International Staging System Score Research Articles

Primary analysis of a prospective cohort study of Japanese patients with plasma cell neoplasms in the novel drug era (2016-2021).

The emergence of novel drugs has significantly improved outcomes of patients with plasma cell neoplasms (PCN). The Japanese Society of Hematology conducted a prospective observational study in newly diagnosed PCN patients between 2016 and 2021. The analysis focused on 1385 patients diagnosed with symptomatic PCN between 2016 and 2018. The primary endpoint was the 3-year overall survival (OS) rate among patients requiring treatment (n = 1284), which was 70.0% (95%CI 67.4-72.6%). Approximately 94% of these patients received novel drugs as frontline therapy. The 3-year OS rate was 90.3% (95%CI 86.6-93.1%) in the 25% of patients who received upfront autologous stem cell transplantation (ASCT), versus just 61.4% (95%CI 58.0-64.6%) in those who did not receive upfront ASCT. The only unfavorable prognostic factor that affected OS in ASCT recipients was an age of 65 or higher. For patients who did not receive ASCT, independent unfavorable prognostic factors included frontline treatment with conventional chemotherapies, international staging system score of 2/3, extramedullary tumors, and Freiberg comorbidity index of 2/3. This study unequivocally demonstrates that use of novel drugs improved OS in Japanese myeloma patients, and underscores the continued importance of upfront ASCT as the standard of care in the era of novel drugs.

In the era of Bortezomib-based Induction, intensification of Melphalan-based conditioning with Bortezomib does not improve Survival Outcomes in newly diagnosed Multiple Myeloma: a study from the Chronic Malignancies Working Party of the EBMT

Bortezomib (Vel)- Melphalan 200 mg/m2 (Mel200) (Vel-Mel) has been utilised to intensify conditioning in autologous hematopoietic stem cell transplantation (AHCT) for multiple myeloma (MM). This EBMT registry-based study compared Vel-Mel with Mel200 during upfront AHCT. Between 2010 and 2017, MM patients who received Vel-Mel (n = 292) conditioning were compared with 4,096 Mel200 patients in the same 58 centres. Pre-AHCT, compared to Mel200 patients, Vel-Mel patients had similar International Staging System (ISS) scores and cytogenetic risk profiles; a similar proportion had received bortezomib-based induction (85% and 87.3%, respectively) though they were younger with a better performance status. Vel-Mel patients were more likely to achieve CR post-induction (40.6% vs 20.3%, p < 0.001) and by day 100 of AHCT (CR/VGPR: 70.2 % vs. 57.2%, p < 0.001). There was no difference in 3-year PFS (49% vs 46%, p = 0.06) or early post-AHCT mortality. In multivariable analysis, Vel-Mel associated with inferior PFS (HR: 1.69 (1.27–2.25, p < 0.001) and OS (HR:1.46 (1.14–1.86,p = 0.002), similar to negative effects on PFS of advanced ISS (HR:1.56 (1.33–1.83, p < 0.001), high-risk cytogenetics (HR:1.43(1.18–1.74, p < 0.001) and poor post-induction response(<=PR)(HR: 1.43(1.25–1.62, p < 0.001) Overall, despite superior pre- and post-AHCT responses, there was no improvement in PFS or OS following Vel-Mel. This data supports the findings of the smaller prospective IFM study.

Pomalidomide, Dexamethasone, and Daratumumab Versus Other Triplet Regimens in Patients with Relapsed or Refractory Multiple Myeloma: A Population-Adjusted Indirect Treatment Comparison

Introduction: Multiple myeloma (MM) is an incurable malignant plasma cell disorder in which most patients eventually relapse or become refractory to treatment. Lenalidomide (LEN) is typically administered as part of first-line regimens; however, patients who receive LEN usually relapse, necessitating improved options in later lines of therapy. The phase 2, non-randomized MM-014 trial (NCT01946477) demonstrated promising efficacy of pomalidomide (POM) plus dexamethasone and daratumumab (DPd) among patients with relapsed or refractory MM (RRMM), with an overall response rate of 77.7% and a median overall survival (OS) of 56.7 months at a median follow-up of 41.9 months. With the evolving treatment landscape of RRMM, however, there is limited head-to-head data comparing DPd to other standard of care therapies to inform clinical decision-making. Objective: To investigate the comparative efficacy of DPd versus non-POM-containing triplets in adult patients with RRMM using population-adjusted indirect comparison (PAIC) approaches. Methods: A PAIC was conducted using individual patient-level data of 112 adult patients with RRMM who were exposed to LEN (75.9% refractory to LEN) from cohort B of the MM-014 trial. Investigator-assessed OS was the primary endpoint of this analysis. A systematic literature review was performed to identify comparable interventional studies assessing the efficacy of non-POM-containing triplets for RRMM as well as potential prognostic variables (PVs). PVs verified by clinicians were selected for inclusion if significantly associated with OS (p &amp;lt; 0.1) in the MM-014 trial based on univariate Cox regression model. The suitability of these potential trials for PAIC was assessed by considering the comparability of study design, inclusion/exclusion criteria, patients' baseline characteristics, and outcomes. A retrospective analysis utilizing Flatiron electronic health record data from Jan 2011 to July 2022 was previously performed to evaluate the effect of LEN-refractory status on OS using multivariable Cox regression. Given the lack of a common comparator, unanchored PAIC was performed for OS using matching-adjusted indirect comparison (MAIC) and confirmatory simulated trial comparison (STC). A sensitivity analysis was conducted to explore the impact of LEN-refractory status as a PV. Results: Six trials were systematically identified as eligible comparators in initial screening including TOURMALINE-MM1, CANDOR, CASTOR, POLLUX, ASPIRE, and LEPUS. The analyses using Flatiron data showed that patients who were refractory to LEN had significantly shorter OS than those exposed to LEN but not refractory (Hazard ratio: 1.51; 95% CI: 1.17, 1.94), indicating the unsuitability to compare treatments based on studies with large variations in proportion of LEN-refractory patients. Four trials were excluded due to differences violating the transitivity assumption (0% LEN-refractory patients in TOURMALINE-MM1 and POLLUX; LEN-refractory status not reported in ASPIRE; only Chinese patients in LEPUS). The remaining two trials are phase 3 randomized controlled trials investigating carfilzomib plus dexamethasone and daratumumab (DKd) (CANDOR; NCT03158688; Usmani et al. Blood Adv. 2023; Epub ahead of print) and daratumumab plus bortezomib and dexamethasone (DVd) (CASTOR; NCT02136134; Sonneveld et al. J Clin Oncol. 2023; 41:1600-1609). In the base case MAIC adjusting for creatinine clearance, time from diagnosis, International Staging System score, and refractory to LEN, DPd was associated with numerical reduction in the risk of death compared to DKd and DVd (Table). In addition, the base case STC showed significant improvement of OS for DPd over DKd and DVd, confirming the findings from MAIC (Table). In the sensitivity analyses excluding LEN-refractory status, the effect estimates were substantially different from those in the base case analyses (&amp;gt;40% difference), demonstrating the importance of adjusting for LEN refractory status. Conclusions: In patients with RRMM, consistent OS benefit was found for DPd versus DKd and DVd regardless of the PAIC technique used. These findings support the use of DPd over DKd and DVd in treating patients with RRMM, especially given the oral route of administration of pomalidomide. This study also highlighted the importance of considering LEN refractory status when comparing efficacy of treatments for RRMM across trials.

