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EJHaem Jun 2024Multiple myeloma remains an incurable cancer mostly affecting older adults and is characterized by a series of remission inductions and relapses. This study aims to...
Long-term follow-up of outcomes including progression-free survival 2 in patients with transplant-ineligible multiple myeloma in the real-world practice: A multi-institutional report from the Canadian Myeloma Research Group (CMRG) database.
Multiple myeloma remains an incurable cancer mostly affecting older adults and is characterized by a series of remission inductions and relapses. This study aims to evaluate the outcomes in newly diagnosed transplant-ineligible patients using bortezomib/lenalidomide-based regimens in the Canadian real world as well as their outcomes in the second line. The Canadian Myeloma Research Group Database (CMRG-DB) is a national database with input from multiple Canadian Centres with now up to 8000 patients entered. A total of 1980 transplant ineligible patients were identified in the CMRG-DB between the years of 2007-2021. The four most commonly used induction regimens are bortezomib/melphalan/prednisone (VMP) (23%), cyclophosphamide/bortezomib/dexamethasone (CyBorD) (47%), lenalidomide/dexamethasone (Rd) (24%), and bortezomib/lenalidomide/dexamethasone (VRd) (6%). After a median follow-up of 30.46 months (0.89-168.42), the median progression-free survival (mPFS) and median overall survival (mOS) of each cohort are 23.5, 22.9, 34.0 months, and not reached (NR) and 64.1, 51.1, 61.5 months, and NR respectively. At the time of data cut-off, 1128 patients had gone on to second-line therapy. The mPFS2 based on first-line therapy, VMP, CyBorD, Rd, and VRd is 53.3, 48.4, 62.7 months, and NR respectively. The most common second-line regimens are Rd (47.4%), DRd (12.9%), CyBorD (10.3%), and RVd (8.9%) with a mPFS and a mOS of 17.0, 31.1, 15.4, and 14.0 months and 34.7, NR, 47.6, 33.4 months, respectively. This study represents the real-world outcomes in newly diagnosed transplant-ineligible myeloma patients in Canada. The spectra of therapy presented here reflect the regimens still widely used around the world. While this is sure to change with anti-CD38 monoclonal antibodies now reflecting a new standard of care in frontline therapy, this cohort is reflective of the type of multiple myeloma patient currently experiencing relapse in the real-world setting.
PubMed: 38895063
DOI: 10.1002/jha2.894 -
Cancers May 2024Locoregionally advanced and metastatic melanoma represent a challenging clinical problem, but in the era of immune checkpoint blockade and intralesional and infusional... (Review)
Review
Locoregionally advanced and metastatic melanoma represent a challenging clinical problem, but in the era of immune checkpoint blockade and intralesional and infusional therapies, more options are available for use. Isolated limb infusion (ILI) was first introduced in the 1990s for the management of advanced melanoma, followed by the utilization of isolated extremity perfusion (ILP). Following this, intralesional oncolytic viruses, xanthene dyes, and cytokines were introduced for the management of in-transit metastases as well as unresectable, advanced melanoma. In 2015, the Food and Drug Administration (FDA) approved the first oncolytic intralesional therapy, talimogene laherparepvec (T-VEC), for the treatment of advanced melanoma. Additionally, immune checkpoint inhibition has demonstrated efficacy in the management of advanced melanomas, and this improvement in outcomes has been extrapolated to aid in the management of in-transit metastatic disease. Finally, percutaneous hepatic perfusion (PHP), also approved by the FDA, has been reported to have a significant impact on the treatment of hepatic disease in uveal melanoma. While some of these treatments have less utility due to inferior outcomes as well as higher toxicity profiles, there are selective patient profiles for which these therapies carry a role. This review highlights intralesional and infusional therapies for the management of metastatic melanoma.
PubMed: 38893078
DOI: 10.3390/cancers16111957 -
Coexistence of variant-type transthyretin and immunoglobulin light-chain amyloidosis: a case report.European Heart Journal. Case Reports Jun 2024Determining the type of amyloid deposits is clinically important for choosing the specific therapies for cardiac amyloidosis.
BACKGROUND
Determining the type of amyloid deposits is clinically important for choosing the specific therapies for cardiac amyloidosis.
