Dismal prognosis of Pneumocystis jirovecii pneumonia in patients with multiple myeloma.

Patients with multiple myeloma (MM) are at high risk for infections, including opportunistic infections such as Pneumocystis jirovecii pneumonia (PJP). We conducted a retrospective analysis of patients with MM developing PJP over a 6-year period between January 2016 and December 2021 at the University Hospital of Würzburg by screening cases of microbiologically documented PJP. A total of 201 positive results for P. jirovecii in respiratory specimens were retrospectively retrieved through our microbiology database. Of these cases, 13 patients with MM fulfilled the definition of probable PJP according to EORTC fungal disease definitions. We observed two peaks in PJP incidence, one after stem cell transplantation during first-line treatment (n = 5) and the other in heavily pretreated patients with six or more prior lines of therapy (n = 6). There was high morbidity with nine (69%) patients admitted to the ICU, seven of whom (78%) required mechanical ventilation, and high mortality (62%, n = 8). Notably, only two of the 13 patients (15%) had received PJP prophylaxis. The main reason for discontinuation of prophylaxis with trimethoprim-sulfamethoxazole was grade IV neutropenia. The observed morbidity and mortality of PJP in MM patients are significant and even higher than reported for patients with other hematologic malignancies. According to most current guidelines, the use of prophylaxis would have been clearly recommended in no more than three (23%) of the 13 patients. This illustrates the need to critically reconsider the indications for PJP prophylaxis, which remain incompletely defined.

Progressive multifocal leukoencephalopathy in a patient post allo-HCT successfully treated with JC virus specific donor lymphocytes.

BACKGROUND: Progressive multifocal leukoencephalopathy is a demyelinating CNS disorder. Reactivation of John Cunningham virus leads to oligodendrocyte infection with lysis and consequent axonal loss due to demyelination. Patients usually present with confusion and seizures. Late diagnosis and lack of adequate therapy options persistently result in permanent impairment of brain functions. Due to profound T cell depletion, impairment of T-cell function and potent immunosuppressive factors, allogeneic hematopoietic cell transplantation recipients are at high risk for JCV reactivation. To date, PML is almost universally fatal when occurring after allo-HCT. METHODS: To optimize therapy specificity, we enriched JCV specific T-cells out of the donor T-cell repertoire from the HLA-identical, anti-JCV-antibody positive family stem cell donor by unstimulated peripheral apheresis [1]. For this, we selected T cells responsive to five JCV peptide libraries via the Cytokine Capture System technology. It enables the enrichment of JCV specific T cells via identification of stimulus-induced interferon gamma secretion. RESULTS: Despite low frequencies of responsive T cells, we succeeded in generating a product containing 20 000 JCV reactive T cells ready for patient infusion. The adoptive cell transfer was performed without complication. Consequently, the clinical course stabilized and the patient slowly went into remission of PML with JCV negative CSF and containment of PML lesion expansion. CONCLUSION: We report for the first time feasibility of generating T cells with possible anti-JCV activity from a seropositive family donor, a variation of virus specific T-cell therapies suitable for the post allo transplant setting. We also present the unusual case for successful treatment of PML after allo-HCT via virus specific T-cell therapy.

[Diagnostic and therapeutic considerations on recurrence of multiple myeloma : A current overview]. / Diagnostische und therapeutische Betrachtungen zum Rezidiv des multiplen Myeloms : Eine aktuelle Übersicht.

The treatment of multiple myeloma remains in a state of profound change. Over the past decades both disease-free survival and overall survival have been significantly prolonged by the approval of new drugs; however, despite high response rates and achievement of deep responses to primary treatment, recurrence of the disease is still expected in nearly all patients treated. Fortunately, good treatment options for myeloma patients in relapse are also currently available and the possible combinations of approved substances are numerous. Patient-specific criteria, such as primary response, comorbidities and treatment-associated toxicity can thus be taken into account more frequently in the selection of a suitable treatment of recurrences; however, the lack of comparative studies of new substances and extensive interindividual disease heterogeneity continue to make it difficult to select the best treatment of recurrence in a specific case. Therefore, the treatment of recurrence of multiple myeloma, especially for patients with high-risk features, remains a clinical challenge. This review article deliberately dispenses with the commonly used combination of mere study results and a more practical approach should be taught for the rational planning of treatment for recurrent multiple myeloma. This includes new insights into tumor evolution and taking current developments in the drug treatment of multiple myeloma into account.

Genomic characterization of high-count MBL cases indicates that early detection of driver mutations and subclonal expansion are predictors of adverse clinical outcome.