Long-Term Outcomes from the Phase 3 OCEAN (OP-103) Study: Melflufen and Dexamethasone (Dex) Versus Pomalidomide (Pom) and Dex in Relapsed Refractory Multiple Myeloma (RRMM)

Background/Introduction: Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases resulting in rapid release of alkylating agents inside tumor cells. Based on the phase 2 HORIZON study and supported by the phase 3, randomized, controlled OCEAN study, melflufen was approved in Europe for use in patients (pts) with triple-class refractory RRMM with ≥3 prior lines of therapy (LoTs) and without prior autologous stem cell transplantation (ASCT) or with a time to progression (TTP) &amp;gt;36 mo after prior ASCT. In the OCEAN study (NCT03151811), melflufen + dex showed superior progression-free survival (PFS) compared with pom + dex (6.8 vs 4.9 mo; hazard ratio [HR]: 0.79; P=0.032); PFS benefit in the melflufen + dex group was mainly driven by pts who had not received prior ASCT. Overall survival (OS) trended in favor of melflufen + dex in pts without prior ASCT and favored pom + dex in pts with prior ASCT (Schjesvold et al. Lancet Haematol. 2022;9:e98). Post-hoc analyses of OCEAN and HORIZON demonstrated that a TTP &amp;lt;36 mo after prior ASCT was a negative prognostic factor for OS with melflufen + dex (Sonneveld et al. Clin Lymphoma Myeloma Leuk. 2023;S2152). Here, we present long-term OS and safety data from the final analysis of the OCEAN study. Methods: Pts with RRMM (2-4 prior LoTs including lenalidomide [len] and a proteasome inhibitor) refractory to len and last LoT were randomized 1:1 (stratified by age, no. of prior LoTs, and International Staging System score) to receive 28-day (d) cycles of melflufen 40 mg intravenously on d1 or pom 4 mg orally (PO) daily on d1 to 21. All pts received dex 40 mg (20 mg for pts ≥75 y) PO on d1, 8, 15, and 22. Pts received therapy until disease progression or unacceptable toxicity. The primary endpoint was PFS, as assessed by independent review committee per IMWG Uniform Response Criteria, and key secondary endpoints were overall response rate, OS, and safety. Results: As of 3 Feb 2023, 495 pts were randomized (246 to melflufen; 249 to pom); median age was 68 y (range, 39-91) and median prior LoTs was 3. In the intent-to-treat (ITT) melflufen and pom populations, median OS was 20.2 mo vs 24.0 mo (HR, 1.09 [95% CI, 0.88-1.35]), at a median follow-up of 40.3 mo and 38.1 mo, respectively. In the target subgroup of the melflufen and pom groups (pts without a prior ASCT or TTP &amp;gt;36 mo after an ASCT), median OS was 23.6 mo vs 19.1 mo (HR, 0.88 [95% CI, 0.67-1.16]); in the non-target population (pts with TTP &amp;lt;36 mo after ASCT), median OS was 15.7 mo vs 27.5 mo (HR, 1.60 [95% CI, 1.15-2.21]), respectively. While any grade hematologic toxicities were more common with melflufen, the occurrence of non-hematologic toxicities was similar in the 2 groups. Grade 3/4 (G3/4) treatment-emergent adverse events (TEAEs) in the safety population (melflufen [n=228] and pom [n=246]) occurred in 90% vs 76% of pts, respectively; most commonly thrombocytopenia (78% vs 13%; occurring with G3/4 hemorrhage in 1% vs 0%), neutropenia (64% vs 50%; occurring with G3/4 infections in 4% vs 7%), anemia (43% vs 19%), and infection and infestations (14% vs 24%). Serious AEs occurred in 43% vs 50% of pts (including pneumonia [6% vs 9%], COVID-19 pneumonia [5% vs 6%], and anemia [4% vs 2%]), and fatal AEs in 14% vs 15% (including COVID-19 pneumonia [4% vs 2%] and pneumonia [2% vs 2%]) in the melflufen and pom groups, respectively. With melflufen and pom, TEAEs led to dose reductions in 52% vs 28% of pts (most frequently thrombocytopenia [32% vs 2%] and neutropenia [12% vs 8%]), and discontinuations in 30% vs 24% of pts, respectively. Deaths occurred in 74% vs 68% of pts in the melflufen and pom groups, with AEs being the primary cause of death ≤30 d after last dose in 8% and 11%, respectively. Conclusion: Long-term results were consistent with those of previous analyses (Schjesvold, et al. Lancet Haematol. 2022;9:e98-e110). While OS trended in favor of pom in the ITT population, OS outcomes continued to be more favorable with melflufen in pts with no prior ASCT or with TTP &amp;gt;36 mo after ASCT. No new safety signals were reported, and AEs were manageable with dose modifications, consistent with previous reports. This long-term follow-up of OCEAN confirms the favorable safety and OS outcomes of melflufen + dex in the target population and supports its continued use as an alternative treatment choice for pts with RRMM who have received ≥2 prior LoT and who have not received ASCT.

