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Patients with multiple myeloma (MM) have up to a 20-fold increased risk of venous thromboembolism (VTE) compared with the general population, with most events occurring within the first 6 months of diagnosis. Treatment with immunomodulatory drugs (IMiDs) is a strong risk factor for VTE in MM. In a meta-analysis of 2 large, randomized trials comparing anticoagulant thromboprophylaxis vs placebo in ambulatory patients with cancer at high risk of VTE based on a validated risk score, the risk of VTE decreased without increasing the risk of major bleeding. However, few patients with MM participated in these trials (1.1%). Initial guidance for risk-stratifying patients with MM resulted in persistent rates of VTE >10% and highlighted the need for improved VTE risk stratification in patients with MM. Three validated risk scores are now available to quantify risk of VTE in patients with MM: SAVED, IMPEDE VTE, and PRISM scores. Using best available data, thromboprophylaxis should be strongly considered in patients with MM assessed as high risk for VTE, especially newly diagnosed patients receiving IMiD-based combination therapies. However, prospective studies are needed to further validate available models and identify the optimal thromboprophylactic agent for each VTE risk category., (Copyright © 2022 by The American Society of Hematology.)

Purpose of Review: Advances in multiple myeloma therapies have greatly improved outcomes for patients living with the disease, although to date there is yet to be a cure. Cellular and immunotherapies, approved or in development, offer the promise of significantly advancing toward that possibility. The aim of this review is to provide a synopsis and commentary on the current and future states of bispecific agents aimed at harnessing the antineoplastic potential of T-cells in treating and eradicating myeloma., Recent Findings: Numerous bispecific agents are in clinical development with some on the precipice of regulatory approval. While BCMA remains the principal target, some agents are directed at novel targets such as GPRC5D and FcRH5. The constructs vary in design and pharmacokinetics which has dosing and administration implications. The toxicity profiles of these agents generally reflect that of other immune therapies, including cytokine release syndrome and rarely neurotoxicity, although immunosuppression has also led to elevated infection risks. However, the toxicities are generally manageable and offset by unprecedented efficacy seen in such heavily pretreated cohorts. Bispecific agents are poised to significantly alter the treatment paradigms for myeloma. They provide a convenient "off-the-shelf" platform with often deep and durable responses. Toxicities are often limited in duration and severity. In the early-phase trials, many patients have been able to remain on treatment for extended periods, even among those with high-risk features. Upcoming trials are likely to explore earlier implementation of these agents in order to offer this therapeutic opportunity to broader cohorts., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The IMPEDE VTE score has recently emerged as a novel risk prediction tool for venous thromboembolism (VTE) in multiple myeloma (MM). We retrospectively reviewed 839 patients with newly diagnosed MM between 2010 and 2015 at Cleveland Clinic and included 575 patients in final analysis to validate this score. The c-statistic of the IMPEDE VTE score to predict VTE within 6 months of treatment start was 0·68 (95% CI: 0·61-0·75). The 6-month cumulative incidence of VTE was 5·0% (95% CI: 2·1-7·9) in the low risk group, compared to 12·6% (95% CI: 8·9-16·4%) and 24·1% (95% CI: 12·2-36·1) in the intermediate and high risk groups (P < 0·001 for both). In addition, a higher proportion of patients in the VTE cohort had ECOG performance status of ≥2 as compared to the no VTE cohort (33% vs. 16%, P = 0·001). Other MM characteristics such as stage, immunoglobulin subtype, and cytogenetics were not predictors of VTE. In summary, we have validated the IMPEDE VTE score in our patient cohort and our findings suggest that it can be utilized as a VTE risk stratification tool in prospective studies looking into investigating VTE prophylaxis strategies in MM patients., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Lenalidomide (LEN) is commonly used as part of induction therapy in transplant-eligible patients with multiple myeloma. However, LEN use is associated with increased chance of peripheral blood stem cell (PBSC) collection failure. This has led to early collection in patients receiving induction with LEN-containing regimens, and the use of mobilization agents such as plerixafor. Despite potential significant clinical implications, the impact of LEN on autograft composition is unclear. We examined the effect of LEN exposure on hematopoietic progenitors in collected grafts of 94 patients who underwent autologous stem cell transplantation (HSCT) at our institution. LEN exposure resulted in lower myeloid and erythroid progenitors in collected grafts, but this effect was not seen in patients who received plerixafor-based mobilization. Exposure to LEN did not affect PBSC collection, possibly due to high plerixafor use in our cohort (70%). LEN changes the composition of PBSC grafts; the clinical implication of this finding is unknown.

