Elotuzumab for the treatment of extramedullary myeloma: a retrospective analysis of clinical efficacy and SLAMF7 expression patterns.

Extramedullary disease (EMD) represents a high-risk state of multiple myeloma (MM) associated with poor prognosis. While most anti-myeloma therapeutics demonstrate limited efficacy in this setting, some studies exploring the utility of chimeric antigen receptor (CAR)-modified T cells reported promising results. We have recently designed SLAMF7-directed CAR T cells for the treatment of MM. SLAMF7 is a transmembrane receptor expressed on myeloma cells that plays a role in myeloma cell homing to the bone marrow. Currently, the only approved anti-SLAMF7 therapeutic is the monoclonal antibody elotuzumab, but its efficacy in EMD has not been investigated thoroughly. Thus, we retrospectively analyzed the efficacy of elotuzumab-based combination therapy in a cohort of 15 patients with EMD. Moreover, since the presence of the target antigen is an indispensable prerequisite for effective targeted therapy, we investigated the SLAMF7 expression on extramedullary located tumor cells before and after treatment. We observed limited efficacy of elotuzumab-based combination therapies, with an overall response rate of 40% and a progression-free and overall survival of 3.8 and 12.9 months, respectively. Before treatment initiation, all available EMD tissue specimens (n = 3) demonstrated a strong and consistent SLAMF7 surface expression by immunohistochemistry. Furthermore, to investigate a potential antigen reduction under therapeutic selection pressure, we analyzed samples of de novo EMD (n = 3) outgrown during elotuzumab treatment. Again, immunohistochemistry documented strong and consistent SLAMF7 expression in all samples. In aggregate, our data point towards a retained expression of SLAMF7 in EMD and encourage the development of more potent SLAMF7-directed immunotherapies, such as CAR T cells.

CIC Mutation as a Molecular Mechanism of Acquired Resistance to Combined BRAF-MEK Inhibition in Extramedullary Multiple Myeloma with Central Nervous System Involvement.

Combined MEK-BRAF inhibition is a well-established treatment strategy in BRAF-mutated cancer, most prominently in malignant melanoma with durable responses being achieved through this targeted therapy. However, a subset of patients face primary unresponsiveness despite presence of the activating mutation at position V600E, and others acquire resistance under treatment. Underlying resistance mechanisms are largely unknown, and diagnostic tests to predict tumor response to BRAF-MEK inhibitor treatment are unavailable. Multiple myeloma represents the second most common hematologic malignancy, and point mutations in BRAF are detectable in about 10% of patients. Targeted inhibition has been successfully applied, with mixed responses observed in a substantial subset of patients mirroring the widespread spatial heterogeneity in this genomically complex disease. Central nervous system (CNS) involvement is an extremely rare, extramedullary form of multiple myeloma that can be diagnosed in less than 1% of patients. It is considered an ultimate high-risk feature, associated with unfavorable cytogenetics, and, even with intense treatment applied, survival is short, reaching less than 12 months in most cases. Here we not only describe the first patient with an extramedullary CNS relapse responding to targeted dabrafenib and trametinib treatment, we furthermore provide evidence that a point mutation within the capicua transcriptional repressor (CIC) gene mediated the acquired resistance in this patient. KEY POINTS: BRAF mutations constitute an attractive druggable target in multiple myeloma. This is the first genomic dissection of the central nervous system involvement in a multiple myeloma patient harboring a druggable BRAFV600E mutation. Deep genomic characterization of the extramedullary lesion prompted a personalized therapeutic approach. Acquisition of CIC mutation confers a mechanism of BRAF-MEK inhibitor drug resistance in multiple myeloma. The in silico interrogation of the CoMMpass clinical study revealed 10 patients with somatic mutations of CIC and its downregulation at gene expression level in multiple myeloma. CIC gene silencing decreases the sensitivity of multiple myeloma cells to BRAF-MEK inhibition in vitro. The correlation between CIC downregulation and ETV4/5 nuclear factor expression in multiple myeloma BRAF-mutant cells is shown for the first time. CIC mutation, its downregulation, and the related downstream effect on MMP24 support disseminative potential providing new clues in the extramedullary biology definition.

