive and drug-resistant cell lines. PU-H71 activates the unfolded protein response and induces caspase-dependent apoptosis. The stable gp96 knockdown human myeloma cell line was found to be more resistant to PU-H71 and other HSP90 inhibitors including 17-AAG and 17-DMAG, even though these cells are more sensitive to conventional anti-myeloma drugs.</p> <p>Conclusion</p> <p>We conclude that PU-H71 is a promising drug for the treatment of myeloma. Our finding further suggests that PU-H71 and the geldanamycin analogues work in part by inhibiting the endoplasmic reticulum gp96 along with the cytosolic HSP90.</p

Exposure-Response and Population Pharmacokinetic Analyses of a Novel Subcutaneous Formulation of Daratumumab Administered to Multiple Myeloma Patients

We report the population pharmacokinetic (PK) and exposure-response analyses of a novel subcutaneous formulation of daratumumab (DARA) using data from 3 DARA subcutaneous monotherapy studies (PAVO Part 2, MMY1008, COLUMBA) and 1 combination therapy study (PLEIADES). Results were based on 5159 PK samples from 742 patients (DARA 1800 mg subcutaneously, n = 487 [monotherapy, n = 288; combination therapy, n = 199]; DARA 16 mg/kg intravenously, n = 255 [all monotherapy, in COLUMBA]; age, 33-92 years; weight, 28.6-147.6 kg). Subcutaneous and intravenous DARA monotherapies were administered once every week for cycles 1-2, once every 2 weeks for cycles 3-6, and once every 4 weeks thereafter (1 cycle is 28 days). The subcutaneous DARA combination therapy was administered with the adaptation of corresponding standard-of-care regimens. PK samples were collected between cycle 1 and cycle 12. Among monotherapy studies, throughout the treatment period, subcutaneous DARA provided similar/slightly higher trough concentrations (Ctrough) versus intravenous DARA, with lower maximum concentrations and smaller peak-to-trough fluctuations. The PK profile was consistent between subcutaneous DARA monotherapy and combination therapies. The exposure-response relationship between daratumumab PK and efficacy or safety end points was similar for subcutaneous and intravenous DARA. Although the ≤65-kg subgroup reported a higher incidence of neutropenia, no relationship was found between the incidence of neutropenia and exposure, which was attributed, in part, to the preexisting imbalance in neutropenia between subcutaneous DARA (45.5%) and intravenous DARA (19%) in patients ≤50 kg. A flat relationship was observed between body weight and any grade and at least grade 3 infections. The results support the DARA 1800-mg subcutaneous flat dose as an alternative to the approved intravenous DARA 16 mg/kg.The clinical studies and the analyses presented here were supported by research funding from Janssen Research & Development, LLC

Reactive Absorption of CO2 Using Ethylaminoethanol Promoted Aqueous Potassium Carbonate Solvent

Atmospheric concentration of CO2, which is considered as one of the major greenhouse gases (GHGs), has increased up to 398 ppmv as of 2015. CO2 concentration in atmosphere was 280 ppmv in pre-industrial era, and due to the continuous discharge, it is expected to increase up to 550 ppmv by 2050. Many of the major industrial sources of CO2 emissions are natural gas fired power plants, synthesis gas used in integrated gasification combined cycle (IGCC) and power generation, gas streams produced after combustion of fossil fuels or other carbonaceous materials, and oxyfuels. Reactive absorption of CO2 from the industrial off gases by using chemical solvents is considered as one of the most common, efficient, and cost effective technologies utilized by the industry for CO2 capture. The captured CO2 can be stored by using the geological or oceanic sequestration approaches. As an alternative to geological or oceanic sequestration, the captured CO2 can be re-energized into CO by using solar energy and combined with H2, which can be generated from different methods, to produce syngas. The syngas produced can be further processed to liquid fuels such as methanol, gasoline, jet fuel, etc. via the catalytic Fischer-Tropsch process. In past, a variety of chemical solvents (mostly aqueous amines and there derivatives) have been used for CO2 capture from different gaseous streams via reactive absorption. Though the amines are attractive for the CO2 capture application, there are several disadvantages such as very strong corrosion to equipment and piping, high energy requirement during the stripping of CO2 and they are prone to oxidative and thermal degradation. Recently, use of aqueous potassium carbonate (K2CO3) as a solvent for the absorption of CO2 has gained widespread attention. The usage of K2CO3 has been employed in a number on industries for the removal of CO2 and H2S. Due to its high chemical solubility of CO2, low toxicity and solvent loss, no thermal and oxidative degradation, low heat of absorption, and absence of formation of heat stable salts, K2CO3 seems to be more attractive compared to the conventional amines towards CO2 capture. However, K2CO3 solvent shows slow rate of reaction with CO2 and, consequently, low mass transfer in the liquid phase as compared to the amine solvents. Hence, several investigators are focused towards improving the rate of reaction of CO2 in K2CO3 solvent with the help of different types of promoters. In this paper, the kinetics of absorption of CO2 into an aqueous K2CO3 (20 wt %) promoted by ethylaminoethanol (EAE) solution (hereafter termed as APCE solvent) was studied in a glass stirred cell reactor using a fall in pressure method. Reactive absorption of CO2 in EAE promoted aqueous K2CO3 solution (APCE solvent) was studied at different initial EAE concentrations (0.6 to 2 kmol/m3) and reaction temperatures (303 to 318 K). The reaction between the CO2 and APCE solvent was very well represented by the zwitterion mechanism. The N2O analogy was employed for the determination of H_(CO2) in the APCE solvent. The H_(CO2) was observed to be decreased by 5 and 31% due to the increase in the EAE concentration from 0.6 to 2 kmol/m3 and reaction temperature from 303 to 318 K, respectively. The D_(CO2) in the APCE solvent was also decreased by 21% due to the similar increase in the initial EAE concentration. In contrast, the D_(CO2) increased with the rise in the reaction temperature from 303 to 318 K by a factor of 1.678. The rate of absorption of CO2 in the APCE solvent was observed to increase by 35.10% and 47.59% due to the increase in EAE concentration (0.6 to 2 kmol/m3) and reaction temperature (303 to 318 K). The absorption kinetics was observed to be of overall second order i.e. first order with respect to both CO2 and EAE concentrations, respectively. The rate constant (k_2) for the absorption of CO2 in the APCE solvent was observed to be equal to 45540 m3/kmol√s at 318 K. The temperature dependency of k_2 for the CO2 – APCE solvent system was experimentally determined as: k_2 = (1.214 × [10]^18)√exp(( − 9822.7)/T). Findings of this study indicate EAE as a promising promoter for the aqueous K2CO3 solution.qscienc