Adolescents and Young Adults with Multiple Myeloma, Kuwait Experience

Background Multiple myeloma MM is an incurable plasma cell malignancy with a median age of 65 years at diagnosis worldwide, a small number of publications were focused on young adult Multiple myeloma MM with special characteristics and clinical outcomes. Objectives To evaluate the incidence of MM among adolescent and young adults (AYA) in Kuwait aged 40 and below. Also, to describe the clinical characteristics, high risk features and treatment outcomes at the Kuwait Cancer Control Centre (KCCC). Materials &amp; Methods We collected data retrospectively from the hematological malignancy registry at KCCC and looked at AYA patients (pts) with a confirmed diagnosis of Multiple myeloma at our center from 2015 till 2022, we looked at age of onset, gender, nationality, year of myeloma diagnosis, presence of extramedullary disease, International Staging System score (ISS score), cytogenetic aberrations, induction therapy, receipts of auto-transplant and maintenance therapy. Results From 2015 till 2022, 340 patients were diagnosed with MM in Kuwait, eleven patients were found 40 years old or younger, only one was female patients, the median age was 35 years old, around a third were Kuwaiti, 73% were non-Kuwaiti of middle eastern background, 4 patients were found to have extramedullary disease at diagnosis, with advanced stage ISS III found in 3/9 pts. One patient was found with 1Q gain and the rest of the 10 patients were with negative del17p, t (4,14), t(14,16), gain1q and t(11,14). Of note, interphase FISH cytogenetic is not done with CD138 selection. Six patients were treated with RVD induction (Lenalidomide, Bortizomib, Dexamethasone), two patients treated by CTD (Cyclophosphamide, Thalidomide, Dexamethasone), one pt treated by VCD (Bortizomib,Cyclophosphamide,Dexamethasone), one patient treated by Daratumumab RVD, and one patient treated by VTD. Overall response rate (ORR) was 90.9%, (10/11) responded patients proceeded to HDCT/ASCT and all these patients went on maintenance post-transplant, two patients were lost to follow up while 9 patients still under follow up, median follow up 33 months, one pt had a relapse after transplant. Conclusion MM is an uncommon disease among AYA in Kuwait (3.2%) of all myeloma patients, with favorable durable responses in this group of patients.

T Cell Ig and ITIM Domains (TIGIT) Expression in Multiple Myeloma

Background Neoplastic myeloma cells show a wide variety of mechanisms that induce the microenvironment, allowing immune evasion and promoting their proliferation, survival, migration and drug resistance. In this context, immunocheckpoints are particularly important, representing the modulators of signal pathways responsible for immune tolerance, a mechanism that prevents the destruction of cancer cells by the immune system. T cell Ig and ITIM domains (TIGIT), a member of the poliovirus (PVR) /nectin receptor family, is a new immune checkpoint that negatively regulates T cell functions. In Multiple Myeloma (MM), TIGIT could play a relevant role leading to immunological escape. TIGIT performs its task mainly through binding ligands: CD155 and CD112, through which it inhibits the cytotoxicity of CD8+ T cells, as well as that of NK. In This Study, we evaluate the presence of TIGIT in bone marrow using instant digital pathology. AIMS Aims of this study are to develop a valid and reproducible workflow for instant digital pathology, to demonstrate the presence of TIGIT-positive T lymphocytes in bone marrow of patients with MM and to evaluate its correlation with clinical features PATIENTS and Methods 18 patients with newly diagnosed MM not previously treated, were evaluated in this study. The sample was enrolled from November 2022 to May 2023. Bone marrow blood was loaded on a porous matrix able to retain cells (Cytomatrix, UCS Diagnostics srl, Rome) for real time assessment of sample adequacy, morphological details preservation, and composition of hematopoietic subpopulations, using an ex-vivo fluorescent confocal microscope (FCM). Expert pathologists compared the digital FCM images with permanent Formalin Fixed Paraffin Embedded (FFPE) sections of the matrix and trephine bone marrow biopsy. Immunohistochemistry for TIGIT (TG-1 Clone, OncoDianova) was performed on matrix FFPE sections. RESULTS Our results showed that 15/17 (88%) patients resulted positive for TIGIT and 2/17 (12%) were negative. TIGIT expression was found mainly on CD8+ T lymphocytes, TIGIT positivity was correlated with parameters that define the aggressiveness of myeloma disease such as PC &amp;gt; 60% or FLC &amp;gt; 100, ISS score, R-ISS score, cytogenetic risk and LDH &amp;gt; 220mU/ml. Among the patients defined as “ultra-High Risk”, 9/10 (90%) resulted positive for TIGIT. Comparing TIGIT with the MM International Staging System (ISS), we observed that all patients with scores II and III were positive for TIGIT (100%) while 78% of them with ISS I results positive. Conclusions Our results suggest that FCM can be applied immediate evaluation of bone marrow aspirates, preserving the cellular sample for final histological analysis. “Furthermore, our data shows the positivity of TIGIT in 88% of patients, demonstrating the presence of this immune checkpoint in the bone marrow microenvironment. These data will need to be confirmed in a larger group of patients, but they open up the possibility of new target treatments in multiple myeloma

