Immunotherapy has shown efficacy in relapsed multiple myeloma (MM). However, these therapies may depend on a functional tumor immune microenvironment (iTME) for their efficacy. Characterizing the ...evolution of the iTME over the disease course is necessary to optimize the timing of immunotherapies. We performed mass cytometry, cytokine analysis, and RNA sequencing on bone marrow samples from 39 (13 newly diagnosed NDMM, 11 relapsed pre-daratumumab exposure RMM, and 13 triple-refractory TRMM) MM patients. Three distinct cellular iTME clusters were identified; cluster 1 comprised mainly of NDMM and RMM patients; and clusters 2 and 3 comprised primarily of TRMM patients. We showed that naive T cells were decreased in clusters 2 and 3, cluster 2 was characterized by increased senescent T cells, and cluster 3 by decreased early memory T cells. Plasma cells in clusters 2 and 3 upregulated E2F transcription factors and MYC proliferation pathways, and downregulated interferon, TGF-beta, interleuking-6, and TNF-αlpha signaling pathways compared to cluster 1. This study suggests that the MM iTME becomes increasingly dysfunctional with therapy whereas the MM clone may be less dependent on inflammation-mediated growth pathways and less sensitive to IFN-mediated immunosurveillance. Our findings may explain the decreased sensitivity of TRMM patients to novel immunotherapies.
Advancements in chimeric antigen receptor engineered T-cell (CAR-T) therapy have revolutionized treatment for several cancer types over the past decade. Despite this success, obstacles including the ...high price tag, manufacturing complexity, and treatment-associated toxicities have limited the broad application of this therapy. Chimeric antigen receptor engineered natural killer cell (CAR-NK) therapy offers a potential opportunity for a simpler and more affordable "off-the-shelf" treatment, likely with fewer toxicities. Unlike CAR-T, CAR-NK therapies are still in early development, with few clinical trials yet reported. Given the challenges experienced through the development of CAR-T therapies, this review explores what lessons we can apply to build better CAR-NK therapies. In particular, we explore the importance of optimizing the immunochemical properties of the CAR construct, understanding factors leading to cell product persistence, enhancing trafficking of transferred cells to the tumor, ensuring the metabolic fitness of the transferred product, and strategies to avoid tumor escape through antigen loss. We also review trogocytosis, an important emerging challenge that likely equally applies to CAR-T and CAR-NK cells. Finally, we discuss how these limitations are already being addressed in CAR-NK therapies, and what future directions may be possible.
Survival has improved in patients diagnosed with multiple myeloma (MM) over the last two decades; however, there remains a paucity of data on the causes of death in MM patients and whether causes of ...death change during the disease trajectory. We conducted a retrospective population-based study to evaluate the rates of MM-specific vs non-MM cause of death and to identify factors associated with cause specific death in MM patients, stratified into autologous stem cell transplant (ASCT) and non-ASCT cohorts. A total of 6677 patients were included, 2576 in the ASCT group and 4010 in the non-ASCT group. Eight hundred and seventy-three (34%) ASCT patients and 2787 (68%) non-ASCT patients died during the follow-up period. MM was the most frequent cause of death, causing 74% of deaths in the ASCT group and 67% in the non-ASCT group. Other cancers were the second leading cause of death, followed by cardiac and infectious diseases. Multivariable analysis demonstrated that a more recent year of diagnosis and novel agent use within 1 year of diagnosis were associated with a decreased risk of MM-specific death, whereas a history of previous non-MM cancer, older age, and the presence of CRAB criteria at diagnosis increased the risk of non-MM death. Our data suggests that despite improvement in MM outcomes in recent years, MM remains the greatest threat to overall survival for patients. Further advances in the development of effective MM therapeutic agents in both ASCT and non-ASCT populations and patient access to them is needed to improve outcomes.
