SummaryThe introduction of chimeric antigen receptor (CAR)-modified T cells has revolutionized immunotherapy and cancer treatment as a whole. However, so far, clinical efficacy has only been demonstrated for CD19-positive B cell lymphomas. For Multiple Myeloma (MM), the second most common haematological malignancy, there are currently no clinical results supporting the usefulness of the adoptive transfer of CAR-modified T cells. This might be related to the fact that an ideal surface target has not yet been identified or the presence of strong local immunosuppression in the tumour microenvironment, which is a hallmark of MM. In this review, we provide a comprehensive overview of promising target molecules for CAR T cell approaches in MM and we outline a number of ways in which the local immunosuppression in MM can be overcome. By providing a strategy for the design of CAR T cell treatments for MM we hope to transform this new therapeutic approach into a valuable tool within the therapeutic armamentarium for MM.Keywords: chimeric antigen receptors, multiple myeloma, immunotherapy, tumour immunology.Multiple Myeloma (MM) is an incurable plasma cell (PC) malignancy, which develops in the bone marrow (BM) and eventually causes renal failure, immunosuppression with repeated infections, anaemia and bone lesions (Palumbo & Anderson, 2011). There have been significant therapeutic advances over the past decade and the median survival of MM patients has increased to approximately 6 years (Kumar et al, 2014). However, most patients will still eventually suffer a fatal relapse after an initially effective therapy. This is due to the persistence of chemotherapy-resistant PC clones (Chaidos et al, 2013) in the BM even after destruction of the bulk of tumour cells (Rawstron et al, 2013) and, accordingly, the disease will become more and more refractory to chemotherapy after each additional line of treatment.Multiple Myeloma cells primarily localize to the BM and remain readily accessible to immune effector cells (Raab et al, 2009). However, as the disease progresses, the adaptive immune system will become more and more paralysed, resulting in severely compromised B cell and T cell responses (Villunger et al, 1997;Schutt et al, 2006). As MM itself is dependent on the suppression of the adaptive immune response, the development of immunotherapeutic approaches correcting this dysfunction seems an attractive option for MM patients. Allogeneic stem cell transplantation (alloSCT) is one of the most promising ways of restoring the immune system's ability to recognize and destroy MM cells and is currently, in addition to the intensive Total Therapy protocols introduced by the Arkansas group (Barlogie et al, 2014), the only potentially curative approach for MM patients (Lokhorst et al, 2010). However, this therapeutic modality has been severely hampered by its high treatment-related morbidity and mortality (Lokhorst et al, 2010), resulting predominantly from graft-versus-host disease (GvHD) (Vekemans et al, 2014). Therefore, more speci...

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Multiple Myeloma (MM) is a plasma cell (PC) malignancy, which despite significant therapeutic advances, is still considered incurable. This is due to the persistence of chemotherapy-resistant minimal residual disease in the patients' bone marrow (BM) after an effective induction therapy. Immunotherapies targeting surface molecules expressed on the bulk of tumor cells and the chemotherapy-resistant, myeloma-propagating cells could play a central role in this clinical setting. We recently described surface molecule CD229 as a potential therapeutic target for MM. In our current study we assessed the expression of CD229 on different PC subtypes and on cells with a myeloma-propagating phenotype in a total of 77 patients with PC dyscrasias independently at 2 different cancer centers. We found that CD229 was strongly and homogeneously overexpressed on the PC of patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma, MM, and PC leukemia. CD229 was particularly overexpressed on those PC showing an abnormal phenotype such as expression of CD56. Most importantly, CD229 was also highly expressed on those cells in the patients' BM displaying the phenotype of chemotherapy-resistant and myeloma-propagating cells. In conclusion, our combined findings suggest that immunotherapies targeting CD229 will not only be effective for the bulk of tumor cells but will also help to eradicate chemotherapy-resistant cells remaining in the patients' BM after induction treatment. Hopefully, the design of CD229-specific monoclonal antibodies or chimeric antigen receptor-transduced T cells will help to achieve prolonged remissions or even cures in MM patients.

Distal upper limb myopathy/cachexia is not previously described with dominant POLG mutations and our observations further highlight the diverse clinical spectrum of POLG-related mitochondrial disorders. These data indicate that dominant POLG mutations should be considered in the differential diagnosis of distal upper limb predominant myopathy.