Mohyuddin, Ghulam Rehman

Abstract Background: Social determinants of health (SDOH) are critical drivers of cancer care access and outcomes. In multiple myeloma (MM), access to cellular therapies including autologous stem cell transplantation and CAR-T therapy often depends on formal or informal caregiver support. Traditional SDOH measures (e.g., race, income, or education) are often used as proxies for access to care; however, these measures may overlook individual realities pertaining to cellular therapies where a caregiver is generally required. In response to feedback from a HealthTree Patient Advisory Board questioning the practice of inferring caregiver support, this study evaluated a simple survey question by a large cross-sectional survey. Methods: After development of a dedicated single-question (“What best describes your current caregiving support?”) through iterative feedback from the Patient Advisory Board and MM experts, four key answers were settled on: (1) cohabitation with dedicated caregiver(s) to support care (“family support”); (2) presence of non-cohabiting caregiver(s) to provide dedicated support (“external support”); (3) lack of dedicated caregiver, hence support is arranged when needed (“arrangeable support ”); or (4) lack of dedicated caregiver, hence finding any support is a struggle (“inadequate support”). We deployed this new demographic question from February through July 2025 through HealthTree. Responses were analyzed across SDOH variables using Fisher exact or chi square tests, and random forest classifiers were employed for predictive modeling. Results: Of 1231 respondents, 71% had dedicated caregivers (68%, n=839, with family support, and 3%, n=41, with external support). In contrast, 23% (n=287) of patients routinely arranged support while 5% (n=64) had inadequate support (struggle to find support). The inadequate-support group had significant demographic differences from the sample as a whole: a higher proportion were women (78% vs 56%, p = 0.04), Black (9% vs 4%, p < 0.01), lived >50 miles from their treatment center (17% vs 6%, p < 0.01), and had an annual income <$50,000 (17% vs 6%, p = 0.02). This group had a numerically higher proportion of patients whose employment status was disabled (12% vs 5%, p=0.08) as well. No proportion difference in age (67 ± 9 yr), military status, or severity of diagnosis - precursor disease (17%) v. multiple myeloma (81%). Rates of inadequate support were overall low in patients who lived with only their spouse (1%) or lived with their spouse & children (3%). In contrast, rates of inadequate support were higher (than 5%) in patients who lived alone (21%), divorced (20%), lived with adult children (14%), lived with friends (13%), separated (11%), or widowed (9%) (p < 0.001). However, the arrangeable-support group comprised 12% of patients who lived only with their spouse, 19% of patients who lived with their spouse and children, and 61% of patients who lived with their adult children (p < 0.001). Finally, a random forest classifier failed to identify any individual in the inadequate-support category, suggesting that unmeasured or more complex patterns may underlie this classification. Conclusions: To our knowledge, this is the largest analysis of caregiver support and its relationship with other SDOH in patients with MM to date. Despite the importance of caregiving to transplantation and CAR-T therapy, we found that 5% of patients with MM struggle to find caregiver support; this figure likely underestimates the true prevalence, given potential selection bias among patients who are digitally engaged through the HealthTree platform. Even among patients who lived with their spouses, an additional 10-20% of patients routinely had to arrange caregiving support on a visit-by-visit basis; for patients who lived with their adult children, this proportion was over 60%. The requirement to arrange caregiving support can create time toxicity and financial toxicity for patients, although these factors were not directly queried in our study. Finally, caregiver availability cannot be routinely inferred from traditional SDOH variables. Our data highlight the importance of including caregiver status as a standard demographic question in clinical and research settings. Further interventions are needed to improve caregiver support for vulnerable patients with MM as well as to reduce the duration of caregiver requirements for procedures such as CAR-T therapy.

