Time trends in survival and causes of death in multiple myeloma: a population-based study from Germany

Abstract Background Steady evolution of therapies has improved prognosis of patients with multiple myeloma (MM) over the past two decades. Yet, knowledge about survival trends and causes of death in MM might play a crucial role in long-term management of this patient collective. Here, we investigate time trends in myeloma-specific survival at the population level over two decades and analyse causes of death in times of prolonged survival. Methods Age-standardised and age group-specific relative survival (RS) of MM patients aged < 80 years at diagnosis was estimated for consecutive time periods from 2000–2019 using data from the Cancer Registry of North Rhine-Westphalia in Germany. Conditional RS was estimated for patients who already survived one to five years post diagnosis. Causes of death in MM patients were analysed and compared to the general population using standardised mortality ratios (SMR). Results Three thousand three hundred thirty-six MM cases were included in the time trend analysis. Over two decades, age-standardised 5-year RS increased from 37 to 62%. Age-specific survival improved from 41% in period 2000–2004 to 69% in period 2015–2019 in the age group 15–69 years, and from 23 to 47% in the age group 70–79 years. Conditional 5-year RS of patients who survived five years after diagnosis slightly improved as compared to unconditional 5-year RS at diagnosis. MM patients are two times more likely to die from non-myeloma malignancies (SMR = 1.97, 95% CI 1.81–2.15) and from cardiovascular diseases (SMR = 2.01, 95% CI 1.86–2.18) than the general population. Conclusions Prognosis of patients with MM has markedly improved since the year 2000 due to therapeutic advances. Nevertheless, late mortality remains a major concern. As survival improves, second primary malignancies and cardiovascular events deserve increased attention

Structural Variants as a Basis for Targeted Therapies in Hematological Malignancies

Structural variants (SV) are changes in the genomic landscape that can alter gene expression levels and thus lead to disease development. The most common and best studied SVs in hematological malignancies are chromosomal translocations. Here, parts of two genes that are normally on different chromosomes come into close proximity due to a failure in DNA repair. As a consequence, fusion proteins which show a different function and/or cellular localization compared to the two original proteins are expressed, sometimes even at different levels. The identification of chromosomal translocations is often used to identify the specific disease a patient is suffering from. In addition, SVs such as deletions, duplications, inversions and single nucleotide polymorphisms (SNPs) can occur in hematopoietic cells and lead to their malignant transformations. Changes in the 3D genome structure have also recently been shown to impact disease development. In this review, we describe a variety of SVs occurring in different subtypes of hematological malignancies. Currently, most therapeutic approaches target fusion proteins which are the cellular product of chromosomal translocations. However, amplifications and SNPs also play a role in disease progression and can be targeted. We present some examples for different types of structural variants and how they are currently treated

Long-term survival and polyclonal immunoglobulin reconstitution after allogeneic stem cell transplantation in multiple myeloma

Despite significant progress made in the treatment of patients with multiple myeloma (MM) in the last decade, for patients with early relapse or rapidly progressing high-risk disease, allogeneic hematopoietic stem cell transplantation (SCT) might be an option leading to long-term survival. Here, we retrospectively analyzed the outcomes of 90 MM patients who received allogeneic SCT in our center between 1999 and 2017. We specifically assessed the association of impaired humoral immune reconstitution, referred to as immunoparesis, and post-transplant survival. Sixty-four patients received allogeneic SCT in relapse following 2-7 lines of therapy; 26 patients received upfront tandem autologous-allogeneic SCT. With a median follow-up of 76 months, OS and PFS were 52.6% (95% CI 42.9-64.3) and 36.4% (95% CI 27.6-47.9) at 2 years and 38.6% (95% CI 29.2-51.1) and 25.3% (95% CI 17.5-36.4) at 5 years, respectively. Receiving more than two therapy lines prior to transplantation was an independent risk factor for OS (HR 3.68, 95% CI 2.02-6.70) and PFS (HR 3.69, 95% CI 2.09-6.50). In a landmark analysis at day 200, prolonged immunoparesis was associated with reduced OS (HR 3.22, 95% CI 1.14-9.11). Allogeneic stem cell transplantation offers an additional treatment element that may lead to long-term remission in selected patients with poor prognosis, probably exploiting graft-versus-myeloma effects. Immunoparesis could potentially serve as an indicator for impaired survival following allogeneic transplantation, an observation to be further studied prospectively

Long-lived macrophage reprogramming drives spike protein-mediated inflammasome activation in COVID-19

Innate immunity triggers responsible for viral control or hyperinflammation in COVID-19 are largely unknown. Here we show that the SARS-CoV-2 spike protein (S-protein) primes inflammasome formation and release of mature interleukin-1 beta (IL-1 beta) in macrophages derived from COVID-19 patients but not in macrophages from healthy SARS-CoV-2 naive individuals. Furthermore, longitudinal analyses reveal robust S-protein-driven inflammasome activation in macrophages isolated from convalescent COVID-19 patients, which correlates with distinct epigenetic and gene expression signatures suggesting innate immune memory after recovery from COVID-19. Importantly, we show that S-protein-driven IL-1 beta secretion from patient-derived macrophages requires non-specific monocyte pre-activation in vivo to trigger NLRP3-inflammasome signaling. Our findings reveal that SARS-CoV-2 infection causes profound and long-lived reprogramming of macrophages resulting in augmented immunogenicity of the SARS-CoV-2 S-protein, a major vaccine antigen and potent driver of adaptive and innate immune signaling