Aasiya Matin

Inhibiting MEK in MAPK pathway-activated myeloma.

Over the last decade, new drugs have significantly changed the paradigm for treating multiple myeloma (MM), resulting in improved outcomes and reduced toxicity. However, many patients with MM relapse, and those who are refractory to or relapse after therapy with an immune-modulatory drug and a proteasome inhibitor have a dismal prognosis.1 Improving the outcome of relapsed and refractory MM is a significant clinical challenge. Importantly, in this respect, recently published data have established the frequent mutation of the RAS/mitogen-activated protein kinase (MAPK) pathway,2, 3, 4, 5 with mutations in NRAS, KRAS or BRAF being present in up to 50% of newly diagnosed MM cases. We routinely perform comprehensive genomic profiling using the FoundationOne Heme assay (Supplementary Methods). Review of these data shows the majority of the NRAS, KRAS and BRAF mutations occur in hotspots causing constitutive activation of the corresponding proteins. This makes the MAPK pathway a significant therapeutic target in MM.

Update on the optimal use of bortezomib in the treatment of multiple myeloma

The proteasome inhibitor (PI) “bortezomib” has now been in routine clinical practice for over a decade. It is now considered an important backbone therapy for all stages of the disease, and data continue to grow to support its use in newly diagnosed patients, relapsed and relapsed/refractory disease, maintenance therapy, high risk, and renal failure. Much has been learnt about the most clinically effective way of delivering therapy, with patients often benefiting more from a triplet bortezomib combination compared to a doublet combination. It is well tolerated and can be administered in the outpatient setting with manageable toxicity. The key to good results is managing side effects so that patients remain on therapy with minimal interruptions. Therefore, proactive management of peripheral neuropathy and thrombocytopenia is advised using dose delay and reduction strategies. The recent introduction of second- and third-generation PIs with different chemical and biological properties has resulted in a plethora of new clinical studies and has confirmed the ongoing role of this class of drugs in future myeloma therapy.

Myelosuppression-sparing treatment of central nervous system nocardiosis in a multiple myeloma patient utilizing a tedizolid-based regimen: a case report

Central nervous system (CNS) nocardiosis is a recognised opportunistic infection in immunocompromised patients. Treatment involves prolonged institution of antibiotics, making oral agents a convenient and desired option. Unfortunately, devising an effective, well-tolerated antimicrobial for the duration required to treat CNS nocardiosis is challenging owing to treatment intolerance and toxicities. This report highlights myelosuppression-sparing treatment with an oral tedizolid-based regimen following a complicated course with standard agents. A 68-year-old female from Florida (USA) with low-risk lambda light chain multiple myeloma complicated by persistently low CD4 counts, absolute neutrophil counts and IgG levels presented 18 months after diagnosis with fever, pneumonia, new-onset atrial fibrillation, right-sided hemiparesis, encephalopathy and slurred speech. Magnetic resonance imaging (MRI) showed numerous ring-enhancing lesions, and blood cultures were positive for Nocardia farcinica. The patient failed initial therapy with trimethoprim/sulfamethoxazole (SXT), linezolid and imipenem plus surgical debridement of the frontal lobe abscess. Intraoperative cultures were positive for N. farcinica. The treatment course was also complicated by steadily declining white blood cell and platelet counts despite receiving filgrastim. She was therefore placed on SXT and tedizolid for 6 months. Subsequent brain MRI showed complete resolution of the lesions and thus chemotherapy for multiple myeloma was re-initiated. In conclusion, tedizolid-based regimens may be an option for patients with myelosuppression requiring prolonged antibiotic therapy for CNS nocardiosis.

