Chakraborty, Rajshekhar

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.

Background: Despite substantial improvements in early mortality (EM) for patients with systemic light chain amyloidosis (AL), rates remained high in the bortezomib-era, at approximately 25% (Muchtar et al. Blood. 2017). However, the therapeutic landscape in AL amyloidosis has changed with the ANDROMEDA trial, which led to the approval of daratumumab in combination with bortezomib, cyclophosphamide, and dexamethasone (Dara-VCd) in the frontline setting. The incidence and predictors of EM in the context of daratumumab-based frontline therapy have not been studied. Methods: We performed an international multicenter retrospective cohort study of all consecutive patients with newly diagnosed AL treated with frontline Dara-VCd or Dara-Vd, and followed until 12/31/2023. EM was defined as death from any cause within 6 months of treatment initiation. Our primary objective was to identify the rate and significant predictors of EM. Univariate logistic regression was used to identify significant predictors of EM, which were then included in a multivariate logistic regression model. The receiver operator characteristic (ROC) analysis was used to determine the best threshold values that discriminated EM rates for the following continuous variables: age, dFLC (involved-uninvolved), eGFR, NT-proBNP, albumin, and high-sensitivity Troponin-T (hs-TnT). Other variables tested in univariate analysis were the following: ECOG performance status, NYHA functional class, sex, race, light chain isotype, percent bone marrow plasma cells, status of the following cytogenetic abnormalities-t(11;14), +1q, hyperdiploidy, del(13q), high-risk translocations, and del(17p), and the number of organs involved (2 vs 1). To build the clinical prediction score, each variable was weighted according to the β coefficient (natural logarithm of odds ratio) obtained from the multivariable regression. The β coefficients were rounded to the nearest 0.5 and multiplied by 2 to obtain an even number. Results The study cohort included 335 AL patients treated with daratumumab-based frontline therapy (92.2% Dara-VCd, 7.8% Dara-Vd), with all surviving patients having at least 6 months of follow-up. The median age at diagnosis was 66.5 years (range, 59.4 - 71.3), and 6.7% (n = 22) were Non-Hispanic blacks. Median dFLC at diagnosis was 22.91 mg/dL (range, 0.2-1093.4), and median NT-proBNP was 2415 pg/mL (range, 13-70,000). Mayo 2004 stages IIIA/IIIB represented 44% of the total cohort, with 17% having ECOG ≥ 2 and 25.4% having NYHA Class III/IV symptoms. The cumulative incidence of EM was 10.7%, with the incidence in patients with Mayo 2004 stage I, II, IIIA, and IIIB being 0%, 8%, 12.5%, and 25% respectively. On univariate analysis with unadjusted odds ratio (OR), the following variables significantly predicted EM: Age ≥ 75 (OR=2.8, p=0.013) ECOG ≥ 2, (OR 4.9, p<0.001), NYHA Class ≥ III (OR=4.95, p<0.001), dFLC ≥9 mg/dL (OR, 10.18, p=0.023), eGFR <33 mL/min/1.73 m2 (OR=2.7, p=0.026), NT-proBNP >5276 pg/mL (OR=7.69, p <0.001), hs-TnT >70 ng/L (OR=5.88, p<0.001), and absence of t(11; 14) (OR=2.33, p=0.041). These variables were entered into multivariate regression, except for ECOG and NYHA, which were combined to create a single variable (values ranging from 0-8), and hs-TnT was dropped due to substantial missing data as centers used different troponin assays. NT-proBNP was rounded to 5300 pg/ml for ease of clinical application. Based on the multivariate analysis, the following scores were assigned to each variable: Age ≥75 (2.0), ECOG+NYHA (1.0 x combined score), NT-proBNP >5,300 pg/ml (2.0), and absence of t(11;14) (3.0). This led to a score ranging from 1-15, and two risk-groups: low-risk (score <9; 87.5%) and high-risk (score ≥9; 12.5%). The respective cumulative incidence of EM was 6.1% versus 50% (p<0.001). The c-index of the model was 0.725 (95% CI, 0.676-0.774). Conclusion: Using variables that are readily available in the clinic, we have developed a two-tiered risk-prediction model for EM in AL amyloidosis in the context of daratumumab-based frontline therapy. The model needs to be externally validated in an independent dataset.

