Novel approaches to the treatment of multiple myeloma.

The treatment landscape for multiple myeloma (MM) has evolved significantly over the last decade with the approval of novel therapies and combinations in the newly diagnosed and relapsed/refractory settings. There has also been a shift toward a risk-adapted approach to induction and maintenance regimens, with the goal of achieving better response rates for those with high-risk disease. The incorporation of anti-CD38 monoclonal antibodies into induction regimens has led to longer progression-free survival and higher rates of measurable residual disease negativity. In the relapsed setting, the emergence of B-cell maturation antigen-directed therapy, including antibody-drug conjugates, chimeric antigen receptor T-cell therapy, and more recently, bispecific antibodies, has produced deep and durable responses in heavily pretreated patients. This review article describes novel approaches to the treatment of MM in both the newly diagnosed and the relapsed/refractory setting.

Incidence of breakthrough fungal infections on isavuconazole prophylaxis compared to posaconazole and voriconazole.

BACKGROUND: Invasive fungal infections (IFIs) are a common infectious complication during the treatment of acute myeloid leukemia (AML), high-risk myelodysplastic syndrome (MDS) or post hematopoietic cell transplantation (HCT). For these patients, the National Comprehensive Cancer Network recommends posaconazole or voriconazole for IFI prophylaxis. In clinical practice, however, there has been increased use of isavuconazole due to favorable pharmacokinetic and pharmacodynamic parameters despite limited data for this indication. The comparative prophylactic efficacy of antifungals in this patient population has not been reported, and an analysis is warranted. METHODS: This retrospective, matched cohort, single-center study, included AML, MDS, or HCT patients who began treatment or underwent transplant between January 1, 2015 and July 31, 2021. Isavuconazole patients were matched 1:2 with patients receiving posaconazole or voriconazole prophylaxis. RESULTS: A total of 126 patients were included, 42 received isavuconazole, 81 received posaconazole, and three received voriconazole. The majority of patients were male receiving secondary IFI prophylaxis while receiving steroids for treatment of GVHD. The incidence of possible, probable or proven IFI was 16.7% in the isavuconazole group compared to 10.7% in the posaconazole and voriconazole group (OR 1.28, 95% CI -0.9-1.4; p = .67). Hepatotoxicity occurred in 16 total patients, 14 receiving posaconazole and two receiving isavuconazole. CONCLUSION: Patients who received isavuconazole prophylaxis during AML induction therapy or post-HCT experienced a similar incidence of breakthrough fungal infections compared to those who received posaconazole or voriconazole. These results suggest no difference in antifungal prophylactic efficacy; however larger prospective comparative studies are needed.

Contributions of elastic fibers, collagen, and extracellular matrix to the multiaxial mechanics of ligament.

Elastin is a biopolymer known to provide resilience to extensible biologic tissues through elastic recoil of its highly crosslinked molecular network. Recent studies have demonstrated that elastic fibers in ligament provide significant resistance to tensile and especially shear stress. We hypothesized that the biomechanics of elastic fibers in ligament could be described as transversely isotropic with both fiber and matrix components in a multi-material mixture. Similarly, we hypothesized that material coefficients derived using the experimental tensile response could be used to predict the experimental shear response. Experimental data for uniaxial and transverse tensile testing of control tissues, and those enzymatically digested to disrupt elastin, were used as inputs to a material coefficient optimization algorithm. An additive decomposition of the strain energy was used to model the total stress as the sum of contributions from collagen fibers, elastic fibers, elastic matrix, and ground substance matrix. Matrices were modeled as isotropic Veronda-Westmann hyperelastic materials, whereas fiber families were modeled as piecewise exponential-linear hyperelastic materials. Optimizations provided excellent fits to the tensile experimental data for each treatment case and material model. Given the disparity in magnitude of stresses between longitudinal and transverse/shear tests and agreement between models and experiments, the hypothesized transversely isotropic material of elastin symmetry was supported. In addition, the coefficients derived from uniaxial and transverse tensile experiments provided reasonable predictions of the experimental behavior during shear deformation. The magnitudes of coefficients representing stress, nonlinearity, and stiffness supported the experimental evidence that elastic fibers dominate the low strain tensile and shear response of ligament. These findings demonstrate that the additive decomposition modeling strategy can represent each discrete fiber and matrix constituent and their relative contribution to the material response of the tissue. These experimental data and the validated constitutive model provide essential inputs and a framework to refine existing computational models of ligament and tendon mechanics by explicitly representing the mechanical contributions of elastic fibers.

Elastin governs the mechanical response of medial collateral ligament under shear and transverse tensile loading.

Elastin is a highly extensible structural protein network that provides near-elastic resistance to deformation in biological tissues. In ligament, elastin is localized between and along the collagen fibers and fascicles. When ligament is stretched along the primary collagen axis, elastin supports a relatively high percentage of load. We hypothesized that elastin may also provide significant load support under elongation transverse to the primary collagen axis and shear along the collagen axis. Quasi-static transverse tensile and shear material tests were performed to quantify the mechanical contributions of elastin during deformation of porcine medial collateral ligament. Dose response studies were conducted to determine the level of elastase enzymatic degradation required to produce a maximal change in the mechanical response. Maximal changes in peak stress occurred after 3h of treatment with 2U/ml porcine pancreatic elastase. Elastin degradation resulted in a 60-70% reduction in peak stress and a 2-3× reduction in modulus for both test protocols. These results demonstrate that elastin provides significant resistance to elongation transverse to the collagen axis and shear along the collagen axis while only constituting 4% of the tissue dry weight. The magnitudes of the elastin contribution to peak transverse and shear stress were approximately 0.03 MPa, as compared to 2 MPa for axial tensile tests, suggesting that elastin provides a highly anisotropic contribution to the mechanical response of ligament and is the dominant structural protein resisting transverse and shear deformation of the tissue.