Daratumumab for patients with myeloma with early or late relapse after initial therapy:subgroup analysis of CASTOR and POLLUX

High-risk multiple myeloma (MM) is often defined based on cytogenetic abnormalities, but patients who relapse early after initial therapy are considered a functional high-risk group. In the phase 3 CASTOR and POLLUX studies, daratumumab plus bortezomib/dexamethasone (D-Vd) or lenalidomide/dexamethasone (D-Rd) improved progression-free survival (PFS) and overall survival (OS), regardless of cytogenetic risk, and achieved higher rates of complete response or better (≥CR) and minimal residual disease (MRD) negativity vs that with Vd/Rd alone in relapsed/refractory MM. Post hoc analyses of CASTOR and POLLUX evaluated patient subgroups with 1 prior line of therapy based on timing of progression/relapse (early or late) after initiation of first line of therapy. PFS consistently favored the daratumumab-containing regimens across subgroups using both a 24- and 18-month early-relapse cutoff. In the CASTOR/POLLUX pooled data set, daratumumab reduced the risk of disease progression or death by 65% (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.26-0.48; P &lt; .0001) in the early-relapse (&lt;24 months) subgroup and by 65% (HR, 0.35; 95% CI, 0.26-0.47; P &lt; .0001) in the late-relapse (≥24 months) subgroup. OS also favored the daratumumab-containing regimens in both the early-relapse (HR, 0.62; 95% CI, 0.45-0.86; P = .0036) and late-relapse (HR, 0.67; 95% CI, 0.48-0.93; P = .0183) subgroups in the pooled population using a 24-month cutoff. Rates of ≥CR and MRD negativity (10-5) were higher with daratumumab vs control, regardless of progression/relapse timing. Although daratumumab is unable to fully overcome the adverse prognosis of early relapse, our results support the use of daratumumab for patients with 1 prior line of therapy, including for those who progress/relapse early after initial therapy and are considered to have functional high-risk MM.</p

Clinical predictors of long-term survival in newly diagnosed transplant eligible multiple myeloma - an IMWG Research Project

Purpose: multiple myeloma is considered an incurable hematologic cancer but a subset of patients can achieve long-term remissions and survival. The present study examines the clinical features of long-term survival as it correlates to depth of disease response. Patients & Methods: this was a multi-institutional, international, retrospective analysis of high-dose melphalan-autologous stem cell transplant (HDM-ASCT) eligible MM patients included in clinical trials. Clinical variable and survival data were collected from 7291 MM patients from Czech Republic, France, Germany, Italy, Korea, Spain, the Nordic Myeloma Study Group and the United States. Kaplan–Meier curves were used to assess progression-free survival (PFS) and overall survival (OS). Relative survival (RS) and statistical cure fractions (CF) were computed for all patients with available data. Results: achieving CR at 1 year was associated with superior PFS (median PFS 3.3 years vs. 2.6 years, p < 0.0001) as well as OS (median OS 8.5 years vs. 6.3 years, p < 0.0001). Clinical variables at diagnosis associated with 5-year survival and 10-year survival were compared with those associated with 2-year death. In multivariate analysis, age over 65 years (OR 1.87, p = 0.002), IgA Isotype (OR 1.53, p = 0.004), low albumin < 3.5 g/dL (OR = 1.36, p = 0.023), elevated beta 2 microglobulin ≥ 3.5 mg/dL (OR 1.86, p < 0.001), serum creatinine levels ≥ 2 mg/dL (OR 1.77, p = 0.005), hemoglobin levels < 10 g/dL (OR 1.55, p = 0.003), and platelet count < 150k/μL (OR 2.26, p < 0.001) appeared to be negatively associated with 10-year survival. The relative survival for the cohort was ~0.9, and the statistical cure fraction was 14.3%. Conclusions: these data identify CR as an important predictor of long-term survival for HDM-ASCT eligible MM patients. They also identify clinical variables reflective of higher disease burden as poor prognostic markers for long-term survival