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.

Abstract We performed an international retrospective study on 283 patients with light chain (AL) amyloidosis to investigate the prognostic impact of cytogenetic abnormalities by fluorescence in situ hybridization, when treated with frontline daratumumab–based therapy. The cytogenetic subgroups of interest were t(11;14), gain/amp(1q) (hereafter, +1q), hyperdiploidy, deletion(13q), del(17p), and myeloma high-risk (HR) translocations (t[4;14], t[14;16], or t[14;20]). The end points of interest were rate of hematologic complete response (heme-CR), very good partial response (VGPR) or better, and hematologic event-free survival (heme-EFS). The incidence of abnormalities was as follows: t(11;14), 53.4%; deletion (13q), 28.9%; +1q, 22.3%; hyperdiploidy, 19.4%; HR translocations, 6.6%; and deletion(17p), 4.5%. The heme-CR rate by cytogenetic subgroups were as follows: t(11;14) vs no t(11;14), 45.2% vs 41.8% (P=0.597); del(13q) vs no del(13q), 46.8% vs 42.8% (P=0.594); +1q vs no +1q, 30.2% vs 47.9% (P=0.022); hyperdiploidy vs no hyperdiploidy, 39.5% vs 44.9% (P=0.541); HR translocations vs none, 45.5% vs 43.1% (P=0.877); and del(17p) vs no del(17p), 50.0% vs 42.9% (P=0.658), respectively. Similarly, +1q was the only subgroup with a significantly lower VGPR or better rate (64.2% vs 79.0%; P=0.033). At a median follow-up of 19.8 months, the median heme-EFS was 49.6 months (95% CI, 24.7-not reached [NR]), and the 2-year overall survival (OS) was 80.98% (95% CI, 75.6-85.4). The presence of +1q was significantly associated with worse heme-EFS on multivariate analysis (HR 2.06, 95% CI, 1.14-3.71; P=0.017). Notably, there was no adverse prognostic impact of t(11;14) on heme-EFS or OS. In conclusion, +1q is associated with worse outcome in the daratumumab-era. Clinical trials testing novel frontline immunotherapies should be enriched in +1q to further improve outcomes in this subgroup.

7533 Background: Maintenance treatment (rx) with lenalidomide (R) improves overall survival (OS) in multiple myeloma (MM). We report a retrospective cohort of patients (pts) with second primary B-cell acute lymphoblastic leukemia (ALL) diagnosed after R-rx for MM. Methods: We included pts who were exposed to at least 1 yr of R for MM rx prior to ALL dx. After approval by institutional review board, data were collected by chart review at participating centers using Redcap. OS was the primary endpoint. We used BlueSky statistics v10.3.1 for analysis. Results: Analysis included 33 ALL pts diagnosed from 2014-2022 at 7 sites. 52% pts were female. Median follow up was 9.6 yrs (95%CI,7.6-11.8) from MM dx and 3.2 yrs (CI, 2.1-4.7) from ALL dx. Pt characteristics at MM dx are given in Table. Induction rx included: proteasome inhibitor (PI) +immunomodulatory drug (IMiD) (43%), PI+alkylator (24%), IMiD (18%) & others (15%). 50% pts received autologous stem cell transplantation (ASCT). Median OS from MM dx was 11.2 yrs (CI, 8.9-NR). Time from MM dx and initial R rx to ALL dx were 5.0 yrs (range, 2.4-18.5) and 4.4 yrs (2.2-10.6) respectively. Median duration of R exposure before ALL dx was 3.8 yrs (1.6-10.4). Table shows characteristics of pts at B-ALL dx and genetic classification based on karyotyping (n=30), ALL FISH (n=28), chromosomal microarray (n=5) and next-generation sequencing (n=5). 31 pts received ALL-directed rx while 1 pt was initially managed with close observation as the pt attained CR on stopping R ( Lakshman et al; ASH 2019 ). Rx was unknown in 1 pt. Initial rx included: hyper-CVAD+/- rituximab- 49%, pediatric inspired protocols-18%, reduced intensity rx for frail pts- 21% and others- 12%. Response to first line rx were: CR- 56%, CRi- 28%, induction failure- 16%. 32% pts attained measurable residual disease (MRD) negativity. 48% pts underwent SCT for ALL. 14 pts died during follow up. 3-yr OS from ALL-dx was 50% (CI, 33%-76%). 3 pts required rx for MM after ALL diagnosis (2 had allo-SCT for ALL before MM relapse). Conclusions: Most pts had standard risk MM and were exposed to R for several years prior to dx of B-ALL, characterized by high incidence of hypodiploid karyotype; IKZF1 loss and TP53 deletions/mutations were detected in a subset of pts.MRD-adapted timely discontinuation of R in standard risk MM may decrease risk of second primary ALL. [Table: see text]