Single Cell Profiling Unravels Plasma Cell Gene Expression Signatures Predictive of Response to Daratumumab Based Therapy, and Prognosis in Multiple Myeloma

Background: Multiple Myeloma (MM) is the second most common hematologic malignancy and remains incurable. Daratumumab (dara) is a potent anti-CD38 monoclonal antibody used for MM treatment, but responses are heterogeneous, and resistance is inevitable. There is hence an urgent need for biomarkers to predict the response to dara. We hypothesized that gene expression profiles (GEP) of tumor subpopulations could be used to predict the response to dara-based therapy. Methodology: We used the Enhanced Single-Cell Analysis with Protein Expression (ESCAPE) RNA-Seq platform (Singleron Biotechnologies) to simultaneously profile the gene and protein expression of plasma cells from the bone marrow of 15 MM patients prior to treatment with dara-based regimens. These data were combined with publicly available single-cell data from Cohen et al. 2021, resulting in a total of 32 samples. Response was defined based on the international myeloma working group (IMWG) criteria, considering patients achieving a very good partial response (VGPR) or better as “responders,” while those achieving a partial response (PR) or worse were deemed “non-responders”. The data were split into 23 training samples (15 responders and 8 non-responders) and 9 validation samples (3 responders and 6 non-responders), each set containing a combination of cases from the two sources of single-cell data. An interpretable machine-learning model was then built to predict the response of each individual cell. The median response score for each sample was used to predict the patient-level response. The Shapley Additive Explanations (SHAP) values from the dara response prediction model were then used as a starting point for creating a general prognostic model. The 200 most influential genes from the dara response prediction model were used to create a linear response model based on the TCGA (MMRF-Compass) bulk RNAseq dataset. The bulk RNAseq dataset was split 80:20 into training and test datasets. Results from the test dataset are presented here. Results: We analyzed single-cell data from a total of 13,094 plasma cells from 32 BM samples. These included 17 cases of relapsed MM described by Cohen et al., who were treated with dara, carfilzomib, lenalidomide, and dexamethasone. The patients treated at our centre comprised 7 cases of relapsed MM treated with dara, thalidomide, and dexamethasone, and 8 samples from patients with newly diagnosed MM treated with dara, bortezomib, and dexamethasone on clinical trials. All 9 patients in the test dataset had their responses correctly predicted (Fig 1). A separate cohort of non-dara-treated patient samples was also tested using the same model, and the response prediction was not accurate (AUC=0.67), suggesting that this model has specificity for predicting response to dara and is not a general response classifier (data not shown). Based on the SHAP values from the dara response prediction model, we developed a prognostic model from bulk RNAseq data consisting of four genes. A combination of this four-gene signature plus the international staging system (ISS) score resulted in a superior prediction of overall survival compared to the ISS alone with a hazard ratio of 13.5 compared to 2.5 for the ISS alone in the same dataset (Fig 2). Conclusions: Combining single-cell RNA sequencing with machine-learning methods may have value in predicting response to immunotherapy in MM. We propose that gene signatures derived from single-cell data may augment clinical decision-making for determining treatment allocation. We also show that these signatures may be combined with existing prognostic scores, resulting in improved delineation of risk groups. Furthermore, the applicability of our gene signature to a bulk gene expression dataset enhances its clinical relevance. Our study demonstrates the power of single-cell omics to identify novel predictors of response to therapy and prognosis in MM, which may be translated into clinical use.

Use of Myeloma Patient Outcome Scale (MyPOS) to gauge the effectiveness of palliative management in patients with multiple myeloma: Experience from a large tertiary academic center in India.

e24137 Background: A diagnosis of Multiple Myeloma (MM) can carry significant physical, social, functional and emotional repercussions. There is a lack of data on Baseline Quality of Life (QOL) in patients with MM and effectiveness of palliative management in the Indian context, especially after the advent of newer chemo-immunotherapeutic agents and autologous stem cell transplant (ASCT). Myeloma Patient Outcome Scale (MyPOS) is the first questionnaire developed specific for MM patients. Objectives and Methods: To evaluate symptom burden and quality of life in MM patients admitted to the medical oncology ward. To assess change in quality of life and symptoms as well as analgesic requirements on telephonic follow up after one and three months from index admission. After institutional ethical clearance, MM inpatients were prospectively enrolled. Clinical and treatment related details were recorded. MyPOS questionnaire was administered as well as a detailed pain assessment using Brief Pain Inventory (BPI) was carried out at baseline, 1 and 3 months. Results: 82 out of 100 MM patients consented for recruitment (Mean age- 52 +/- 9yrs; Male- 55%). Mean duration of the disease since diagnosis was less than 1 year (0.86 years), with a mean International staging system (ISS) score of 2. Up to half (37/82, 45%) of the patients received ASCT in addition to chemotherapy. The baseline Global MyPOS Score was 58 +/- 8.8 while the mean Pain severity (MPS) and interference (MPI) scores were 25+/-8 and 43+/-10 respectively. The most painful region was the back. Only Tramadol was sufficient for a small minority (6/82, 7.4%), most required oral morphine. Most patents had significant interval improvement in their pain and QOL scores with a p less than 0.01 on follow-up (MyPOS at 1 month and 3 month were 81+/-6 and 78+/-5, MPS were 21+/-13 and 17+/-1.1, MPI were 38+/-2.2 and 37+/-2.1 respectively). Conclusions: Adequate pain management can significantly improve quality of life in MM patients. Use of standardized questionnaires such as MyPOS is a quintessential tool for the palliative specialist in order to gauge therapeutic efficacy.