CASE SUMMARY
A 78-year-old woman who had been experiencing fluid retention and dyspnoea on exertion for 6 months was referred to our hospital for the management of heart failure with left ventricular hypertrophy. Since Tc-hydroxymethylene diphosphonate scintigraphy showed mild cardiac uptake and significant elevation of serum free lambda chain (with a difference of 263 mg/L in free light chain), we suspected immunoglobulin light-chain amyloidosis (AL), and endomyocardial biopsy was performed. The deposit site within the myocardial tissue exhibited positive for Congo red staining and transthyretin immunostaining, however negative or non-specific for light-chain immunostaining including lambda and kappa staining. Genetic testing confirmed a mutation in V122I, variant-type transthyretin amyloidosis (ATTRv). Despite the administration of patisiran, her condition exhibited progressive deterioration. Additionally, she displayed macroglossia, an atypical manifestation in ATTRv amyloidosis. Further biopsies from tongue and abdominal wall fat culminated in a final diagnosis: the coexistence of ATTRv and AL (of the lambda type). Although treatment with melphalan and dexamethasone was started, she passed away 24 months after the initial visit. When the endomyocardial biopsy specimen underwent mass spectrometry as a analysis, both ATTR and AL amyloid were significantly detected.
DISCUSSION
Coexistence of ATTRv and AL within cardiac amyloidosis is extremely uncommon. In situations where incongruities arise between the amyloid type determined via immunohistochemistry findings and the amyloid type assumed based on other clinical findings, mass spectrometry should be considered.
PubMed: 38872953
DOI: 10.1093/ehjcr/ytae264 -
European Journal of Cancer (Oxford,... Jun 2024Frailty in newly-diagnosed multiple myeloma (NDMM) patients is associated with treatment-related toxicity, which negatively affects health-related quality of life...
BACKGROUND
Frailty in newly-diagnosed multiple myeloma (NDMM) patients is associated with treatment-related toxicity, which negatively affects health-related quality of life (HRQoL). Currently, data on changes in HRQoL of frail and intermediate-fit MM patients during active treatment and post-treatment follow-up are absent.
METHODS
The HOVON123 study (NTR4244) was a phase II trial in which NDMM patients ≥ 75 years were treated with nine dose-adjusted cycles of Melphalan-Prednisone-Bortezomib (MPV). Two HRQoL instruments (EORTC QLQ-C30 and -MY20) were obtained before start of treatment, after 3 and 9 months of treatment and 6 and 12 months after treatment for patients who did not yet start second-line treatment. HRQoL changes and/or differences in frail and intermediate-fit patients (IMWG frailty score) were reported only when both statistically significant (p < 0.005) and clinically relevant (>MID).
RESULTS
137 frail and 71 intermediate-fit patients were included in the analysis. Compliance was high and comparable in both groups. At baseline, frail patients reported lower global health status, lower physical functioning scores and more fatigue and pain compared to intermediate-fit patients. Both groups improved in global health status and future perspective; polyneuropathy complaints worsened over time. Frail patients improved over time in physical functioning, fatigue and pain. Improvement in global health status occurred earlier than in intermediate-fit patients.
CONCLUSION
HRQoL improved during anti-myeloma treatment in both intermediate-fit and frail MM patients. In frail patients, improvement occurred faster and, in more domains, which was retained during follow-up. This implies that physicians should not withhold safe and effective therapies from frail patients in fear of HRQoL deterioration.
PubMed: 38870747
DOI: 10.1016/j.ejca.2024.114153 -
Blood Cell Therapy May 2024Melphalan-induced encephalopathy is a rare complication observed in patients undergoing autologous stem cell transplantation (ASCT) and is characterized by symptoms...
Melphalan-induced encephalopathy is a rare complication observed in patients undergoing autologous stem cell transplantation (ASCT) and is characterized by symptoms ranging from drowsiness to seizures. Previous reports have described similar cases, including a review of a large cohort of patients in whom melphalan-associated encephalopathy was identified in 2% of the patients undergoing ASCT. We describe the case of a 63-year-old male with Multiple Myeloma and underlying chronic kidney disease (CKD) who underwent ASCT with a reduced dose of melphalan due to renal dysfunction in complete remission following induction therapy and subsequent neurological deterioration, which necessitated an extensive evaluation of several neurological and infective etiologies. In this report, we highlight that melphalan-associated encephalopathy is a distinct entity complicating ASCT in patients with myeloma, especially in those with preexisting renal insufficiency, and consider its management.
PubMed: 38854402
DOI: 10.31547/bct-2023-025 -
BioRxiv : the Preprint Server For... May 2024Normal hematopoietic stem and progenitor cells (HSPCs) inherently accumulate somatic mutations and lose clonal diversity with age, processes implicated in the...