Introduction: High dose chemotherapy and autologous stem cell transplantation (ASCT) is one of the most effective therapies in light chain (AL) amyloidosis. It is associated with a high hematologic response rate and leads to durable remissions. High dose melphalan is the most frequently used conditioning chemotherapy, as has been used in multiple myeloma (MM). Melphalan dose is based on renal function, age, degree of cardiac involvement and patients' frailty and is predictive of outcomes. While studies that assessed the conditioning schedule have been conducted in MM, with variable results, no such studies were done in AL amyloidosis. Methods: In this retrospective study, we explored the impact of the conditioning schedule on post-transplant outcomes in a large multicenter study. Patients with AL amyloidosis who underwent ASCT for the primary diagnosis of AL amyloidosis between January 1, 2003, and December 31, 2020, were included in this study. Results: One thousand seven hundred and eighteen (n=1718) patients from 9 centers are included. The median age was 58 years, and 61% were male. Most patients had one (43%) or two (33%) involved organs, with the most involved organs were the kidneys (69%) followed by the heart (52%). Induction therapy was given to 52% of patients. The conditioning regimen was almost exclusively melphalan (99.2%), with 65% receiving full dose melphalan (≥170 mg/m 2). Melphalan was given over two days in most patients (80%). A rest day between conditioning and stem cell infusion was provided in 53% of patients, mostly in those who received melphalan on a single day rather than over 2 days (87% vs 44%, P<0.001). Post-transplant hematologic response was available for 1569 patients (91% of patients) and were assessed from baseline. Complete response (CR) and very good partial responses (VGPR) were achieved post-ASCT in 33.7% of patients each. Low dFLC-partial response (PR) was achieved in 2.7% and PR in 18% of patients. Altogether, satisfactory post-ASCT response (CR, VGPR, or low-dFLC PR combined) was achieved in 70% of patients. Compared to no induction, less than a PR to induction was associated with a lower probability of achieving satisfactory post-ASCT response, while PR or better to induction had higher chances of satisfactory post-ASCT response (65% vs 46% vs 84%, P<0.001). A single day of melphalan conditioning was associated with a higher probability of satisfactory post-ASCT response compared to two days of conditioning (82% vs 67%, P<0.001). Omitting a day of rest between conditioning and stem cell infusion was also associated with higher satisfactory post-ASCT response compared to having a rest day (76% vs 65%, P<0.001). The Table lists other predictors for a post-ASCT satisfactory hematologic response. In a nominal multivariate logistic regression analysis, independent predictors for higher post-ASCT satisfactory hematological response rate included: PR or better to induction therapy, female gender, kappa light chain isotype, lower dFLC at baseline, and kidney and liver involvement. In addition, full dose melphalan, conditioning given over a single day and having no rest day between conditioning and stem cell infusion were also associated with a higher likelihood of satisfactory post-ASCT response. Post-ASCT hematologic CR rate was higher in those receiving full dose conditioning (36% vs 28%, P<0.001), in those having no rest day (40% vs 28%, P<0.001) but not in those who received one day of conditioning versus two days (35% vs 33%, P=0.5). The rate of ICU admission was higher in those receiving no day rest (17.7% vs 12.6%), P=0.003) and among those who received reduced dose melphalan (18.1% vs 13.3%, P=0.008) but not based on number of conditioning days (P=0.56). Day 100 mortality was significantly higher in the no rest day group (5.6% vs 3.2%, P=0.01) and among those receiving reduced dose melphalan (6.8% vs 3.1%, P=0.004) compared to their counterparts, but not based on the number of days of conditioning (P=0.89). The median follow-up in the entire cohort was 104 months (95% CI 98-110). In a multivariate analysis for overall survival (OS), the conditioning dose but not the conditioning schedule was independently associated with OS. Conclusions: This study is the first to demonstrate the effect of melphalan conditioning schedule on post-transplant response. This study supports a single day melphalan conditioning in AL amyloidosis to improve post-ASCT response.