Multiple myeloma (MM) treatment outcomes in developing countries may be impacted by resource constraints. This systematic review and meta-analysis evaluated efficacy outcomes of MM treatments across developing regions. Comprehensive searches in five major databases identified 37 eligible studies from Asia, Africa, Latin America, and Eastern Europe. The Newcastle-Ottawa Scale was used to assess risk of bias. Newer novel agents including daratumumab, carfilzomib, and pomalidomide showed limited use across studies. For patients receiving autologous stem cell transplantation (ASCT), the pooled overall survival rate at longest follow-up (2.5-12.5 years) was 62% (95% CI: 48-75%), with high heterogeneity (I²=92%), while the progression-free survival rate at longest follow-up (3-8 years) was 44% (95% CI: 23-67%). Comparative analyses demonstrated ASCT was associated with significantly superior 5-year survival compared to conventional chemotherapy (RR: 1.59; 95% CI: 1.38-1.82). Bortezomib-based regimens showed better outcomes than thalidomide-based therapies (HR for overall survival (OS) at 4 years: 0.73; 95% CI: 0.53-1.0) and alkylating agent-based regimens (HR: 0.48; 95% CI: 0.28-0.83). Despite resource limitations, ASCT and certain novel agents are associated with improved survival outcomes for MM patients in developing countries. However, substantial heterogeneity in outcomes suggests variability in healthcare infrastructure, treatment accessibility, and clinical expertise across these regions.

Introduction: With improving overall survival among MM patients, there is an increasing need to both understand the absolute risk and identify risk factors for developing a second primary malignancy (SPM). Understanding these risk and potential modulation factors may help guide decisions regarding treatment options, monitoring surveillance strategies, and patient counselling. Furthermore, understanding this baseline SPM risk will help contextualize the future SPM risk associated with newer therapeutics, including chimeric antigen receptor therapies. Thus, we conducted a population-based study with following objectives: 1) to evaluate the rate and distribution of SPMs, and 2) to identify risk factors including a history of prior malignancy associated with an increased risk of SPMs in patients with MM. Methods: We conducted a retrospective population-based study using data from Institute for Clinical Evaluative Sciences (ICES), an administrative database that captures all health records in the publicly funded health care system in Ontario, Canada. Adult patients treated for newly diagnosed MM between 2007-2022 were identified using ICD-O-3 code 9732/3 (MM). The list of secondary cancers (excluding non-melanoma skin cancers) were identified from pathology codes maintained in the Cancer Care Ontario Registry. Additional risk factors were also collected including a history and type of any pre-existing cancer (at least 1 year prior to MM diagnosis), treatment details including history of autologous stem cell transplantation (ASCT) and lenalidomide usage. The Kaplan-Meier method was used to estimate the median overall survival (OS). We estimated the cumulative incidence of secondary cancer accounting for death as a competing risk. To identify the association of prognostic factors on the risk of developing a SPM, we performed competing risks regression and estimated the subdistribution hazard ratios (sHR) accounting for death as a competing risk. Results: A total of 12123 patients . The median age at diagnosis was 70 (IQR 61-77) years, 6860 (57%) of our cohort had a male sex. In our 4511 (37%) received at least one ASCT, 8062 (67%) were lenalidomide exposed and 6917 (57%) were cyclophosphamide exposed at any time post MM diagnosis, and 3017 (16%) received oral melphalan based induction regimens. The median follow up for cohort was 4.53 (95% CI 4.4-4.7) years. A total of 2079 patients (17%) had a prior cancer diagnosis at least 1 year prior to their MM diagnosis. Of these patients, 665 (32%) had received chemotherapy and 553 (27%) had received radiation to treat their prior malignancy. The three most common prior cancers were: prostate cancer (25%), breast cancer (13%) and heme malignancies (4%).The median time from diagnosis of a prior malignancy to MM diagnosis was 6.4 (IQR 2.04-13.26) years. A total of 1070 (8.8%) of the cohort developed a SPM. The cumulative incidence of SPM post MM diagnosis, accounting for death as a competing risk, was 3.7% at 2 years, 7.6% at 5 years, and 11.5% at 10 years. The three most common SPMs were hematologic (21%), prostate (7%), and lung (7%) cancer. The three most common hematological SPMs were acute myeloid leukemia (37%), B-acute lymphoblastic leukemia (16%), and myelodysplastic syndrome (19%). The median OS following after any SPM diagnosis was 1.64 (95% CI 1.36-1.92) years, was 1.85 (95% CI 1.54-2.28) years for patients that developed a non-hematologic SPM, and was 1.05 (95% CI 0.88-1.40) years for patients that developed a hematologic SPM. Conclusion: This study represents one of the largest real-world cohort studies examining the rates, risk factor and outcomes of MM patients developing secondary cancers. We show that a prior malignancy diagnosis increased the risk of SPM after adjusting for ASCT and lenalidomide exposure, sex, and age at MM diagnosis. These data are important for patients and physicians to understand the risks associated with treatment of MM.