Normal hematopoietic stem and progenitor cells (HSPCs) inherently accumulate somatic mutations and lose clonal diversity with age, processes implicated in the development of myeloid malignancies . The impact of exogenous stressors, such as cancer chemotherapies, on the genomic integrity and clonal dynamics of normal HSPCs is not well defined. We conducted whole-genome sequencing on 1,032 single-cell-derived HSPC colonies from 10 patients with multiple myeloma (MM), who had undergone various chemotherapy regimens. Our findings reveal that melphalan treatment distinctly increases mutational burden with a unique mutation signature, whereas other MM chemotherapies do not significantly affect the normal mutation rate of HSPCs. Among these therapy-induced mutations were several oncogenic drivers such as and . Phylogenetic analysis showed a clonal architecture in post-treatment HSPCs characterized by extensive convergent evolution of mutations in genes such as and . Consequently, the clonal diversity and structure of post-treatment HSPCs mirror those observed in normal elderly individuals, suggesting an accelerated clonal aging due to chemotherapy. Furthermore, analysis of matched therapy-related myeloid neoplasm (t-MN) samples, which occurred 1-8 years later, enabled us to trace the clonal origin of t-MNs to a single HSPC clone among a group of clones with competing malignant potential, indicating the critical role of secondary mutations in dictating clonal dominance and malignant transformation. Our findings suggest that cancer chemotherapy promotes an oligoclonal architecture with multiple HSPC clones possessing competing leukemic potentials, setting the stage for the selective emergence of a singular clone that evolves into t-MNs after acquiring secondary mutations. These results underscore the importance of further systematic research to elucidate the long-term hematological consequences of cancer chemotherapy.
PubMed: 38826462
DOI: 10.1101/2024.05.23.595594 -
Clinical Hematology International 2024Globally, multiple myeloma (MM) ranks 24 among the most common cancers. The Middle East and Africa are affected by an increasing trend in MM incidence, owing to several...
BACKGROUND
Globally, multiple myeloma (MM) ranks 24 among the most common cancers. The Middle East and Africa are affected by an increasing trend in MM incidence, owing to several underlying factors. This systematic review aims to assess the epidemiology, patient characteristics, and treatment outcomes associated with MM in selected countries in the Middle East and Africa.
METHODS
An electronic search was performed in the PubMed/MEDLINE database. Abstracts presented at the annual meetings of the American Society of Clinical Oncology, American Society of Hematology, and European Society for Medical Oncology and the GLOBOCAN registry were searched. Qualitative analysis was performed.
RESULTS
A total of 412 articles were screened, and 14 were selected. The five-year prevalence per 100,000 gathered from country-wise GLOBOCAN data ranged between 155 in Kuwait and 5,625 in North Africa. The identified treatment options were proteasome inhibitors such as bortezomib, drugs such as thalidomide, lenalidomide, dexamethasone, melphalan, and cyclophosphamide, and newer drugs such as daratumumab.
CONCLUSION
Improved diagnostic capability has increased the incidence of MM in this region. However, advanced drugs and treatment regimens remain unaffordable in many countries of these regions. Therefore, understanding the trends of the disease and improving healthcare settings are imperative.
PubMed: 38817690
DOI: 10.46989/001c.92555 -
Clinical Case Reports Jun 2024We report an observation of a young patient presenting with severe type 1 cryoglobulinemic vasculitis revealing a monoclonal gammopathy of clinical significant....
KEY CLINICAL MESSAGE
We report an observation of a young patient presenting with severe type 1 cryoglobulinemic vasculitis revealing a monoclonal gammopathy of clinical significant. Treatment with Melphalan-Thalidomide Prednisone improved the symptoms. Early diagnosis would prevent serious tissue damage.
ABSTRACT
Monoclonal gammopathy encompass diverse clinical forms. Only the cancerous form, multiple myeloma (MM), is treated based on specific diagnostic criteria. A new clinical entity, monoclonal gammopathy of clinical significance (MGCS), warrants special attention due to its need for specific treatment. It involves patients with signs of potentially severe organ involvement that do not meet MM criteria. We present the case of a 34-year-old Malagasy woman with severe type I cryoglobulinemic vasculitis associated with noncancerous monoclonal gammopathy, showing a favorable outcome after treatment with Thalidomide. Symptoms included toe necrosis, a severe ulcer on the left calf evolving for 3 months, and stocking-like dysesthesias. Investigations revealed monoclonal gammopathy at 30.1 g/L, proteinuria at 1 g/24 h, medullary plasma cell at 6%, and circulating cryoglobulin of Ig kappa type. CRAB criteria (anemia, hypercalcemia, renal insufficiency, and osteolysis) were absent. Treatment with Thalidomide, combined with corticosteroids and local care for 4 months, resulted in ulcer healing, disappearance of dysesthesias, and persistent normalization of gammaglobulin. Our case underscores the importance of specific treatment for MGCS.