High-dose melphalan (HDM) followed by autologous hematopoietic cell transplantation (auto-HCT) remains the standard-of-care therapy for multiple myeloma (MM) even with the availability of proteasome inhibitors and immunomodulatory drugs. Gastrointestinal (GI) toxicity is the main cause of morbidity after HDM. Amifostine, a cytoprotective agent, may reduce HDM-associated GI toxicity. We conducted a case control study comparing HDM + auto-HCT with or without amifostine for MM patients. One hundred and seven patients treated at University Hospitals Cleveland Medical Center who received pre-transplant amifostine were compared to 114 patients treated at MD Anderson Cancer Center without use of this agent. Amifostine 740 mg/m 2 was administered as a bolus infusion at 24 h and 15 min before HDM. Patients' characteristics were similar in both the groups. Amifostine therapy was well tolerated without any significant adverse effects. Grade II or greater oral mucositis (27.1% vs 47.4%; p = .002), nausea (31.8% vs. 86.0%; p = .0001), vomiting (18.7% vs. 52.6%; p = .0001) and diarrhea (56.1% vs. 72.7%; p = .006) occurred less frequently in the amifostine-treated group. There was no discernable effect of amifostine on engraftment, progression-free or overall survival. Our results indicate that amifostine decreases GI toxicity while preserving anti-myeloma efficacy of HDM and auto-HCT.

Purpose: Drug development in oncology is resource intensive, time consuming, and frequently unsuccessful. Here, we hypothesized that therapeutic benefit of published phase I studies of antimyeloma investigational agents was associated with advancement to phase II and future regulatory approval., Patients and Methods: Seventy four phase I trials that treated patients with multiple myeloma (n = 2,408) conducted from 2004 to 2015 were analyzed to assess drug safety, efficacy, phase advancement, and regulatory approval., Results: The median overall response rate (ORR) for all single-agent trials evaluated was 13.2%. However, the ORR in trials that advanced to phase II was 19%, whereas it was only 4% in trials that failed to advance. The median ORR was 23% for trials testing agents that were ultimately approved by the US Food and Drug Administration compared with only 8% for trials testing agents that were not approved (hazard ratio, 2.21; 95% CI, 2.01 to 2.61; P = .012). Importantly, the absolute number of phase I trials in multiple myeloma, but not the success rate, significantly increased over the period studied. The proportion of industry-sponsored trials also steadily increased over that same period. The ratio of initial dose to maximum tolerated dose was 0.29, suggesting that many patients were undertreated., Conclusion: Investigational agents with higher ORRs in phase I trials were more likely to advance to phase II trials and achieve US Food and Drug Administration approval. Our results suggest that designing phase I trials to maximize the antimyeloma efficacy of a given compound may lead to more successful and cost-effective drug development.