Infectious Complications of Bispecific Antibody Therapy in Patients with Multiple Myeloma

Introduction Infection is a leading contributor to morbidity in heavily treated patients with multiple myeloma (MM) with severe infection rates of up to 30% reported (Lim et. al. Clin Lymphoma Myeloma Leuk 2021). Bispecific antibody (BsAb) therapy is increasingly used in the treatment of multiple myeloma (MM) patients, but the infectious risks and optimal antimicrobial prophylaxis are not well-characterised. A retrospective observational study was conducted to describe the epidemiology, infectious complications, and outcomes to better guide antimicrobial prophylaxis and empiric treatment in this cohort. Methods All MM patients who received BsAb therapy at the Peter MacCallum Cancer Centre between 1st January 2018 to 30th May 2022 were included. Retrospective chart review of patients was conducted, and demographic, clinical, and microbiological data related to disease and infection episodes were collected. Complications of BsAb therapy such as cytokine release syndrome (CRS) were defined according to published criteria. Episodes of infection were graded by CTCAE criteria, and categorised as microbiologically-defined (MDI), clinically-defined (CDI) or fever of unknown focus (FUO) as defined by presence of fever and the absence of compatible microbiology or focal symptoms. Patients were followed up for 6 months post last BsAb dose, until next line of treatment, or death. Descriptive statistics were utilised to summarise clinical data and univariate and multivariate logistic regression performed to identify factors associated with MDI. Statistical analysis was conducted on Rstudio with p<0.05 considered statistically significant. Results: Overall, 39 patients were included. Patients were predominantly male (24, 62%), with a mean age of 62 (range: 27-78). The majority (67%) had IgG type myeloma, 28% had an International Staging System (ISS) score of 3 and had a median of 6 (IQR 4-7) lines of therapy prior to BsAb. Patients received a median of 5 (IQR 2-11) cycles of therapy and CRS occurred in 28 (72%) patients. Median duration of neutropenia and lymphopenia <1.0x109/L was 1 (IQR 0-3) and 22 (13-61) days respectively. Baseline characteristics are presented in Table 1. Of the 39 patients, 35 (90%) had at least 1 episode of infection (MDI, CDI, FUO), 15 (38%) had an MDI, and 16 (41%) had a grade 3 or higher infection episode. There was a total of 111 infection episodes and prior valaciclovir prophylaxis was administered in 104 (94%), trimethoprim/sulfamethoxazole in 104 (94%) and antifungals in 38 (34%) episodes. Cumulative prednisone-equivalent dose in the preceding 30 days was median of 266.7mg (IQR 106.7-266.7). Of these 111 episodes, 33 (30%) were MDI, 43 (39%) were CDI, and 35 (32%) were FUO (Table 2). Respiratory system was the commonest site of infection (46, 41%). Of the MDI, viral infections were commonest (22, 67%), particularly rhinovirus/enterovirus (8, 36%), followed by cytomegalovirus (4, 18%) and adenovirus (4, 18%). Bacterial infections were Gram negative in 12 (80%) and Gram positive in 3 (20%). There were no episodes of invasive fungal disease. Majority of FUO were likely CRS (31, 89%). Episodes occurred during a median of 2 (IQR 1-7) cycles of therapy. Hospital admission was associated with 63 (57%) episodes with a median (IQR) length of stay of 4 (3-6) days. Intensive care admission was required in 4 (4%) episodes and all-cause mortality was 3%. Baseline clinical variables age, functional status (ECOG), international staging system stage, lines of therapy, CRS, and its treatment were not found to be associated with increased risk for MDI on univariate or multivariate logistic regression. Conclusions: Infection remains a clinically significant burden in heavily-treated MM patients on BsAb therapy. Clinically diagnosed, respiratory tract infections were most frequently diagnosed. Viral infections were the most common type of MDI identified, facilitating targeting of prevention and surveillance measures. Future larger studies are required to define associated risks for infection. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long-Term Outcomes of Autologous Hematopoietic Cell Transplant of Multiple Myeloma: A 10 Year Follow up Study