Enterococcus raffinosus infection with atypical hemolytic uremic syndrome in a multiple myeloma patient after autologous stem cell transplant

Autologous hematopoietic stem cell transplant (AHSCT) is the standard of care in the treatment of multiple myeloma worldwide. Infections are one of the most common complications of the chemotherapy regimen and AHSCT. Thrombotic microangiopathies are one of the rare but potentially life-threatening complications of infections associated with AHSCT. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome (HUS) are two most common type of thrombotic microangiopathies. The HUS is classically related to diarrheal illness such as with E.coli strain O157: H7 that produce Shiga-like toxins. But it has never been described with Enterococcus raffinosus urinary tract infections (UTI). Here we are describing a case of atypical HUS associated with Enterococcus raffinosus UTI in a patient with multiple myeloma after AHSCT. The management of atypical HUS especially after AHSCT is challenging. Eculizumab, a humanized monoclonal antibody against complement protein C5, and thrombomodulin have emerging role in the management of some cases, but more studies are needed to define evidence-based management of this condition.

Clinical characteristics and prognostic factors in multiple myeloma patients with light chain deposition disease

Light chain deposition disease (LCDD) is characterized by monotypic immunoglobulin depositions which will eventually lead to loss of organ function if left untreated. While the kidney is almost always affected, the presence and degree of LCDD in other organs vary. Ten to thirty percent of LCDD patients have underlying Multiple Myeloma (MM), yet outcome and prognostic markers in this particular patient group are still lacking. Here, we analyzed 69 patients with MM and biopsy proven LCDD and report on renal and extra‐renal involvement and its impact on prognosis as well as renal response depending on hematologic response. Coexisting light chain diseases such as AL amyloid and cast nephropathy were found in 30% of patients; those with LCDD and concurrent amyloid tended to have shorter survival. Cardiac involvement by LCDD was seen in one‐third of our patients and was associated with shorter overall survival; such patients also had a significantly higher risk of treatment‐related mortality (TRM) after stem cell transplant (SCT) compared to LCDD patients without cardiac involvement. This study highlights that MM patients with LCDD present with different clinical features compared to previously reported LCDD cohorts. Rapid initiation of treatment is necessary to prevent progressive renal disease and worse outcome. Coexisting light chain diseases and cardiac involvement are more common than previously reported and confer worse clinical outcome, emphasizing the need for careful patient careful patient evaluation and treatment selection.

459Clinical Characteristics and Outcomes of West Nile Neuroinvasive Disease in Immunocompromised Hosts: A case-Control Study

Disease in Immunocompromised Hosts: A case-Control Study Senu Apewokin, MD; Aasiya Matin, MD; Naveen Sanath Kumar, MD; Shebli Atrash, MD; Bakhous Aziz; Jameel Muzaffar; Vyjayanthi Ganga, MD; Monica Grazziutti, MD; Medicine, University Of Arkansas For Medical Sciences, Little Rock, AR; Myeloma Institute or Research and Therapy, UNIVERSTIY OF ARKANSAS FOR MEDICAL SCIENCES, LITTLE ROCK, AR; The Myeloma Institute for Research and Therapy/University of Arkansas for Medical Sciences, Little Rock, AR; Myeloma, UAMS myeloma institute., little rock, AR; Mirt, 4301 West Markham, little ROCK, AR

Severe mucositis and Clostridium difficile infection in adult autologous stem cell recipients: another question of the chicken or the egg?

We read with much interest the article by Alonso et al. where they studied Clostridium difficile infection (CDI) in 873 autologous stem cell transplant recipients and reported various risk factors associated with development of CDI [1]. In their discussion, theymentioned grade 2mucositis was a risk factor for development of CDI, and 2 possible explanations were offered. Their first explanation was a potential sampling bias because CDI testing was only by indication. In the second explanation, they postulated that mucosal damage resulting from chemotherapy-induced colitis as well as alteration in gut microbiome led to CDI, thereby implying severe mucositis preceded CDI. In our opinion, although this may be the possible pathogenesis, it is important to also consider an alternate hypothesis; which is that acquisition of CDI in such patients leads to the development of higher grades of mucositis and not necessarily the converse. In other words, severe mucositis could be a manifestation of CDI. In data published by Silva et al. [2] where lethal doses of methotrexate were administered to hamster models, they demonstrated that in the absence of CDI-active antibiotic treatment, enterocolitis developed in 85% of the hamsters.