Introduction: Although not formally approved for the treatment of multiple myeloma (MM), the BCL2 inhibitor venetoclax (ven) has shown promising activity in patients (pts) with MM whose disease harbors t(11;14). The randomized BELLINI trial (VenVd vs Vd in unselected MM pts, Kumar Lancet Oncol 2020) demonstrated improved PFS, especially in the 35 patients with t(11;14) [HR 0.11], although worse OS in the intention to treat population due to increased treatment related mortality. The subsequent CANOVA trial (Vendex vs Pomdex in MM pts with t(11;14), Mateos IMS 2023) failed to show a PFS benefit (median PFS 9.9 mo vs 5.8 mo, p=0.237), leaving an uncertain future for ven in myeloma, despite the biological rationale and clinical activity. We therefore analyzed real world physician practice patterns using off-label ven for MM in the US. Methods: This retrospective observational study used data from the US nationwide Flatiron Health electronic health record (EHR)-derived de-identified longitudinal database. The Flatiron Health database contains structured and unstructured data curated via technology-enabled abstraction from approx. 280 cancer clinics and 800 unique sites of care. We included all patients in the Flatiron Health database with multiple myeloma (ICD-9 203.0x or ICD-10 C90.0x, confirmed with clinical review) who had received ven as part of any line of MM treatment. This included patients who commenced ven between 2016-2024. The primary endpoint was time to next treatment or death (TTNT) from ven initiation, with overall survival (OS) from ven initiation as the key secondary endpoint, both of which were estimated using the Kaplan-Meier method. Outcomes were compared using Cox proportional hazards model, using R v 4.3.0. Results: We included 208 patients who received ven for MM. They had a median of three prior lines of therapy (range 0-12), a median age of 67 years (Range 34-85 yrs), and 59% were male. Race/ethnicity breakdown was: Non-Hispanic White: 136 pts (72.7%), Black 36 (19.3%), Hispanic 10 (5.3%), Asian 5 (2.7%), other/unknown 21 (10.1%). Most had commercial insurance (188 pts, 91.3%) and 108 pts (52%) were cared for in academic settings while 100 (48%) were in community settings. ECOG performance status was 0 in 50 pts (24%), 1 in 80 pts (38.5%), ≥2 in 31 pts (14.9%) and unknown in 47 (22.6%). ISS Stage was I in 42 pts (20.2%), II in 43 pts (20.7%), III in 52 pts (25.0%) and unknown in 71 (34.1%). 148 pts had t(11;14) (71.2%), while 25 pts did not (12%) and 35 pts had unknown t(11;14) status (16.8%). Most pts received ven as part of a triplet combination (106 pts, 51%), followed by doublets (39, 18.8%; 21 ven+dex and 18 ven+non-dex doublet), quads (38, 18.3%), as a single agent (17, 8.2%) or in other combinations such as with multi-agent cytotoxic chemotherapy or in addition to quadruplet therapy (8, 3.9%). Most common first ven-containing regimens used were VenDd (34 pts), VenKd (31), VenVd (25), Vendex (21), VenDVd (13), VenDKd (7). Ven was used as part of ≥2 different regimens in 20 patients, in 10 of whom those regimens were non-consecutive. Median TTNT was 10.2 months (mo) in all comers, 12 mo in pts with t(11;14), 3.4 mo in pts without t(11;14) and 7.6 mo in pts with unknown t(11;14) status. Median OS was 27.6 mo in all comers, 30.5 mo in pts with t(11;14), 8.1 mo in pts without t(11;14) and 27.9 mo in pts with unknown t(11;14) status. Pts with t(11;14) receiving ven had a significantly longer TTNT than those without t(11;14) [median 12 mo vs 3.4 mo, HR 0.59, 95%CI 0.42-0.84, p=0.003]. and a significantly longer OS [median 30.5 mo vs 8.1 mo, HR 0.58, 95% CI 0.38 - 0.89, p=0.012]. Discussion: We evaluated US ven prescribing patterns in 208 pts with MM in the largest real world study of ven in MM to date. While it was mostly used in pts with t(11;14) (71%), there was occasional use in pts without t(11;14), and it was used in a wide variety of combination regimens. Ven achieved meaningful TTNT in some patients and both TTNT and OS were greater in pts with t(11;14) than those without. This suggest that despite mixed data from clinical trials, clinicians are using ven for MM patients in practice and further data is required to optimize its use and understand its best combination treatment partners in MM.