The role of carfilzomib in treatment of newly diagnosed multiple myeloma.

Despite improvement of prognosis since approval of proteasome inhibitors and immunomodulatory drugs, myeloma remains largely incurable. The outcome of first-line treatment is known to be crucial for survival and, therefore, implementation of novel strategies remains one of the key aims of clinical myeloma research. Since approval of carfilzomib for relapsed and refractory multiple myeloma, a new therapeutic option with a favorable safety profile regarding neuropathy is available. Regarding its superior response rates and progression-free survival (PFS) when combined with other agents in heavily pretreated patients, the compound rapidly became a matter of great interest in search for first-line treatment. With an ORR up to 98% and promising PFS data, it might become an important partner in treatment of newly diagnosed myeloma.

'Real-life' experience of preapproval carfilzomib-based therapy in myeloma - analysis of cardiac toxicity and predisposing factors.

BACKGROUND: Carfilzomib, the second-generation proteasome inhibitor, is still awaiting approval for the treatment of multiple myeloma in Europe. Results from clinical trials have demonstrated favorable efficacy in advanced disease but have opened an ongoing debate on cardiac complications related to carfilzomib treatment. 'Real-life' data are scarce. METHODS/PATIENTS: At our institution, 22 patients were registered within the European Carfilzomib Access Program for treatment with carfilzomib, dexamethasone, and a third combination partner depending on patient characteristics and prior treatment. Patients had received a median of six previous lines of therapy, and most were refractory to bortezomib (77%) and immunomodulatory drugs (95%). RESULTS: Overall response rate was 65% with a median progression-free survival of 6.0 months and a median duration of response of 6.8 months. Median overall survival was 14.9 months. Grade 3/4 adverse events (AEs) occurred in 50% of patients with 23% experiencing left ventricular failure. The risk of cardiac AEs was markedly increased after previous radiotherapy of the thoracic spine and concomitant administration of doxorubicin. CONCLUSION: Carfilzomib-based treatment is efficient in advanced multiple myeloma. In our 'real-life' patients, we found considerable cardiotoxic effects in some cases, indicating a need for careful patient selection and close monitoring of the at-risk population.

The lymphoma-like polychemotherapy regimen "Dexa-BEAM" in advanced and extramedullary multiple myeloma.

Extramedullary disease (EMD) in multiple myeloma (MM) is characterised by an aggressive biology and an adverse prognosis especially when occurring at relapse. Due to the high proliferation found in EMD lesions, we analysed outcome data of patients treated with a lymphoma-type therapy not based on novel compounds, the Dexa-BEAM protocol. Retrospective analysis of MM patients having received Dexa-BEAM (including dexamethasone, carmustine, cytarabine, etoposide and melphalan) at our institution from January 2007 to November 2012. In all, 18 patients were identified, 11 of whom had EMD. Objective response (≥PR) to Dexa-BEAM was achieved in more than half of the patients with EMD (6/11); consecutive high-dose consolidation strategy with autologous or allogeneic stem cell transplantation improved upon the depth of remission in two thirds of EMD patients (4/6) with ongoing remissions in three patients. In contrast, all patients without consolidation relapsed. Progression-free survival after Dexa-BEAM was short in both patient groups with intramedullary or extramedullary myeloma with a median of 3 and 4 months, respectively. Toxicity was relevant with one treatment-related death and grades 3 and 4 toxicities in all 18 patients. Dexa-BEAM is an effective induction regimen in medically fit patients with extramedullary manifestations to regain disease control prior to an intended autologous or allogeneic transplantation.

3D osteocyte lacunar morphometry of human bone biopsies with high resolution microCT: From monoclonal gammopathy to newly diagnosed multiple myeloma.