High-count monoclonal B-cell lymphocytosis (MBL) is an asymptomatic expansion of clonal B cells in the peripheral blood without other manifestations of chronic lymphocytic leukemia (CLL). Yearly, 1% of MBLs evolve to CLL requiring therapy; thus being critical to understand the biological events that determine which MBLs progress to intermediate/advanced CLL. In this study, we performed targeted deep sequencing on 48 high-count MBLs, 47 of them with 2-4 sequential samples analyzed, exploring the mutation status of 21 driver genes and evaluating clonal evolution. We found somatic non-synonymous mutations in 25 MBLs (52%) at the initial time point analyzed, including 12 (25%) with >1 mutated gene. In cases that subsequently progressed to CLL, mutations were detected 41 months (median) prior to progression. Excepting NOTCH1, TP53 and XPO1, which showed a lower incidence in MBL, genes were mutated with a similar prevalence to CLL, indicating the early origin of most driver mutations in the MBL/CLL continuum. MBLs with mutations at the initial time point analyzed were associated with shorter time-to-treatment (TTT). Furthermore, MBLs showing subclonal expansion of driver mutations on sequential evaluation had shorter progression time to CLL and shorter TTT. These findings support that clonal evolution has prognostic implications already at the pre-malignant MBL stage, anticipating which individuals will progress earlier to CLL.

Carfilzomib and the cardiorenal system in myeloma: an endothelial effect?

Carfilzomib (Cfz) has been associated with an ~5% incidence of unexplained and unpredictable cardiovascular toxicity in clinical trials. We therefore implemented a detailed, prospective, clinical cardiac and renal evaluation of 62 Cfz-treated myeloma patients, including serial blood pressure (BP), creatinine, troponin, NT-proBNP and pre- and post-treatment echocardiograms, including ejection fraction (EF), average global longitudinal strain and compliance. Pre-treatment elevations in NT-proBNP and BP, as well as abnormal cardiac strain were common. A rise in NT-proBNP occurred frequently post-treatment often without corresponding cardiopulmonary symptoms. A rise in creatinine was common, lessened with hydration and often reversible. All patients had a normal EF pre-treatment. Five patients experienced a significant cardiac event (four decline in EF and one myocardial infarction), of which 2 (3.2%) were considered probably attributable to Cfz. None were rechallenged with Cfz. The ideal strategy for identifying patients at risk for cardiac events, and parameters by which to monitor for early toxicity have not been established; however, it appears baseline echocardiographic testing is not consistently predictive of toxicity. The toxicities observed suggest an endothelial mechanism and further clinical trials are needed to determine whether or not this represents a class effect or is Cfz specific.

Cereblon binding molecules in multiple myeloma.

Immunomodulation is an established treatment strategy in multiple myeloma with thalidomide and its derivatives lenalidomide and pomalidomide as its FDA approved representatives. Just recently the method of action of these cereblon binding molecules was deciphered and results from large phase 3 trials confirmed the backbone function of this drug family in various combination therapies. This review details the to-date knowledge concerning mechanism of IMiD action, clinical applications and plausible escape mechanisms in which cells may become resistant/refractory to cereblon binding molecule based treatment.

Longitudinal analysis of 25 sequential sample-pairs using a custom multiple myeloma mutation sequencing panel (M(3)P).

Recent advances in genomic sequencing technologies now allow results from deep next-generation sequencing to be obtained within clinically meaningful timeframes, making this an attractive approach to better guide personalized treatment strategies. No multiple myeloma-specific gene panel has been established so far; we therefore designed a 47-gene-targeting gene panel, containing 39 genes known to be mutated in ≥3 % of multiple myeloma cases and eight genes in pathways therapeutically targeted in multiple myeloma (MM). We performed targeted sequencing on tumor/germline DNA of 25 MM patients in which we also had a sequential sample post treatment. Mutation analysis revealed KRAS as the most commonly mutated gene (36 % in each time point), followed by NRAS (20 and 16 %), TP53 (16 and 16 %), DIS3 (16 and 16 %), FAM46C (12 and 16 %), and SP140 (12 and 12 %). We successfully tracked clonal evolution and identified mutation acquisition and/or loss in FAM46C, FAT1, KRAS, NRAS, SPEN, PRDM1, NEB, and TP53 as well as two mutations in XBP1, a gene associated with bortezomib resistance. Thus, we present the first longitudinal analysis of a MM-specific targeted sequencing gene panel that can be used for individual tumor characterization and for tracking clonal evolution over time.

[Multiple myeloma]. / Das multiple Myelom.

Multiple myeloma (MM) is a cancer originating from terminally differentiated B lymphocytes, the plasma cells and is classified as a B cell non-Hodgkin lymphoma. As clonal plasma cells secrete immunoglobulin molecules (lacking antigenic specificity), an "M component" can incidentally be detected. Besides intact immunoglobulin molecules, free light chains can be produced. Although there is no specific treatment for monoclonal gammopathy of undetermined significance (MGUS), which is the defined as the presence of clonal bone marrow plasma cells and low levels (serum and/or urine) of the M component, it should be followed up in affected individuals. The symptoms of MM are numerous and often nonspecific. Diagnosis includes the quantification of monoclonal proteins in serum and urine, blood count, electrolytes and renal function, imaging of the skeleton and bone marrow puncture. The cornerstone of therapy includes melphalan- or cyclophosphamide-based regimens incorporating one of the "novel drugs" (i.e. bortezomib, thalidomide, or lenalidomide).