Jagoda Jasielec

Carfilzomib, lenalidomide, and low-dose dexamethasone in elderly patients with newly diagnosed multiple myeloma

A number of combination regimens with immunomodulatory agents or proteasome inhibitors have been developed for use in elderly patients with newly diagnosed multiple myeloma (NDMM). Regimens including bortezomib, melphalan, and prednisone (VMP), and including melphalan, prednisone, and thalidomide (

Synergistic Myeloma Cell Death via Novel Intracellular Activation of Caspase-10–Dependent Apoptosis by Carfilzomib and Selinexor

Exportin1 (XPO1; also known as chromosome maintenance region 1, or CRM1) controls nucleo-cytoplasmic transport of most tumor suppressors and is overexpressed in many cancers, including multiple myeloma, functionally impairing tumor suppressive function via target mislocalization. Selective inhibitor of nuclear export (SINE) compounds block XPO1-mediated nuclear escape by disrupting cargo protein binding, leading to retention of tumor suppressors, induction of cancer cell death, and sensitization to other drugs. Combined treatment with the clinical stage SINE compound selinexor and the irreversible proteasome inhibitor (PI) carfilzomib induced synergistic cell death of myeloma cell lines and primary plasma cells derived from relapsing/refractory myeloma patients and completely impaired the growth of myeloma cell line–derived tumors in mice. Investigating the details of SINE/PI-induced cell death revealed (i) reduced Bcl-2 expression and cleavage and inactivation of Akt, two prosurvival regulators of apoptosis and autophagy; (ii) intracellular membrane-associated aggregation of active caspases, which depended on caspase-10 protease activity; and (iii) novel association of caspase-10 and autophagy-associated proteins p62 and LC3 II, which may prime activation of the caspase cascade. Overall, our findings provide novel mechanistic rationale behind the potent cell death induced by combining selinexor with carfilzomib and support their use in the treatment of relapsed/refractory myeloma and potentially other cancers. Mol Cancer Ther; 15(1); 60–71. ©2015 AACR.

Current approaches to the initial treatment of symptomatic multiple myeloma.

The treatment of newly diagnosed multiple myeloma has dramatically changed since the emergence of proteasome inhibitors and immunomodulatory drugs. Front-line combination regimens incorporating novel drugs such as thalidomide, bortezomib and lenalidomide, have significantly improved response rates and are the standard of care for induction regimens. Although the timing and role of autologous stem cell transplant are now being questioned, it remains an important part of the treatment paradigm in eligible patients. In addition, the concept of extended sequential therapy has recently emerged, including consolidation and/or maintenance in both the post-transplant setting and in nontransplant candidates. In this article we focus on management strategies in newly diagnosed multiple myeloma, including choice of induction regimens in transplant-eligible and -ineligible patients, as well as the role of autologous stem cell transplant, consolidation therapy and maintenance therapy.

Evolving Strategies in the Initial Treatment of Multiple Myeloma

Until the advents of novel agents, partial response (PR) or better was the established gold standard to initial therapy of multiple myeloma (MM), and treatment goals were focused on relieving symptoms, prevention of organ damage, and modest improvements in survival. With the introduction of autologous stem cell transplant (ASCT), deeper responses, including complete responses (CRs) were more frequent, and contributed to longer survival. In the era of novel therapies, ASCT remains commonly used and its impact on outcome appears superior, albeit less so than when compared with conventional therapy, and its survival benefit is yet to be established in either setting. In addition, in non-transplant candidates, novel therapies have now significantly improved the overall response rates, depth of response, and clinical benefit, to the levels previously only observed with ASCT, which now increasingly challenges the role and timing of ASCT in eligible patients. Nevertheless, the two approaches of treatment, transplant or no transplant, remain commonly accepted. With an improvement in the tolerability of newer regimens and the deferral of ASCT in transplant candidates, the debate has emerged whether the two-pathway approach to the treatment of newly diagnosed myeloma should be re-evaluated. At the same time, treatment goals are also shifting. Many believe that MM can be converted into a chronic disease and that a functional cure maybe a realistic goal, for at least a proportion of patients. This contribution will review these points of discussion and the evolving approach to treatment of newly diagnosed MM.

Proteomic profiling of naïve multiple myeloma patient plasma cells identifies pathways associated with favourable response to bortezomib-based treatment regimens

Toward our goal of personalized medicine, we comprehensively profiled pre‐treatment malignant plasma cells from multiple myeloma patients and prospectively identified pathways predictive of favourable response to bortezomib‐based treatment regimens. We utilized two complementary quantitative proteomics platforms to identify differentially‐regulated proteins indicative of at least a very good partial response (VGPR) or complete response/near complete response (CR/nCR) to two treatment regimens containing either bortezomib, liposomal doxorubicin and dexamethasone (VDD), or lenalidomide, bortezomib and dexamethasone (RVD). Our results suggest enrichment of ‘universal response’ pathways that are common to both treatment regimens and are probable predictors of favourable response to bortezomib, including a subset of endoplasmic reticulum stress pathways. The data also implicate pathways unique to each regimen that may predict sensitivity to DNA‐damaging agents, such as mitochondrial dysfunction, and immunomodulatory drugs, which was associated with acute phase response signalling. Overall, we identified patterns of tumour characteristics that may predict response to bortezomib‐based regimens and their components. These results provide a rationale for further evaluation of the protein profiles identified herein for targeted selection of anti‐myeloma therapy to increase the likelihood of improved treatment outcome of patients with newly‐diagnosed myeloma.