Introduction: The outcomes of patients diagnosed with multiple myeloma (MM) have improved significantly with the advent of immunomodulatory drugs, proteasome inhibitors, anti-CD38 monoclonal antibodies, and high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT). Further advancements include immune-based approaches such as bispecific antibodies and chimeric antigen T-cell receptor therapy. However, most of these therapies are predominantly available in developed countries, with limited access globally. Our study aimed to ascertain the landscape of interventions being used in developing countries for MM, and their efficacy. Methods: A comprehensive search was conducted on March 13, 2023, using Embase via Elsevier, PubMed, Scopus, CINAHL, and CENTRAL. We included retrospective and prospective studies that were evaluating interventions for patients with plasma cell dycrasias in the developing country setting. We defined developing country according to the United Nations. For comparative studies, we calculated the risk ratio (RR) for binary outcomes such as overall survival (OS) and progression-free survival (PFS), estimating 95% confidence intervals (CIs) and pooling data using the DerSimonian and Laird random effects model. For non-comparative studies, we calculated overall event rates and transformed them using the Freeman-Tukey double arcsine method, then pooled the data using the same random effects model. All statistical analyses were conducted using R version 4.4.0. Results: A total of 448 records were identified, of which 37 studies met the eligibility criteria. The overall risk of bias was moderate. The included studies evaluated induction treatments using doublet and triplet-based therapies, including TD (thalidomide and dexamethasone), VD (bortezomib and dexamethasone), MP (melphalan and prednisone), CTD (cyclophosphamide, thalidomide, and dexamethasone), VTD (bortezomib, thalidomide, and dexamethasone), and VAD (vincristine, doxorubicin, and dexamethasone). Lenalidomide was notably absent in the induction regimens apart from one non-comparative study reported on the use of RVD (lenalidomide, bortezomib, and dexamethasone). Studies were divided into comparative (n=11) and non-comparative groups (n=26). Comparative studies included: HSCT vs. no HSCT, induction with alkylating agents vs. thalidomide or bortezomib, and thalidomide vs. bortezomib or CTD vs. VTD. Lenalidomide use in comparative studies was reported only post-HSCT, compared against observation. High-dose chemotherapy followed by autologous HSCT was commonly utilized, with most studies reporting outcomes for patients who underwent autologous HSCT. Two comparative studies from 2 countries (Colombia and India) compared the overall survival of autologous HSCT in patients diagnosed with MM (N=130) vs. patients who never received ASCT (N=293). At one year of follow-up, there was no significant difference in overall survival (OS) between patients who received autologous HSCT and those who did not (relative risk [RR] = 1.11, 95% CI: 0.93-1.33). However, a significant improvement in OS was observed at five years post-autologous HSCT (RR = 1.59, 95% CI: 1.38-1.82). The pooled estimate for five-year OS in single-arm studies, which included nine cohorts from seven countries (Pakistan, India, Colombia, Algeria, Sri Lanka, Mexico, and Peru), was 62% (95% CI: 48-75). Progression-free survival (PFS) at five years post-HSCT, reported in three cohorts from three countries (India, Algeria, and Mexico), was 44% (95% CI: 23-67). Conclusions: Most of the recent advancements in MM treatment, including immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies, were not widely utilized globally, particularly in developing countries. This limited access is a major issue, hindering the potential improvement in patient outcomes. However, high-dose chemotherapy followed by autologous HSCT showed good outcomes, demonstrating a significant survival advantage at five years follow-up. The lack of survival benefits at one-year post-HSCT may be due to high toxicity and/or limited resources to manage side effects in developing countries. Addressing the disparity in treatment availability is crucial for improving MM management and patient survival globally.