Osteocytes are mechanosensitive, bone-embedded cells which are connected via dendrites in a lacuno-canalicular network and regulate bone resorption and formation balance. Alterations in osteocyte lacunar volume, shape and density have been identified in conditions of aging, osteoporosis and osteolytic bone metastasis, indicating patterns of impaired bone remodeling, osteolysis and disease progression. Osteolytic bone disease is a hallmark of the hematologic malignancy multiple myeloma (MM), in which monoclonal plasma cells in the bone marrow disrupt the bone homeostasis and induce excessive resorption at local and distant sites. Qualitative and quantitative changes in the 3D osteocyte lacunar morphometry have not yet been evaluated in MM, nor in the precursor conditions monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). In this study, we characterized the osteocyte lacunar morphology in trabecular bone of the iliac crest at the ultrastructural level using high resolution microCT in human bone biopsy samples of three MGUS, two SMM and six newly diagnosed MM. In MGUS, SMM and MM we found a trend for lower lacunar density and a shift towards larger lacunae with disease progression (higher 50 % cutoff of the lacunar volume cumulative distribution) in the small osteocyte lacunae 20-900 µm3 range compared to control samples. In the larger lacunae 900-3000 µm3 range, we detected significantly higher lacunar density and microporosity in the MM group compared to the MGUS/SMM group. Regarding the shape distribution, the MGUS/SMM group showed a trend for flatter, more elongated and anisotropic osteocyte lacunae compared to the control group. Altogether, our findings suggest that osteocytes in human MM bone disease undergo changes in their lacunae density, volume and shape, which could be an indicator for osteolysis and disease progression. Future studies are needed to understand whether alterations of the lacunae architecture affect the mechanoresponsiveness of osteocytes, and ultimately bone adaptation and fracture resistance in MM and its precursors conditions.

Elotuzumab, pomalidomide, and dexamethasone is a very well tolerated regimen associated with durable remission even in very advanced myeloma: a retrospective study from two academic centers.

BACKGROUND: The anti-SLAMF7 monoclonal antibody, elotuzumab (elo), plus lenalidomide (len) and dexamethasone (dex) is approved for relapsed/refractory MM in the U.S. and Europe. Recently, a small phase 2 study demonstrated an advantage in progression-free survival (PFS) for elo plus pomalidomide (pom)/dex compared to pom/dex alone and resulted in licensing of this novel triplet combination, but clinical experience is still limited. PURPOSE: To analyze the efficacy and safety of elo/pom/dex in a "real world" cohort of patients with advanced MM, we queried the databases of the university hospitals of Würzburg and Vienna. FINDINGS: We identified 22 patients with a median number of five prior lines of therapy who received elo/pom/dex prior to licensing within an early access program. Patients received a median number of 5 four-week treatment cycles. Median PFS was 6.4 months with 12-month and 18-month PFS rates of 35% and 28%, respectively. The overall response rate was 50% and 64% of responding patients who achieved a longer PFS with elo/pom/dex compared to their most recent line of therapy. Objective responses were also seen in five patients who had been pretreated with pomalidomide. Low tumor burden was associated with improved PFS (13.5 months for patients with ISS stage I/II at study entry v 6.4 months for ISS III), although this difference did not reach statistical significance. No infusion-related reactions were reported. The most frequent grade 3/4 adverse events were neutropenia and pneumonia. CONCLUSION: Elo/pom/dex is an active and well-tolerated regimen in highly advanced MM even after pretreatment with pomalidomide.

Clinical and biological characteristics of myeloma patients influence response to elotuzumab combination therapy.

Based on ELOQUENT-2, combination therapy with the monoclonal antibody elotuzumab was approved for relapsed/refractory multiple myeloma in the US and Europe. However, outside clinical trials, the optimal integration of elotuzumab into the sequence of treatment lines remains to be determined. Therefore, we analyzed safety and efficacy of elotuzumab/immunomodulatory drug combinations in a real-life cohort of 33 patients from our institution. The most frequent grade 3/4 adverse event was lymphopenia which did not increase the incidence of viral reactivations. After a median of four prior treatment lines, an overall response rate of 60% and a median progression-free survival (PFS) of 8 months were observed. The presence of cytogenetic high-risk status had no impact on PFS while low disease burden and high numbers of natural killer (NK)-cells at treatment initiation were associated with longer PFS. We observed an extramedullary relapse in three patients, associated with reduced expression of the elotuzumab target antigen SLAMF7 on extramedullary myeloma cells in one patient. Thus, biomarkers like disease burden, NK-cell count and SLAMF7 expression on myeloma cells may help to define myeloma patients with high likelihood to respond to elotuzumab treatment. Prospective trials investigating these biomarkers in larger patient cohorts are highly warranted.