Autologous stem cell transplantation (ASCT) has been used for treating multiple myeloma (MM) for over three decades and is generally reserved for patients younger than 65. Herein we report on ...outcomes of outpatient ASCT in a cohort of patients with MM aged ≥75 years. Between October 2005 and August 2020, 50 patients aged ≥75 years, received an ASCT at Mayo Clinic, Rochester. Median time from diagnosis to ASCT was 6.85 months (IQR 5.2-10.52) and 50%. received reduced intensity conditioning with melphalan 140 mg/m
. 48% of patients completed the ASCT without requiring hospitalization and 52% (n = 26) of patients required hospitalization with a median duration of hospital admission of 9 days (IQR 5-13). Reasons for hospitalization included fever or infection (32%), cardiac arrhythmia (36%), and dehydration (32%). Overall response rate was 100% with a complete response seen in 57% of patients. Median overall survival and progression free survival for the cohort were 82 months and 33 months, respectively. One patient died within 100 days of transplant representing a 2% 100-day mortality rate. ASCT is safe and efficacious in carefully selected MM patients aged 75 or above and we believe that age should not be an exclusion factor for ASCT in MM.
Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant clonal disorder that progresses to multiple myeloma (MM), or other plasma-cell or lymphoid disorders at a rate of 1%/year. ...We evaluate the contribution of body mass index (BMI) to MGUS progression beyond established clinical factors in a population-based study. We identified 594 MGUS through a population-based screening study in Olmsted County, Minnesota, between 1995 and 2003. Follow-up time was calculated from the date of MGUS to last follow-up, death, or progression to MM/another plasma-cell/lymphoid disorder. BMI (kg/m
< 25/≥25) was measured close to screening date. We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of BMI ≥ 25 versus BMI < 25 with MGUS progression and also evaluated the corresponding c-statistic and 95% CI to describe discrimination of the model for MGUS progression. Median follow-up was 10.5 years (range:0-25), while 465 patients died and 57 progressed and developed MM (N = 39), AL amyloidosis (N = 8), lymphoma (N = 5), or Waldenstrom-macroglobulinemia (N = 5). In univariate analyses, BMI ≥ 25 (HR = 2.14,CI:1.05-4.36, P = 0.04), non-IgG (HR = 2.84, CI:1.68-4.80, P = 0.0001), high monoclonal (M) protein (HR = 2.57, CI:1.50-4.42, P = 0.001), and abnormal free light chain ratio (FLC
) (HR = 3.39, CI:1.98-5.82, P < 0.0001) were associated with increased risk of MGUS progression, and were independently associated in a multivariable model (c-statistic = 0.75, CI:0.68-0.82). The BMI association was stronger among females (HR = 3.55, CI:1.06-11.9, P = 0.04) vs. males (HR = 1.39, CI:0.57-3.36, P = 0.47), although the interaction between BMI and sex was not significant (P = 0.15). In conclusion, high BMI is a prognostic factor for MGUS progression, independent of isotype, M protein, and FLC
. This association may be stronger among females.
The Mayo-2018 smoldering multiple myeloma (SMM) risk score is used routinely in the clinical setting but has only been validated at diagnosis. In SMM patients, the progression risk decreases over ...time. However, the utility of applying risk stratification models after diagnosis is unknown. We retrospectively studied 704 SMM patients and applied the Mayo 2018 and IMWG-2020 risk stratification models at annual landmark timepoints up to 5 years post diagnosis. The Mayo-2018 and IMWG-2020 models reliably stratified patients based on progression risk when applied post diagnosis. The respective 2-year progression risk in Mayo-2018 high risk patients versus IMWG-2020 intermediate-high risk patients was 51% versus 62% at the 1-year landmark and 47% versus 45% at the 4-year landmark. We showed that patients categorized at Mayo-2018 high-risk at follow-up had a similar risk of progression if the baseline risk assessment was low-intermediate versus high-risk (HR 1.04, 95% CI 0.46-2.36, p = 0.931 at 5-year landmark). Patients migrating to a higher risk category during follow up had a higher progression risk compared to patients with stable/decreased risk categorization. Our findings support the use of these risk scores post-diagnosis and suggest that patients evolving to a high-risk category may benefit from early intervention therapeutic approaches.