Introduction: Multiple myeloma (MM) is a disorder of plasma cell proliferation that affects 1 in 132 humans in the United States. While the disease is generally characterized by good initial response rates, the majority of MM patients eventually relapse. Autologous Hematopoietic Cell Transplantation (AHCT) is the current standard of care for patients who demonstrate response to initial therapy; however, long-term studies looking at the association between certain demographic, clinical and cytogenetic factors with long-term outcomes post-AHCT are scarce. We report herein our AHCT outcomes over the past 10 years. Methods: We retrospectively reviewed the electronic medical records of all MM patients who underwent AHCT at Cleveland Clinic between January 1st, 2011 and January 15th 2021. Demographic characteristics, time to transplant, cytogenetic risk, International Scoring System (ISS), labs, lines of treatment, response (per International Myeloma Working Group criteria), overall survival and progression free survival were collected through chart review. Cox proportional hazards regression analysis using the Statistical Package for Social Sciences (SPSS) was performed to determine factors that significantly and independently affect relapse and overall survival. Kaplan-Meier analysis was performed to compare the median overall survival (mOS) and median progression free survival (mPFS) according to the cytogenetic risk. Results: A total of 517 patients with median follow up of 32.9 months were included, of whom FISH cytogenetics and ISS were available in 413 and 424, respectively. Our cohort had a median age at AHCT of 60.2 years and male preponderance of 58.2%. ECOG performance status was 0 in 158 (30.6%), 1 in 321 (62.2%), 2 in 36 (7%) and 3 in 1 (0.2%) at AHCT. Of patients with available ISS, 160 (37.7%) had stage I, 165 (38.9%) had stage II and 99 (23.3%) had stage III. Standard risk (SR) and high risk (HR) FISH were present in 279 (67.6%) and 134 (32.4%) patients, respectively, and the most common abnormalities were del (13q) (33.9%) followed by t(11;14) (22.0%), gain 1q (18.2%), del(17p) (10.7%) and t(4;14) (7.7%). Most patients had IgG (68.9%) followed by IgA (23.5%) MM. Median lines of treatment pre-AHCT was 1 (range 1-9), while 132 (25.5%) had complete response (CR), 176 (34%) had very good partial response (VGPR), and 209 (40.4%) had partial response (PR) pre-AHCT. Looking into factors affecting outcomes, our analysis suggested that HR cytogenetics (HR 2.34, 1.34-4.03 95% CI, P=0.003) and treatment lines of ≥2 pre-AHCT (HR 1.35, 1.03-1.7 95% CI, P=0.024) were independent risk factors for lower OS. In contrast, age at AHCT (HR 1.04, 0.98-1.04 95% CI), male sex (HR 1.05, 0.63-1.73 95% CI), white ethnicity (vs African American HR 1.23, 0.49-3.08 95% CI; vs Other ethnicities HR 1.19, 0.16-9.00 95% CI), time to transplant of ≥12 months (HR 1.35, 0.77-2.39 95% CI), ISS stage III (vs stage I HR 0.94, 0.49-1.82 95% CI; vs stage II HR 1.29, 0.69-2.39 95% CI), and PR disease status pre-ASCT (vs VGPR HR 1.26, 0.71-2.2 95% CI; vs CR HR 1.46, 0.68-3.12 95% CI) did not significantly influence OS. On the other hand, HR cytogenetics (HR 3.12, 2.09-4.66 95% CI, P<0.0001), smoking history (vs never smokers HR 1.51, 1.12-2.04 95% CI, P=0.006) and PR disease status pre-AHCT (vs CR HR 2.11, 1.25-3.56, P=0.005; vs VGPR HR 1.19, 0.81-1.74 95% CI) were found to be independent risk factors for earlier relapse, as opposed to the rest of the factors similarly analyzed for OS. We then focused our Cox model on determining specific HR cytogenetic features that independently affect either OS or PFS. Our results suggested that t(14;16) (HR 3.93, 1.94-7.97 95% CI, P<0.0001), followed by del(17p) (HR 2.75, 1.51-5.00 95% CI, P=0.001) and t(4;14) (HR 2.10, 1.17-3.77 95% CI, P=0.013) independently lower OS. Similarly t(14;16) (HR 5.05, 2.83-8.99 95% CI, P<0.0001), del(17p) (HR 3.49, 2.23-5.44 95% CI, P<0.0001), t(4;14) (HR 2.46, 1.56-3.88 95% CI, P<0.0001) as well as gain (1q) (HR 2.32, 1.54-3.51 95% CI, P=0.009) independently lower PFS. Kaplan Meier-based survival analysis further confirmed a lower mOS (67.4 months vs unreached, P<0.0001) (Fig 1A) and mPFS (21.9 vs 64.2 months, P<0.0001) (Fig 1B) for HR vs SR cytogenetics. Conclusion: OS post-AHCT in MM patients is mainly affected by HR cytogenetics and number of treatment lines pre-AHCT. HR cytogenetics affects PFS as well, which is also influenced by a smoking history and the pre-AHCT disease status. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Role of prognostic scores in the evolution of renal involvement in patients with multiple myeloma after bone marrow transplantation

Introduction: Treatment of multiple myeloma (MM) with chemotherapy and autologous bone marrow transplantation (BMT) commonly results in renal dysfunction associated with early mortality. Prognostic scores for MM are assessed by either Durie and Salmon (DS) or International Staging System (ISS) methods. Few studies have examined the relationship between these scores and renal damage after BMT. Aims: To evaluate DS and ISS prognostic scores as they relate to renal function and mortality in MM patients who have undergone BMT. Methods: Retrospective, observational cohort of 95 MM patients who underwent BMT between 2012 and 2014. Renal function was assessed using data on proteinuria, serum creatinine, and estimated glomerular filtration rate from the time of hospital admission to 6 months post-BMT. Results: Neither score was significantly associated with death or proteinuria, but patients in DS stage IIIB were 12.8 times more likely to experience renal dysfunction than those in DS stage I–II. Both DS and ISS scores reflected a progressive increase in the chance of renal functional impairment with increased disease staging. Conclusions: The prognostic methods studied were useful in the initial recognition of renal dysfunction and after 6 months post BMT, the DS score was still able to predict the reduction of eGFR. Patients in the advanced stages of MM were associated with altered renal function, and these results could help to establish early treatment strategies to reduce the risk of renal damage.

Unsupervised machine learning improves risk stratification in newly diagnosed multiple myeloma: an analysis of the Spanish Myeloma Group

The International Staging System (ISS) and the Revised International Staging System (R-ISS) are commonly used prognostic scores in multiple myeloma (MM). These methods have significant gaps, particularly among intermediate-risk groups. The aim of this study was to improve risk stratification in newly diagnosed MM patients using data from three different trials developed by the Spanish Myeloma Group. For this, we applied an unsupervised machine learning clusterization technique on a set of clinical, biochemical and cytogenetic variables, and we identified two novel clusters of patients with significantly different survival. The prognostic precision of this clusterization was superior to those of ISS and R-ISS scores, and appeared to be particularly useful to improve risk stratification among R-ISS 2 patients. Additionally, patients assigned to the low-risk cluster in the GEM05 over 65 years trial had a significant survival benefit when treated with VMP as compared with VTD. In conclusion, we describe a simple prognostic model for newly diagnosed MM whose predictions are independent of the ISS and R-ISS scores. Notably, the model is particularly useful in order to re-classify R-ISS score 2 patients in 2 different prognostic subgroups. The combination of ISS, R-ISS and unsupervised machine learning clusterization brings a promising approximation to improve MM risk stratification.

