Functional Imaging in the Evaluation of Treatment Response in Multiple Myeloma: The Role of PET-CT and MRI.

Bone disease is among the defining characteristics of symptomatic Multiple Myeloma (MM). Imaging techniques such as fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET/CT) and magnetic resonance imaging (MRI) can identify plasma cell proliferation and quantify disease activity. This function renders these imaging tools as suitable not only for diagnosis, but also for the assessment of bone disease after treatment of MM patients. The aim of this article is to review FDG PET/CT and MRI and their applications, with a focus on their role in treatment response evaluation. MRI emerges as the technique with the highest sensitivity in lesions' detection and PET/CT as the technique with a major impact on prognosis. Their comparison yields different results concerning the best tool to evaluate treatment response. The inhomogeneity of the data suggests the need to address limitations related to these tools with the employment of new techniques and the potential for a complementary use of both PET/CT and MRI to refine the sensitivity and achieve the standards for minimal residual disease (MRD) evaluation.

The third dose of mRNA SARS-CoV-2 vaccines enhances the spike-specific antibody and memory B cell response in myelofibrosis patients.

Vaccination against SARS-CoV-2 using mRNA-based vaccines has been highly recommended for fragile subjects, including myelofibrosis patients (MF). Available data on the immune responsiveness of MF patients to mRNA SARS-CoV-2 vaccination, and the impact of the therapy with the JAK inhibitor ruxolitinib, are still fragmented. Here, we profile the spike-specific IgG and memory B-cell response in MF patients, treated or not with ruxolitinib, after the second and the third dose of SARS-CoV-2 BNT162b2 (BioNTech) and mRNA-1273 (Moderna) vaccines. Plasma and peripheral blood mononuclear cells samples were collected before vaccination, post the second and the third doses and tested for spike-specific antibodies, ACE2/RBD antibody inhibition binding activity and spike-specific B cells. The third vaccine dose significantly increased the spike-specific IgG titers in both ruxolitinib-treated and untreated patients, and strongly enhanced the percentage of subjects with antibodies capable of in vitro blocking ACE2/RBD interaction, from 50% up to 80%. While a very low frequency of spike-specific B cells was measured in blood 7 days after the second vaccination dose, a strong and significant increase was elicited by the third dose administration, generating a B cell response similar to the one detected in healthy controls. Despite the overall positive impact of the third dose in MF patients, two patients that were under active concomitant immunosuppressive treatment at the time of vaccination, and a patient that received lymphodepleting therapies in the past, remained low responders. The third mRNA vaccine dose strongly increases the SARS-CoV-2 specific humoral and B cell responses in MF patients, promoting a reactivation of the immune response similar to the one observed in healthy controls.

Carfilzomib plus dexamethasone in patients with relapsed and refractory multiple myeloma: A retro-prospective observational study.

OBJECTIVE: We investigate safety and efficacy in common clinical practice of the combination of carfilzomib and dexamethasone (Kd56) approved for the ENDEAVOR trial for the treatment of relapsed or refractory multiple myeloma. METHODS: We retro-prospective analyzed 75 patients in three centers in Tuscany, 48 of whom had a clinically relevant comorbidity and 50 of whom were older than 65 years, treated with a median use in the fourth line of therapy. We assessed the efficacy based on the International Myeloma Working Group criteria. RESULTS: The overall response rate was 60%. Median PFS was 10 months in the general cohort; in patients treated for more than 1 cycle of therapy PFS was 12 months. Quality of response to Kd56 treatment was found to positively impact PFS. Refractory status to previous line of therapy or to lenalidomide or an history of exposure to pomalidomide, seemed to have no impact on survival. We also showed a low adverse events rate, with no neuropathy events, and a relatively small number of cardiovascular events above grade 3 (10%). CONCLUSION: Kd56 is an effective and well tolerated regimen in highly pretreated and elderly patients with a good safety profile.

Assessing gene function in human B cells: CRISPR/Cas9-based gene editing and mRNA-based gene expression in healthy and tumor cells.

Robust methods for manipulation of human B cells, isolated from healthy donors and patients with B cell disorders, has the potential to significantly accelerate B cell research. Our work describes a step-by-step protocol to perform electroporation-based screening of gene function in B cells through the use of Cas9 ribonuclecomplexes and in vitro produced mRNA.

Anti CD38 monoclonal antibodies for multiple myeloma treatment.

CD38 is a transmembrane glycoprotein with ectoenzymatic activity and is highly and uniformly expressed on multiple myeloma (MM) cells. CD38 is expressed also at relatively low levels on normal lymphoid and myeloid cells, and in some tissues of non-hematopoietic origin. The specificity of this target has increased interest in new drugs and triggered the development of the CD38 monoclonal antibodies Daratumumab (fully human) and Isatuximab (chimeric). CD38 antibodies have pleiotropic mechanisms of action including Fc-dependent immune effector mechanisms, direct apoptotic activity, and immunomodulatory effects by the elimination of CD38+ immune-suppressor cells. Monoclonal antibody-based therapy has revolutionized MM therapy in the latest years increasing depth of response. This product review will focus on anti-CD38 monoclonal antibodies Daratumumab and Isatuximab efficacy, safety, pharmacokinetic and pharmacodynamic data from clinical trials.

The Slower Antibody Response in Myelofibrosis Patients after Two Doses of mRNA SARS-CoV-2 Vaccine Calls for a Third Dose.

Immunization with mRNA SARS-CoV-2 vaccines has been highly recommended and prioritized in fragile subjects, including patients with myelofibrosis (MF). Available data on the vaccine immune response developed by MF patients and the impact of ruxolitinib treatment are still too fragmented to support an informed decision on a third dose for this category of subjects. Here, we show that 76% of MF patients develop spike-specific IgG after the second mRNA SARS-CoV-2 vaccine dose, but the response has a slower kinetics compared to healthy subjects, suggesting a reduced capability of their immune system to promptly react to vaccination. A reduced ACE2/RBD binding inhibition activity of spike-specific antibodies was also observed, especially in ruxolitinib-treated patients. Our results, showing slow kinetics of antibody responses in MF patients following vaccination with mRNA SARS-CoV-2 vaccines, support the need for a third vaccine dose.