Abstract Background Smoldering multiple myeloma (SMM), an asymptomatic precursor of multiple myeloma (MM), carries a variable risk of progression to MM. There is little consensus on the efficacy or optimal timing of treatment in SMM. We systematically reviewed the landscape of all clinical trials in SMM. We compared the efficacy of treatment regimens studied in SMM to results from these regimens when used in newly diagnosed multiple myeloma (NDMM), to determine whether the data suggest deeper responses in SMM versus NDMM. Methods All prospective interventional clinical trials for SMM, including published studies, meeting abstracts, and unpublished trials listed on ClinicalTrials.gov up to April 1, 2023, were identified. Trial-related variables were captured, including treatment strategy and efficacy results. Relevant clinical endpoints were defined as overall survival (OS) and quality of life. Results Among 45 SMM trials identified, 38 (84.4%) assessed active myeloma drugs, while 7 (15.6%) studied bone-modifying agents alone. Of 18 randomized trials in SMM, only one (5.6%) had a primary endpoint of OS; the most common primary endpoint was progression-free survival (n = 7, 38.9%). Among 32 SMM trials with available results, 9 (28.1%) met their prespecified primary endpoint, of which 5 were single-arm studies. Six treatment regimens were tested in both SMM and NDMM; 5 regimens yielded a lower rate of very good partial response rate or better (≥VGPR) in SMM compared to the corresponding NDMM trial (32% vs 63%, 43% vs 53%, 40% vs 63%, 86% vs 89%, 92% vs 95%, and 94% vs 87%, respectively). Conclusion In this systematic review of all prospective interventional clinical trials in SMM, we found significant variability in trial design, including randomization status, primary endpoints, and types of intervention used. Despite the statistical limitations, comparison of treatment regimens revealed no compelling evidence that the treatment is more effective when introduced early in SMM compared to NDMM.

Introduction: Extra copies of chromosome 1q21 (+1q: gain=3 copies, amp=4 or more copies) have been associated with worse outcomes for patients with multiple myeloma (MM). We performed a systematic review to evaluate current reporting of +1q, efficacy of existing regimens for +1q, and prognostic implications of +1q in MM randomized controlled trials (RCTs). Methods: We searched three databases for MM RCTs. Our inclusion criteria were all published MM RCTs from 2012-2022. Each MM RCT was analyzed for reported data on +1q. The following features specific to +1q were collected: +1q reported or not as a high-risk cytogenetic alteration, definition of gain1q with respect to percentage of cells with abnormality detected, documentation of distinction between Gain1q and Amp1q in analysis, prevalence of +1q in enrolled population, outcomes of patients [Overall Survival (OS) and Progression Free Survival (PFS)] in patients with +1q in the experimental versus control arm and in patients with and without +1q. Results: A total of 124 trials were included. Among these trials, 28 (23%) studies reported data on +1q, including 26 studies that reported data in the primary manuscript and two studies that reported in separate publication. These trials reported a total of 2692 patients with +1q which represented 25% of all the patients enrolled. Out of 28 trials, three trials (11%) specified the criteria for categorizing patients as +1q (example in IKEMA and IFM-99: the presence of at least three copies in at least 30% of analyzed plasma cells was required). Only four trials (14%) reported survival data on gain and amp separately and the remaining 24 (86%) studies reported for gain or did not specify gain vs amp. Amongst the trials that reported +1q, 22 (79%) considered this to be a high-risk cytogenetic abnormality. Amongst trials that met primary endpoint showing improvement in PFS and clearly reported on +1q, the following drugs also improved PFS for those with +1q (when comparing hazard ratio (HR) for intervention versus control arm in the +1q subgroup): lenalidomide (len) maintenance in Myeloma XI, selinexor in BOSTON, and isatuximab in IKEMA and ICARIA. Several trials met their endpoint and showed improvement in PFS in the +1q cohort in same direction as overall study results but had confidence intervals for +1q subgroup that crossed 1. These included addition of carfilzomib in Myeloma XI, addition of carfilzomib vs bortezomib to len and dex for +1q (but not in Amp1q) in ENDURANCE, addition of elotuzumab to pomalidomide and dex, and bortezomib-based treatment before and after autologous stem cell transplantation (auto-SCT) vs no bortezomib (Table 2). Seven studies reported HR for patients with +1q in the trial (across both arms) compared to those without. In six studies (all studies other than SWOG1211), worse outcomes were seen with respect to OS and PFS for those with +1q versus without (Table 2). Important interventions for which subgroup analysis of +1q was not presented in trial results, and hence conclusions about the efficacy of the drugs specifically for patients with +1q cannot be ascertained included pomalidomide and ixazomib. Although subgroup analysis of various daratumumab trials has shown improvement for high-risk MM, the effect on gain1q was not isolated. Two recent contemporary trials that isolated effect of auto-SCT (DETERMINATION and IFM-2009) did not report +1q. However, in FORTE Trial, adverse prognostic implications of +1q were not seen in the arm receiving carfilzomib, len, dex and auto-SCT, indicating a possible role of carfilzomib and auto-SCT in ameliorating the adverse prognostic implications of +1q. Although len maintenance improved PFS after auto-SCT as maintenance in Myeloma XI overall for those with +1q, it did not appear to improve PFS for patients with isolated +1q (with no other concurrent genetic abnormalities). Conclusion: This systematic review of MM RCTs finds considerable heterogeneity in the reporting of +1q abnormalities in the literature, and +1q to be inconsistently classified as a poor prognostic factor in subgroup analysis of randomized myeloma trials. Most interventions that have shown to be successful in randomized trials and have clearly reported on the +1q subgroup have shown concordant direction of results and benefit of the applied intervention in the +1q subgroup. A more standardized approach to reporting of this abnormality is needed.

CONCLUSION The most widely used multiple myeloma (MM) staging system, the Revised International Staging System (R-ISS), is based on lactate dehydrogenase (LDH), albumin, high-risk genetic markers by FISH, and beta-2 microglobulin (B2M). However, it does not account for additional risk impacted by multiple genetic abnormalities, or the risk imparted by presence of gain of chromosome 1q, and most patients are staged as R-ISS Stage 2. Two new staging systems, the Mayo Additive Staging System (MASS), and the Second Revision of the International Staging System (R2-ISS) have been recently proposed. A comparison of the performance of these two systems has not previously been done. We aimed to externally demonstrate the application of these staging systems and compare their performances in a large, contemporary cohort of patients in the United States. We conducted a retrospective cohort study using the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database, comprising de-identified patient-level structured and unstructured data, curated via technology-enabled abstraction and originating from approximately 280 US cancer clinics (~800 sites of care). The study included newly diagnosed MM patients initiating treatment between January 1, 2016 and October 1, 2022. We used the Kaplan-Meier method to evaluate real-world overall survival (rwOS) and patients were followed from first-line treatment initiation (index date) until the first of death, end of the study period or last recorded activity. The log-rank test to compare survival curves across derived stages. Multivariable analysis was conducted using stratified Cox models to account for non-proportional hazards by age with covariate adjustment for race/ethnicity, sex, practice type (academic or community) and diagnosis year (2016-2019 vs 2020-2022). Discrimination and calibration were evaluated in crude models using Harrell's c-index and the Hosmer-Lemeshow goodness-of-fit test, respectively. There were 497 patients with MM included. Patient characteristics are listed in Panel A. The distribution of patients across R-ISS stages were as follows, 24%, 63% and 13% for Stage 1, 2 and 3 respectively. rwOS differed across R-ISS stage (log-rank p = 0.0006) and the median OS (OS) was not reached (NR), 63, and 37 months for R-ISS stage 1, 2, and 3, respectively. 