Melflufen or pomalidomide plus dexamethasone for patients with multiple myeloma refractory to lenalidomide (OCEAN): a randomised, head-to-head, open-label, phase 3 study

Melphalan flufenamide (melflufen), an alkylating peptide-drug conjugate, plus dexamethasone showed clinical activity and manageable safety in the phase 2 HORIZON study. We aimed to determine whether melflufen plus dexamethasone would provide a progression-free survival benefit compared with pomalidomide plus dexamethasone in patients with previously treated multiple myeloma. In this randomised, open-label, head-to-head, phase 3 study (OCEAN), adult patients (aged ≥18 years) were recruited from 108 university hospitals, specialist hospitals, and community-based centres in 21 countries across Europe, North America, and Asia. Eligible patients had an ECOG performance status of 0-2; must have had relapsed or refractory multiple myeloma, refractory to lenalidomide (within 18 months of randomisation) and to the last line of therapy; and have received two to four previous lines of therapy (including lenalidomide and a proteasome inhibitor). Patients were randomly assigned (1:1), stratified by age, number of previous lines of therapy, and International Staging System score, to either 28-day cycles of melflufen and dexamethasone (melflufen group) or pomalidomide and dexamethasone (pomalidomide group). All patients received dexamethasone 40 mg orally on days 1, 8, 15, and 22 of each cycle. In the melflufen group, patients received melflufen 40 mg intravenously over 30 min on day 1 of each cycle and in the pomalidomide group, patients received pomalidomide 4 mg orally daily on days 1 to 21 of each cycle. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat (ITT) population. Safety was assessed in patients who received at least one dose of study medication. This study is registered with ClinicalTrials.gov, NCT03151811, and is ongoing. Between June 12, 2017, and Sept 3, 2020, 246 patients were randomly assigned to the melflufen group (median age 68 years [IQR 60-72]; 107 [43%] were female) and 249 to the pomalidomide group (median age 68 years [IQR 61-72]; 109 [44%] were female). 474 patients received at least one dose of study drug (melflufen group n=228; pomalidomide group n=246; safety population). Data cutoff was Feb 3, 2021. Median progression-free survival was 6·8 months (95% CI 5·0-8·5; 165 [67%] of 246 patients had an event) in the melflufen group and 4·9 months (4·2-5·7; 190 [76%] of 249 patients had an event) in the pomalidomide group (hazard ratio [HR] 0·79, [95% CI 0·64-0·98]; p=0·032), at a median follow-up of 15·5 months (IQR 9·4-22·8) in the melflufen group and 16·3 months (10·1-23·2) in the pomalidomide group. Median overall survival was 19·8 months (95% CI 15·1-25·6) at a median follow-up of 19·8 months (IQR 12·0-25·0) in the melflufen group and 25·0 months (95% CI 18·1-31·9) in the pomalidomide group at a median follow-up of 18·6 months (IQR 11·8-23·7; HR 1·10 [95% CI 0·85-1·44]; p=0·47). The most common grade 3 or 4 treatment-emergent adverse events were thrombocytopenia (143 [63%] of 228 in the melflufen group vs 26 [11%] of 246 in the pomalidomide group), neutropenia (123 [54%] vs 102 [41%]), and anaemia (97 [43%] vs 44 [18%]). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]). 27 [12%] patients in the melflufen group and 32 [13%] in the pomalidomide group had fatal treatment-emergent adverse events. Fatal treatment-emergent adverse events were considered possibly treatment related in two patients in the melflufen group (one with acute myeloid leukaemia, one with pancytopenia and acute cardiac failure) and four patients in the pomalidomide group (two patients with pneumonia, one with myelodysplastic syndromes, one with COVID-19 pneumonia). Melflufen plus dexamethasone showed superior progression-free survival than pomalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Oncopeptides AB.

Hispanic or Latin American Ancestry Is Associated with a Similar Genomic Profile and a Trend Toward Inferior Outcomes in Newly Diagnosed Multiple Myeloma As Compared to Non-Hispanic White Patients in the Multiple Myeloma Research Foundation (MMRF) CoMMpassstudy