Multiple myeloma (MM) is a disease of the elderly. Changes that occur in the immune system with aging, also known as immunosenescence, have been associated with decreased tumor immunosurveillance and ...are thought to contribute to the development of MM and other cancers in the elderly. Once MM establishes itself in the bone marrow, immunosenescence related changes have been observed in the immune tumor microenvironment (iTME) and are driven by the malignant cells. The efficacy of novel immunotherapies used to treat MM has been blunted by detrimental iTME changes that occur at later disease stages and are, to some extent, driven by prior therapies. In this review, we discuss general changes that occur in the immune system with aging as well as our current knowledge of immunosenescence in MM. We discuss the differences and overlap between T cell senescence and exhaustion as well as potential methods to prevent or reverse immunosenescence. We focus predominantly on T cell immunosenescence which has been better evaluated in this disease and is more pertinent to novel MM immunotherapies. Our lack of understanding of the drivers of immunosenescence at each stage of the disease, from precursor stages to heavily pretreated MM, represents a major barrier to improving the efficacy of novel and existing therapies.
Unlike IgG monoclonal proteins (MCPs), IgA MCP quantification is unreliable due to beta-migration of IgA MCPs on serum protein electrophoresis (SPEP). The utility of nephelometric quantitative IgA ...(qIgA) to monitor IgA multiple myeloma (MM) is unclear. We retrospectively studied disease response kinetics using qIgA versus MCPs by SPEP, and developed and validated novel qIgA disease assessment criteria in 491 IgA MM patients. The SPEP MCP nadir occurred a median of 41 (IQR 0-102) days before the qIgA. The median time to achieve a partial response (PR) was shorter using standard IMWG versus qIgA response criteria (32 vs 58 days, p < 0.001). Stratification by qIgA criteria, unlike IMWG criteria, led to clear separation of the progression-free survival curves of patients achieving a PR or very good PR. There was a consistent trend toward earlier detection of disease progression using qIgA versus IMWG progression criteria. In conclusion, monitoring IgA MM using MCP-based IMWG criteria may be falsely reassuring, given that MCP levels on SPEP decrease faster than qIgA levels. The qIgA response criteria more accurately stratify patients based on the progression risk and may detect disease progression earlier, which may lead to more consistent measurement of trial endpoints and improved patient outcomes.
Reactivation of hepatitis B virus (HBV) during immunosuppressive therapy (IST) can lead to severe and even fatal hepatitis but can be largely prevented with prophylactic antiviral therapy. Screening ...for HBV prior to starting IST is recommended. Both risk-based and universal screening have been recommended by different societies. For effective risk-based screening, physicians must be aware of risk factors for chronic HBV infection.
The HBV screening practices prior to starting IST of rheumatologists, medical and hematological oncologists were evaluated by survey and chart review. Country of origin, the primary risk factor for HBV exposure, was determined in all patients.
Of 140 rheumatology, 79 medical oncology and 53 hematology patients reviewed, 81%, 11% and 81% were deemed to be at high risk of HBV reactivation by their physicians respectively, however only 27%, 6% and 62% (p<0.0001) were actually screened for HBV prior to starting IST. For patients from HBV-endemic regions, more hematology patients (53%) were correctly identified by their physicians as being at high risk of reactivation than rheumatology patients (2.4%, p=0.0001) or medical oncology patients (15%, p=0.009). However actual screening rates were not increased in patients from endemic regions. A total of 81 patients were screened for HBsAg; 2 were positive. Of the 33 patients screened for anti-HBc, 10 (30%) were positive.
Hematologists, rheumatologists and medical oncologists had low rates of screening for HBV prior to prescribing IST, largely due to poor identification of those at risk for infection. Risk-based screening strategies are unlikely to be effective and should be replaced by universal screening.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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