Hematopoietic cell transplantation (HCT)-specific comorbidity index (Sorror et al. Blood 2005) is highly recommended by National Marrow Donor Program as a risk assessment tool before HCT. Prior malignancies has one of the highest weighted score of 3 in this risk model. The isolated prognostic value of prior malignancies has not been evaluated in Multiple Myeloma (MM) patients (pts) who underwent autologous HCT (AHCT) in large databases. We hereby used national cancer database (NCDB) to evaluate this. NCDB covers more than 70% of newly diagnosed cancer pts in the U.S. We reviewed NCDB, using ICD-O code of 9732, to identify pts who were diagnosed with MM between 2010 and 2014, underwent systemic treatment within 90 days of the diagnosis, and subsequently AHCT. Prior malignancy was not incorporated into Charlson comorbidity index at NCDB and reported separately. Average annual transplant volume of a cancer center for MM is calculated among pts who met the inclusion criteria. Overall survival (OS) was estimated by the Kaplan-Meier method and compared with the log-rank test. Cox hazard analysis was performed to identify independent predictors of OS. We reviewed 12,427 pts and included 4358 pts who met inclusion criteria. Of which, 2481 (57%) were male, 693 (16%) were black, and 412 (10%) had at least one malignancies prior to MM. Median age at the diagnosis and time to initiation of systemic treatment after the diagnosis were 60 years (range: 25 – 80) and 17 days (range: 1 – 90), respectively. The Charlson comorbidity index was 0, 1, and ≥2 for 3646 (84%), 558 (13%), 154 (3%) pts, respectively. Durie-Salmon stage (DSS) at diagnosis was 1, 2, and 3 for 562 (13%), 1040 (24%), 2756 (63%) pts, respectively. Patient and treatment characteristics are compared between prior and no prior malignancy cohorts in table 1. Median follow-up time of pts was 36 months. Five-year OS of MM pts with and without prior malignancies was 75.6% (95% CI: 69.6 – 82.2) and 73.9% (95% CI: 71.6 – 76.2), respectively (p = 0.7) (Figure 1A). On multivariable analysis, each 10-year increase in age (HR 1.14, 95% CI: 1.02 – 1.26, p = 0.017), each 1 increase in comorbidity index (HR 1.24, 95% CI: 1.08 – 1.42, p = 0.002) and year of MM diagnosis (HR 1.15, 95% CI: 1.06 – 1.24, p = 0.0008), DSS 3 vs 1 or 2 (HR 1.38, 95% CI: 1.16 – 1.64, p = 0.0002), immunotherapy prior to AHCT (HR 0.72, 95% CI: 0.61 – 0.86, p = 0.0001), and each 10 increase in annual AHCT volume of a cancer center for MM (HR 0.98, 95% CI: 0.97 – 0.99, p = 0.016) were independent predictors of OS (Table 2). In this large cohort analysis, prior malignancy was not a predictor of OS for MM pts who underwent AHCT. The role of prior malignancies in defining "transplant eligibility" requires future evaluation and the weighted value of this item in the comorbidity index should be considered for downward revision. [ABSTRACT FROM AUTHOR]

Salvage autologous stem cell transplant (sASCT) may be associated with improved survival in multiple myeloma (MM) and is an option for patients with long time to relapse (TTR) after initial Autologous transplant (ASCT1). Due to potential mobilization failure after maintenance therapy (MT), adequate peripheral blood progenitor cells (PBPC) are frequently collected for later sASCT. Evaluate utilization of stored PBPC in MM. Provide a cost analysis of collecting and storing PBPC for sASCT. Determine utilization of sASCT in those eligible who had a prolonged TTR. We included MM patients who received ASCT1 at our institution between 2009 and 2016. Extra day of collection (EDC) was defined as additional collection of ≥2 × 106 cells/kg PBPC for a second transplant. TTR was calculated as months from ASCT1 to relapse. Eligibility for sASCT was defined as TTR ≥18 months without MT or ≥36 months on MT. Patients who underwent tandem transplant (tASCT) (defined as two transplants within 6 months) were excluded from relapse analysis. Patients with inadequate relapse data defined as death or lost to follow up (LTFU) at ≤36 months prior to relapse, or ≤6 months follow up after relapse were excluded. Costs were obtained from the institution charge master. Descriptive statistics were calculated for the final cost benefit analysis. 154 MM patients received ASCT1 from 2009-2016. Median age was 59 years. Median follow up was 151 months. Median TTR was 20 months. 58% were male. Ethnicity was 76% Caucasian and 24% Black. 62% had IgG MM subtype, 23% IgA MM and 15% other. Majority (95%) were European Cooperative Oncology Group (ECOG) 0 or 1. 13% had high risk cytogenetics. 53% received MT. 137(89%) had PBSC stored for sASCT. 3 were used for sASCT and 10 for tASCT. 124 (90.5%) did not use stored cells. 54 (39%) met collection targets for two transplants in single collection while 83 (%) required ≥1 EDC with cumulative 108 EDC. (Figure 1) Cumulative cost savings for plerixafor use, cell collection, processing, analysis and storage was estimated at $2,252,244. (Figure 2). Total 60 doses of plerixafor were used for EDC. (31 patients with 1EDC, 10 with 2EDC and 3 with 3 EDC). 97 patients were studied for relapses. 54 (77.5%) relapsed. 5 deaths and 8 LTFU occurred within ≤6 months of relapse. 42 patients were further analyzed. 25 of them met criteria for sASCT based on TTR and only 2 received sASCT.1 patient with sASCT did not have MT data and was excluded. (Figure 3) Only 25% (24/98) patients who underwent ASCT1 were eligible for sASCT. Only 2% (2/98) received sASCT. Collecting and storing PBPC for sASCT is associated with high cost, but overall utilization at our institution is low. Our findings should be compared against practices at other institutions to help develop guidelines for selection of subset of MM where this practice may be of higher value. [ABSTRACT FROM AUTHOR]