Dasatinib-Related Pulmonary Toxicity Mimicking an Atypical Infection

Case Report A 49-year-old white woman with chronic myeloid leukemia (CML) presented to the hospital with several weeks of increasing dry cough, dyspnea on exertion, and low-grade fevers. She was first diagnosed with CML in chronic phase in October 2009 when she presented with marked leukocytosis and thrombocytosis. After brief cytoreduction with hydroxyurea, she was started on imatinib 400 mg daily, which she tolerated well. Approximately 8 months later, she developed marked pancytopenia, and imatinib was discontinued. Her blood counts recovered several weeks after cessation of treatment, but her bone marrow cytogenetics remained 95% Ph . Therapy was then changed to dasatinib 100 mg daily, but after about 6 weeks, she again developed pancytopenia. Her blood counts recovered after dasatinib was held, but then decreased again on resuming the drug at a lower dose. Because of the lack of a cytogenetic response, in April 2011, she received an allogeneic hematopoietic stem-cell transplantation from a matched unrelated male donor after conditioning with fludarabine, melphalan, and alemtuzumab. She had no post-transplantation complications or graft versus host disease. Her bone marrow exams became morphologically and cytogenetically normal. However, her BCR-ABL quantitative polymerase chain reaction assay remained positive at a low level 1 year after transplantation, and therefore she restarted dasatinib at 100 mg daily. Within several days of starting dasatinib, she developed a dry cough that became progressively worse over the following several weeks. In addition, she experienced low-grade fevers, myalgia, and dyspnea. On admission to hospital, she was febrile to 38.7 C, tachycardic with a heart rate of 112 beats/minute, and breathing at 20 breaths/minute. She was hypoxemic, requiring 2 to 4 L of supplemental oxygen through a nasal cannula. Chest examination revealed diffuse, bilateral rales. The remainder of the physical examination was unremarkable. Her medications before admission included dasatinib 100 mg daily, valacyclovir 1,000 mg three times daily, and a multivitamin. All of her post-transplantation immunizations were up to date. Her past medical history included a 24 pack-year smoking history, although she had quit 5 years earlier. She reported no recent environmental exposures or sick contacts. Her WBC count was 5,000/ L with 58% granulocytes, 24% lymphocytes, 8% monocytes, and 3% eosinophils. The hemoglobin level was 8.8 g/dL and platelets 162,000/ L. Chemistries, including electrolytes and renal and liver functions, were normal. Chest radiograph revealed bilateral nodular and reticular interstitial opacities with small pleural effusions (Fig 1) that were new compared with a radiograph less than 2 months earlier. A computed tomography (CT) scan of chest showed bilateral nodular airspace opacities with diffuse ground glass components predominantly in the upper and middle lobes (Fig 2A). In addition, there was interval development of mediastinal lymphadenopathy in the peritracheal, subcarinal, and pretracheal spaces. The differential for the CT findings included fungal or atypical infection, hypersensitivity reaction due to dasatinib, and possible malignancy. Treatment was initiated with broad-spectrum antimicrobials including cefepime, azithromycin, vancomycin, metronidazole, and voriconazole. Dasatinib was discontinued. She underwent a bronchoscopy with bronchoalveolar lavage and transbronchial biopsy of the right upper lobe. Fluid analysis from the washings showed a total WBC count of 360/ L with 27% neutrophils, 18% lymphocytes, 54% macrophages, and 1% eosinophils. Gram stain, acid fast, bacterial, and fungal cultures returned negative for infection. Fungal stains on the biopsy specimen were negative; cytology demonstrated reactive cellular changes. There were nonspecific findings of focal lymphocytic aggregates within the lung parenchyma, mild type II pneumocyte hyperplasia, scattered fibrin exudates, mild interstitial thickening, and intra-alveolar macrophages. The remainder of the infectious work-up, including bacterial and fungal blood cultures, urine culture, respiratory viral panel, parvovirus serology, streptococcal pneumonia antigen, Legionella antigen, Aspergillus antigen, and histoplasmosis antigen returned negative. Despite 1 week of broad-spectrum antibiotic and antifungal treatment as well as discontinuation of dasatinib, her fevers persisted, and her dyspnea and hypoxia worsened. A repeat CT of the chest showed increasing nodular airspace opacities, particularly in the upper lobes, as well as interval development of bilateral pleural effusions Fig 1. JOURNAL OF CLINICAL ONCOLOGY D I A G N O S I S I N O N C O L O G Y