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.

Introduction The optimal maintenance regimen by prognostic categories remains unclear in newly diagnosed multiple myeloma (NDMM) patients undergoing autologous stem cell transplant (ASCT). Therefore, we conducted a systematic review and network meta-analysis (NMA) to assess the comparative effectiveness of novel agents by different prognostic groups. Methods A comprehensive systematically structured literature search was conducted to identify phase II/III randomized controlled trials (RCTs) evaluating maintenance therapies in post-transplant NDMM patients and reporting data by subgroups including but not limited to international staging system (ISS), and cytogenetic risk. High cytogenetic risk (HCR) and standard cytogenetic risk (SCR) were defined in accordance with the eligible trials. Main outcomes of interest were overall survival (OS) and progression-free survival (PFS). Precomputed hazard ratios (HR) with 95% CI were pooled using an inverse variance approach. A frequentist network meta-analysis was conducted. P-score (PS) were used to assess relative rankings of the treatments and were interpreted in congruency with pairwise estimates. Higher ranks indicated better efficacy. Results This NMA included six RCTs with 4119 participants and six unique treatment arms. In patients with SCR, the combination of carfilzomib, lenalidomide, and dexamethasone (KRd) improved PFS when compared to lenalidomide (Len; HR: 0.44; 95% CI: 0.24-0.81), daratumumab (Dara; 0.27; 0.13-0.55), ixazomib (Ixa; 0.26; 0.13-0.53), and no maintenance therapy (0.17; 0.09-0.32). Similarly, KR improved PFS compared to lenalidomide (Len; 0.56; 0.33-0.96), daratumumab (Dara; 0.34; 0.18-0.65), ixazomib (Ixa; 0.33; 0.17-0.63), and no maintenance therapy (0.21; 0.12-0.38). There was no statistically significant difference between KRd and KR. KRd was ranked as potentially the most efficacious treatment (rank 1) followed by KR (rank 2), Len (rank 3), Dara (rank 4), and Ixa (rank 5) for improving PFS in SCR. In patients with HCR, KRd (0.35; 0.14-0.92), KR (0.32; 0.15-0.67), Dara (0.43; 0.25-0.73), and Len (0.48; 0.35-0.64) improved PFS when compared to no maintenance therapy. No other significant differences were observed in HCR patients. KR was ranked as potentially the most efficacious treatment followed by KRd (rank 2), Dara (rank 3), Len (rank 5), and Ixa (rank 5) for PFS in HCR patients. In patients with ISS-I/II, KRd and KR improved PFS when compared to Dara (KRd vs. Dara - 0.32; 0.16-0.65, KR vs Dara - 0.50; 0.26-0.94), and Ixa (KRd vs. Ixa - 0.22; 0.11-0.45, KR vs Ixa - 0.35; 0.18-0.65). KRd, not KR, improved PFS when compared to Len (0.41; 0.22-0.76). Rankings were consistent with those observed in SCR patients. No significant differences were observed among mixed treatment comparisons for ISS-III patients. Limited number of trials reporting OS precluded formal assessment. Conclusions The current data suggest that KRd and KR may delay disease progression regardless of risk category. Overall survival data is still emerging and, if consistent, may influence clinical practice. We maintain a living meta-analysis to incorporate new evidence constantly.

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]