IntroductionLarge clinical data sets suggest that the natural history and prognosis of newly diagnosed multiple myeloma (NDMM) differs between patients of European and African ancestry, with the latter group exhibiting an earlier age at onset and poorer overall prognosis in some studies. The use of next generation sequencing (NGS) to characterize the genomic landscape of multiple myeloma (MM) suggests that the observed phenotypic differences between these groups of patients may reflect distinct underlying genomic profiles and mutational processes. Thus far, characterizations of this type have focused principally on patients of African ancestry (AA). Here, we characterize the genomic features and outcomes of a large series of patients of Hispanic or Latin American ancestry (HL) as compared to their Non-Hispanic white (NHW) counterparts.MethodsSubjects were selected from the MMRF CoMMpass SM trial, a study that includes 1,154 patients with updated outcome data as of March, 2020. Within this data set, 760 patients had information on race and ethnicity. Among these, 55 HL patients and 478 NHW patients possessed complete clinical and genomic information.We analyzed baseline whole exome sequencing (WES) and long insert whole genome sequencing (WGS) as previously described (Walker, et al. Blood 2019). Our analysis focused on 63 known driver mutations in multiple myeloma and 39 sites of common copy number variation across the study population. Complex structural variants and tumor telomere length were called using previously described bioinformatic tools (Boyle et al. Leukemia 2021). Survival analysis was undertaken using the Kaplan-Meier method with hazard ratios determined by the Cox proportional hazards model.ResultsIn a comparison of clinical features between the Hispanic and NHW population, we did not identify any differences in age of onset, gender, presenting cytogenetics, International Staging System Score (ISS), and IMWG Risk Category. The proportion of patients undergoing autologous stem cell transplantation was similar between groups. We identified no statistically significant differences in the presence of characteristic translocations involving IgH locus or in hyperdiploidy status. No statistically significant differences in tumor mutational burden or loss-of-heterozygosity percentage emerged between HL and NHW patients.We examined non-synonymous variations (NSV) and copy number variations at the loci of known MM driver genes and encountered no statistically significant differences in NSV, copy number, or biallelic status. We further categorized genes into pathways relevant to the pathogenesis of MM and discovered no difference in the proportions of patients harboring mutations in genes related to the MEK/ERK and NF-κB pathways, cell cycle regulation, and epigenetic modification. We were unable to the distinguish either population based on the presence of chromothripsis or in the overall preponderance of an APOBEC mutational signature. Tumor telomere length was not significantly different between the populations.An analysis of overall and progression free survival (PFS) with a median duration of follow up of 44 months revealed a trend toward poorer outcomes among the HL population that did not reach statistical significance. Median PFS was 24 months in HL patients and 35 months in the NHW population (p = 0.19). Median OS was not reached in either ethnic subgroup. In terms of overall survival, age, ISS score, overall number of driver mutations, and the presence of chromothripsis emerged with a negative impact on outcome (Figures 1a, 1b). These variables with the exception of chromothripsis retained their significant impact on progression free survival (Figure 2a, 2b).ConclusionThe correlation between Hispanic or Latin American ancestry and underlying disease biology in MM has yet to be fully elucidated. In our analysis, which was based on self-declared ancestry as opposed to admixture, no obvious differences in significant measures of genomic variation known to impact prognosis in MM emerged between HL and NHW patients. These results may help to inform the future large-scale studies to ascertain the impact of genomics, disease biology and socioeconomic factors on outcomes in this heterogeneous patient population. [Display omitted] DisclosuresWalker: Bristol Myers Squibb: Research Funding; Sanofi: Speakers Bureau. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees.

OCEAN (OP-103): Melflufen Plus Dexamethasone (Dex) Versus Pomalidomide (Pom) and Dex in Relapsed Refractory Multiple Myeloma (RRMM) - Renal Impairment (RI) Analysis

OCEAN (OP-103): Melflufen Plus Dexamethasone (Dex) Versus Pomalidomide (Pom) and Dex in Relapsed Refractory Multiple Myeloma (RRMM) - Renal Impairment (RI) Analysis

OCEAN (OP-103): Melflufen Plus Dexamethasone (Dex) Versus Pomalidomide (Pom) and Dex in Relapsed/Refractory Multiple Myeloma (RRMM) - Impact of Prior Treatments Analysis

OCEAN (OP-103): Melflufen Plus Dexamethasone (Dex) Versus Pomalidomide (Pom) and Dex in Relapsed/Refractory Multiple Myeloma (RRMM) - Impact of Prior Treatments Analysis

OCEAN (OP-103): Melflufen/Dexamethasone (Dex) Compared with Pomalidomide (Pom)/Dex in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (RRMM) - Subgroup Analysis By Prior Alkylator Exposed/Refractory Status

OCEAN (OP-103): Melflufen/Dexamethasone (Dex) Compared with Pomalidomide (Pom)/Dex in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (RRMM) - Subgroup Analysis By Prior Alkylator Exposed/Refractory Status

Impact of Achieving an Early Complete Response in Multiple Myeloma and Predictors of Subsequent Outcome

Impact of Achieving an Early Complete Response in Multiple Myeloma and Predictors of Subsequent Outcome

OCEAN (OP-103): Melflufen/Dexamethasone Compared with Pomalidomide/Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma-Age Subgroup Analysis of Older Patients

OCEAN (OP-103): Melflufen/Dexamethasone Compared with Pomalidomide/Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma-Age Subgroup Analysis of Older Patients

Significance of maintenance therapy after HDT/ASCT in symptomatic multiple myeloma: A multicenter retrospective analysis in Kansai Myeloma Forum.

A total of 129 symptomatic patients with multiple myeloma (MM) who underwent high‐dose chemotherapy with autologous stem cell transplantation (HDT/ASCT) were analyzed. The 4‐year overall survival (OS) of patients with maintenance (n = 82) was 80%, whereas that of patients without maintenance (n = 47) was 72% (p = 0.426). The 4‐year progression‐free survival (PFS) of patients with maintenance was 38%, whereas that of patients without maintenance was 27% (p = 0.088). Multivariate analysis revealed that an International Staging System score ≥2 was associated with worse PFS (hazard ratio 1.62, p = 0.043). Among the 129 patients, two were excluded owing to early relapse, 50 patients achieved complete response (CR), and 77 patients failed to achieve CR. Patients who achieved CR showed better 4‐year PFS than those who failed to achieve CR (41% vs. 30%, p = 0.027); however, 4‐year OS was not different (76% vs. 82%, p = 0.971). In patients who achieved CR, 4‐year OS with/without maintenance was 74%/81% (p = 0.357), 4‐year PFS with/without maintenance was 42%/40% (p = 0.954). In patients who failed to achieve CR, the 4‐year OS with/without maintenance was 97%/91% (p = 0.107), and 4‐year PFS with/without maintenance was 36%/16% (p < 0.001). In patients who failed to achieve CR, maintenance significantly improved the PFS. Maintenance after HDT/ASCT can prolong PFS in patients who fail to achieve CR in real‐world settings.