PubMed: 38813450
DOI: 10.1002/ccr3.8897 -
Frontiers in Oncology 2024Carmustine (BCNU), etoposide, cytarabine, and melphalan (BEAM) are a widely used high-dose chemotherapy regimen for autologous stem cell transplantation transplant...
INTRODUCTION
Carmustine (BCNU), etoposide, cytarabine, and melphalan (BEAM) are a widely used high-dose chemotherapy regimen for autologous stem cell transplantation transplant (ASCT) in lymphoid malignancies. During BCNU shortages, some centers switched to fotemustine-substituted BEAM (FEAM). Neutropenic enterocolitis (NEC) is a life-threatening complication occurring after intestinal mucosa damage related to intensive chemotherapy. NEC mortality may be up to 30%-50%. In our study, we compared NEC incidence, symptoms, mortality, and transplant outcome in terms of overall survival (OS) and progression-free survival (PFS) in the BEAM . FEAM groups. Furthermore, we compared the cost of hospitalization of patients who did . patients who did not experience a NEC episode (NECe).
METHODS
A total of 191 patients were enrolled in this study (N = 129 and N = 62 were conditioned with BEAM and FEAM, respectively). All patients received bed-side high-resolution ultrasound (US) for NEC diagnosis.
RESULTS AND DISCUSSION
NEC incidence and NEC-related mortality were similar in the BEAM and FEAM groups (31% and 40.3%, p = 0.653, and 5% and 8%, p = 0.627, respectively). At a median follow-up of 116 months, no difference was noted between BEAM . FEAM groups in terms of OS and PFS (p = 0.181 and p = 0.978, respectively). BEAM appeared equivalent to FEAM in terms of NEC incidence and efficacy. The high incidence of NEC and the low mortality is related to a timely US diagnosis and prompt treatment. US knowledge in NEC diagnosis allows to have comparable days of hospitalization of patients NECpos . patients NECneg. The cost analysis of NECpos . NECneg has been also performed.
PubMed: 38803538
DOI: 10.3389/fonc.2024.1369601 -
Journal of Personalized Medicine Apr 2024Isolated limb hyperthermic-antiblastic perfusion (ILP) was the most effective local treatment for advanced in-transit melanoma, but the advent of modern effective...
BACKGROUND
Isolated limb hyperthermic-antiblastic perfusion (ILP) was the most effective local treatment for advanced in-transit melanoma, but the advent of modern effective immunotherapy (IT), such as immune checkpoint inhibitors, has changed the treatment landscape.
METHODS
This study evaluated the role of the association between ILP and IT in the treatment of locally advanced unresectable melanoma, particularly in relation to modern systemic therapies. We analyzed 187 consecutive patients who were treated with ILP (melphalan or melphalan associated with TNF-alpha) for advanced melanoma at the Veneto Institute of Oncology of Padua (Italy) and the Padua University Hospital (Italy) between June 1989 and September 2021. Overall survival (OS), disease-specific survival (DSS), local disease-free survival (local DFS) and distant disease-free survival (distant DFS) were evaluated. Local toxicity was classified according to the Wieberdink scale and surgical complications according to the Clavien-Dindo classification. Response to locoregional therapy was evaluated during follow-up according to the RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumor).
RESULTS
A total of 99 patients were treated with ILP and 88 with IT + ILP. The overall response rate was 67% in both groups. At 36 months, OS was 43% in the ILP group and 61% in the ILP + IT group ( = 0.02); DSS was 43% in the ILP group and 64% in the ILP + IT group ( = 0.02); local DFS was the 37% in ILP group and 53% in the ILP + IT group ( = 0.04); and distant DFS was 33% in the ILP group and 35% in the ILP + IT group ( = 0.40). Adjusting for age and lymph node involvement, receiving ILP + IT was associated with improved OS ( = 0.01) and DSS ( = 0.007) but not local DFS ( = 0.13) and distant DFS ( = 0.21).
CONCLUSIONS
Our findings confirm the synergy between ILP and IT. ILP remains a valuable loco-regional treatment option in the era of effective systemic treatments. Further studies are needed to establish the optimal combination of loco-regional and systemic treatments and address the best timing of this combination to obtain the highest local response rate.
PubMed: 38793023
DOI: 10.3390/jpm14050442