Exploration of Artificial Intelligence Use with ARIES in Multiple Myeloma Research.

BACKGROUND: Natural language processing (NLP) is a powerful tool supporting the generation of Real-World Evidence (RWE). There is no NLP system that enables the extensive querying of parameters specific to multiple myeloma (MM) out of unstructured medical reports. We therefore created a MM-specific ontology to accelerate the information extraction (IE) out of unstructured text. METHODS: Our MM ontology consists of extensive MM-specific and hierarchically structured attributes and values. We implemented "A Rule-based Information Extraction System" (ARIES) that uses this ontology. We evaluated ARIES on 200 randomly selected medical reports of patients diagnosed with MM. RESULTS: Our system achieved a high F1-Score of 0.92 on the evaluation dataset with a precision of 0.87 and recall of 0.98. CONCLUSIONS: Our rule-based IE system enables the comprehensive querying of medical reports. The IE accelerates the extraction of data and enables clinicians to faster generate RWE on hematological issues. RWE helps clinicians to make decisions in an evidence-based manner. Our tool easily accelerates the integration of research evidence into everyday clinical practice.

The Diagnosis and Treatment of Multiple Myeloma.

BACKGROUND: Multiple myeloma is a malignant disease of plasma cells with a worldwide incidence of 6-7 cases per 100 000 persons per year. It is among the 20 most common types of cancer in Germany. METHODS: This review is based on pertinent publications up to December 2015 that were retrieved by a selective search of PubMed employing the terms "multiple myeloma" AND "therapy" OR "diagnostic." Systematic reviews, meta-analyses, randomized controlled trials, and treatment recommendations from Germany and abroad were considered. RESULTS: The diagnostic evaluation of multiple myeloma comprises thorough history-taking and physical examination, various laboratory tests including analysis of a 24-hour urine sample, a bone-marrow biopsy, and skeletal radiography. Systemic treatment should be administered only when organ damage has been diagnosed. The type of treatment to be given is chosen individually on the basis of the patient's age, comorbidities, and risk profile. High-dose therapy with autologous stem-cell transplantation remains the treatment of choice for patients under age 70 who are otherwise in good health. For patients who are not candidates for high-dose therapy or who have had a recurrence of multiple myeloma after prior high-dose therapy, there are a number of further conventional treatment options. Patients need not only systemic antineoplastic treatment, but also supportive treatment for the prevention of treatment-induced toxicity and myeloma-associated organ damage. CONCLUSION: Recent therapeutic advances have made the treatment of multiple myeloma both more complex and more costly. In particular, the median survival of patients with multiple myeloma has been markedly prolonged through the use of targeted drugs such as proteasome inhibitors and immune modulators.

Long-term disease control by pomalidomide-/dexamethasone-based therapy in a patient with advanced multiple myeloma: a case report and review of the literature.

BACKGROUND: Therapy for multiple myeloma (MM) has substantially improved in the era of immunomodulatory drugs and bortezomib. However, the prognosis of patients with progressive disease despite treatment with these 'novel agents' remains poor. Recently, pomalidomide was approved in this setting, but a median progression-free survival of <4 months still leaves room for improvement. Pomalidomide-based combination therapies are currently under investigation, but data on long-term treatment are lacking. CASE REPORT: We present the case of a 68-year-old woman with refractory MM who received pomalidomide in combination with various drugs including anthracyclines, alkylators and proteasome inhibitors. Initially, major hematological toxicities and infectious complications including a hepatitis B virus reactivation were encountered. With careful dose adjustments and selection of combination partners, pomalidomide treatment was maintained for over 4 years and led to a sustained partial remission. In particular, the well-tolerated regimen of bortezomib, cyclophosphamide and dexamethasone together with pomalidomide was administered for >30 cycles. CONCLUSION: This case illustrates the value of an individualized approach to myeloma care given an increasing availability of 'novel agents'. Tailored treatment using these drugs as a backbone is essential to achieve long-lasting responses and minimize side effects.