Therapeutic outcome of early-phase clinical trials in multiple myeloma: a meta-analysis

Great progress in the treatment of patients with multiple myeloma (MM) has been made due to the development of novel drugs. Patients with relapsed/refractory MM (RRMM) can be enrolled in early-phase clinical trials, but their performance across the last decade is unknown. We conducted a meta-analysis on the overall response rate (ORR) and toxicity. PubMed, Embase, and Cochrane Library were systematically searched for phase I and phase II trials investigating an experimental compound as a single agent or in combination with dexamethasone, published from January 1, 2010 to July 1, 2020. Eighty-eight articles were included, describing 61 phase I trials involving 1835 patients and 37 phase II trials involving 2644 patients. There was a high degree of heterogeneity. Using a random-effects model, the 95% CIs of the estimated ORR were 8-17% for phase I trials and 18-28% for phase II trials. There were significant subgroup differences in ORR between the years of publication in phase I trials and between drug classes in both phase I and phase II trials. The ORR in early-phase clinical trials in RRMM is substantial, especially in phase II trials, but due to high heterogeneity a general assessment of clinical benefit before participation is difficult to offer to patients

Identifying clinical response to daratumumab therapy in relapsed/refractory multiple myeloma using a patient-derived in vitro model

Response to daratumumab in patients with relapsed/refractory multiple myeloma is heterogeneous, and a reliable biomarker of response is lacking. We aimed to develop a method that identifies response to daratumumab therapy. Patient-derived MM cells were collected before start of daratumumab treatment and were cultured in a hydrogel-based culture system. The extent of antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity in vitro was associated with both clinical response and progression-free survival in corresponding patients. Together, our results demonstrate that in vitro sensitivity to daratumumab therapy in a hydrogel culture with primary MM cells might be used to identify patients most likely to benefit from treatment

Endomyocardial biopsy with co-localization of a lymphoplasmacytic lymphoma and AL amyloidosis

In about 4% of cases, amyloid light chain (AL) amyloidosis is due to an underlying lymphoplasmacytic lymphoma (LPL) or other monoclonal protein forming low-grade B-cell lymphoma, instead of a plasma cell neoplasm. We report an unusual case of a 55-year-old male with co-localization of an IgG positive LPL and AL amyloidosis in his endomyocardial biopsy (EMB). The patient was diagnosed 4 years earlier with a low grade B-cell non Hodgkin lymphoma stage IV, at the time classified as marginal zone lymphoma. He received several lines of treatment for his lymphoma, which had shown progressive disease. Four years after initial diagnosis, he developed increasing dyspnea on exertion. Echocardiography demonstrated left and right ventricular hypertrophy with classical apical sparing, suspicious for cardiac amyloidosis. Bone marrow biopsy revealed massive infiltration by his low grade B-cell lymphoma, which was now reclassified as LPL based on the demonstration of a MYD88 L265P mutation. An EMB confirmed the presence of amyloid, which was typed as AL amyloidosis by the use of immunoelectron microscopy. In addition, mild B-cell infiltrates were present in the EMB, which were shown to be part of his LPL by the demonstration of the MYD88 L265P mutation using the highly sensitive droplet digital polymerase chain reaction technique. This is a rare case of cardiac AL amyloidosis based on an IgG kappa positive LPL, in which not only the amyloid but also the lymphoma itself were present in the EMB. In addition, this case nicely illustrates the use of 2 highly sensitive techniques (immunoelectron microscopy and droplet digital polymerase chain reaction), which both can be performed on small, formalin-fixed paraffin-embedded biopsies

Toward targeting B cell cancers with CD4+ CTLs: identification of a CD19-encoded minor histocompatibility antigen using a novel genome-wide analysis

Some minor histocompatibility antigens (mHags) are expressed exclusively on patient hematopoietic and malignant cells, and this unique set of antigens enables specific targeting of hematological malignancies after human histocompatability leucocyte antigen (HLA)–matched allogeneic stem cell transplantation (allo-SCT). We report the first hematopoietic mHag presented by HLA class II (HLA-DQA1*05/B1*02) molecules to CD4+ T cells. This antigen is encoded by a single-nucleotide polymorphism (SNP) in the B cell lineage-specific CD19 gene, which is an important target antigen for immunotherapy of most B cell malignancies. The CD19L-encoded antigen was identified using a novel and powerful genetic strategy in which zygosity-genotype correlation scanning was used as the key step for fine mapping the genetic locus defined by pairwise linkage analysis. This strategy was also applicable for genome-wide identification of a wide range of mHags. CD19L-specific CD4+ T cells provided antigen-specific help for maturation of dendritic cells and for expansion of CD8+ mHag-specific T cells. They also lysed CD19L-positive malignant cells, illustrating the potential therapeutic advantages of targeting this novel CD19L-derived HLA class II–restricted mHag. The currently available immunotherapy strategies enable the exploitation of these therapeutic effects within and beyond allo-SCT settings