34%, 35% and 31% for MASS 1, 2, and 3, respectively. The corresponding survival curves were significantly different (p < 0.0001), with associated mOS of 77, 61 and 45 months for MASS stages 1, 2, and 3, respectively. R2-ISS includes four risk categories (stages I-IV) and in our cohort, 20% (n = 100) were stage I (low), 126 (25%) were stage II (low-intermediate), 229 (46%) were stage III (intermediate), and 42 (9%) were stage IV (high). Survival across stages were significantly different (p<0.0001), though the survival curves for low and low-intermediate, and intermediate-high and high, were clustered, suggesting comparable outcomes in stages I-II and stages III-IV. mOS for R2-ISS stages I, II, III, and IV was NR, 69, 50 and 51 months respectively (Panel B). In fully adjusted analyses, as compared to MASS I, the hazards of death were 2.0 (95% CI 1.3-3.2) for MASS II and 2.7 (1.7-4.2) for MASS III. The hazards of death were similar for R2-ISS low and low-int (HR for low-int vs low: 1.2 [0.7, 2.3]). As compared to R2-ISS low, the hazards of death were similarly higher for int-high and high (HRs: 2.4 [1.4, 4.1] and 2.6 [1.3, 5.2], respectively). Discrimination and calibration were similar across all staging systems (c = 0.6, and Hosmer-Lemeshow p>0.05 for all three staging systems). Application of contemporary MM staging systems in a large cohort of US patients shows that they are prognostic for OS in MM. MASS demonstrated a greater separation for OS across stages, whereas R2-ISS intermediate-high and high were largely overlapping. Although our results demonstrate similar accuracy and reliability of MASS and R2-ISS, the discrimination of patients across different stages seen with the newer staging systems, as opposed to R-ISS, calls for greater use of these newer staging systems in routine clinical practice.

e24078 Background: The addition of anti-CD38 mAbs, daratumumab and isatuximab, to standard anti-myeloma regimens have drawn scrutiny towards long-term safety concerns, including the risk of SPMs. ICARIA-MM study reported SPMs in 3.9% patients (pts.) in the Isatuximab, pomalidomide and dexamethasone (Isa-Pd) arm compared to 0.7% in the Pd arm. We hypothesized that exposure to anti-CD38 mAbs could potentially increase risk of SPMs due to prolonged immunosuppression. An assessment of this association is warranted, given the improved life expectancy and growing prevalence of pts. with MM. Methods: We performed a meta-analysis on data obtained from RCTs published between January 2005 and April 2022 that compared anti-CD38 mAb-based regimens to other standard anti-myeloma regimens (control) in pts. with newly diagnosed or relapsed/refractory (r/r) MM. Total number of SPMs (including categories) were extracted for pts. in both groups. Malignant melanomas were included under solid SPM category. Binary outcome data were analyzed using fixed-effect Peto method. Treatment effect estimates were expressed as odds ratio (OR) and 95% confidence interval (CI). I2 > 50% indicated substantial heterogeneity. Results: 10 RCTs involving 4980 pts. were included, with 2824 (57%) and 2156 (43%) pts. randomized to the anti-CD38 mAb and control arms, respectively (Table). Overall, 191 and 112 SPMs were reported in the anti-CD38 mAb and control arms, respectively. At a median follow-up of 35.3 months, anti-CD38 mAb exposure was associated with an increased risk of developing SPMs compared to control (6.8% vs. 5.2%; OR: 1.53 [95% CI: 1.20-1.95]; I2= 0%). Non-melanoma cutaneous cancers were the most common, and higher in the anti-CD38 mAb vs. control arms (92 versus 47; OR: 1.77 [95% CI: 1.25-2.51]; I2= 0%). The increase in solid cancers (including melanoma) (OR: 1.28 [95% CI: 0.85-1.95]) and hematologic SPMs (OR: 1.86; [95% CI: 0.81-4.27] was not significant. On sensitivity analysis, the total number of SPMs were higher in the anti-CD38 mAb arm vs. control arm, regardless of the presence of immunomodulatory drugs in combination regimen. Conclusions: This meta-analysis shows an increased risk of SPMs in pts. with MM exposed to daratumumab or isatuximab, particularly that of non-invasive cutaneous tumors. This association should be further investigated in real-world settings using large databases. [Table: see text]