Transplantation For Multiple Myeloma Research Articles

Strategies to Optimize the Utilization of Stored Autologous Peripheral Blood Stem Cells for Second Transplantation in Multiple Myeloma

Introduction: Autologous stem cell transplantation (ASCT) is the standard of care and a mainstay in the management of eligible patients with multiple myeloma (MM) and remains relevant in the era of novel therapeutics. ASCT requires stem cell mobilization to collect ample stem cells to provide hematological recovery after myeloablative conditioning. Second ASCT (ASCT2) as salvage therapy in relapsed/refractory MM (RRMM) is a treatment option for patients who achieved disease control for 2 to 3 years after first ASCT (ASCT1). The reported difficulties in mobilizing and collecting additional stem cells following myeloablative ASCT1 have led to the currently adopted practice to collect and store adequate peripheral blood stem cells (PBSCs) for two transplants before ASCT. The preferred PBSC cell dose is 2 to 5 × 106 CD34+ cells per kilogram of recipient weight (CD34+ cells/kg) per transplant; however, with the influx of effective novel agents available for RRMM, the use of ASCT2 is declining. A retrospective cost utilization study showed that at a median follow-up of 3.5 years, only 3% of the cohort received ASCT2. The additional cost of collecting and storing these products is an average of 16,590 USD/patient. Given the limited use of salvage ASCT2, current practice of collecting PBSCs for two transplants should be re-evaluated and carefully selected case-by-case. We investigated potential strategies to reduce the financial burden of PBSC collection, processing, and storage by identifying a subgroup of patients who are less likely to receive an ASCT2, herein avoiding storing extra cells. Materials and Methods: With Institutional Review Board approval, we performed a retrospective descriptive analysis of all MM patients who underwent frontline ASCT from 1/1/2012 to 6/23/2022. We excluded patients who had planned tandem transplants and those who underwent a single ASCT and had all cells infused with no remaining stored cells. We classified all patients who collected a sufficient cell dose for ASCT1 and ASCT2 into two cohorts according to the number of ASCT received; those who received ASCT1 and those who received ASCT1 and ASCT2. Results: We report the descriptive statistics of eligible MM patients from a single stem cell transplant center. Over a median follow-up of 2.0 years, we report findings of 240 patients who collected sufficient PBSCs for ASCT1 and ASCT2. Patients’ median age at PBSC collection was 61 (range 32-77). We classified our cohort by gender, age, race, and average number of days for PBSC collection. We aim to collect a cell dose of 10 x 106 CD34+ cells/kg. Our cohort included more males than females (132/108) and a higher prevalence of African Americans (59%) than Caucasians. Our study showed that only 7% of patients underwent ASCT2 (17/240) with average time between ASCT1 and ASCT2 of 2.9 years. We noticed that 88% (15/17) of patients who received ASCT1 and ASCT2 were ≤ 61 years old at the time of ASCT1 and two patients (12%) were ≥ 70 years. Additionally, a higher proportion of patients utilizing ASCT2 in the youngest age groups is noticeable. Six of 30 patients under 50 years and three of seven patients under 40 years of age (20% and 43%, respectively) underwent ASCT2. The data highlights that utilization of ASCT2 is less common in the elderly population; hence considering PBSC collection for one transplant among the elderly would be a cost-effective strategy. Most stem cell transplant centers inherited a strategy to collect PBSC 10 x 106 CD34+ cells/kg. We noticed that 102 patients required >1 day of PBSC collection to meet the collection goal. Of these patients, 35% were age 65 or older. If we were to change practice and consider PBSC collection for one transplant among the elderly, we could have reduced the number of collection days by 25 and reduced the associated costs of collection, processing, storage, and staffing, as well as space requirements for storage. Conclusion: The utilization of ASCT2 in MM patients is decreasing with the influx of novel therapeutics. Potential strategies are needed to change the practice and reduce the additional financial burden of excess stem cell collection and storage. We suggest that elderly MM patients be considered for PBSC collections for a single transplant. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Multiple Myeloma Transplant: Examining the Intersection of Access, Age and Race

Introduction: Autologous Stem Cell Transplant (ASCT) is standard frontline therapy for patients newly diagnosed with Multiple myeloma (MM). Receipt of ASCT is influenced by factors such as race, age, socioeconomic status (SES), and geographic location. The degree to which these factors collectively influence MM transplant access and jointly impact overall survival is not well established. Our study aimed to assess the impact of age, race, rurality, and area-level SES on ASCT transplant receipt and overall survival following MM diagnosis. Methods: An IRB approved retrospective analysis was conducted of adult MM patients diagnosed in 1992-2020 from The Ohio State University Comprehensive Cancer Center (OSUCCC). Patients included were previously consented to the Buckeye Surveillance, Contact, and Research for Multiple Myeloma and Amyloidosis Protocol (NCT01408225); a registry database for patients with suspected plasma cell dyscrasia pursuing care at OSUCCC; and the Bone Marrow Transplant (BMT) registry, an internal database compiled of demographic and transplant-specific data. Area-level SES was measured by census tract-level (2008-2017) Yost indices (a composite of education-, income-, and occupation-related variables.)1, 2 Rural-urban status was measured by census tract-level 2010 Rural-Urban Commuting Area (RUCA) codes.3 Yost were categorized into quartiles where higher quartiles represented higher SES, and RUCA codes were grouped by metropolitan (Primary RUCA 1-3) v. non-metropolitan (Primary RUCA 4-10). Poisson regression models with robust variance were used to evaluate the associations between patient characteristics and receipt of transplant. Overall survival (OS) from diagnosis was analyzed and median OS was estimated using the Kaplan-Meier method. Cox proportional hazard models were used to estimate the hazard ratios of risk of death. Results: In the combined MM registries, a total of 1,799 MM patients were included in this analysis, 1,169 (65%) received a transplant. MM patients median age at diagnosis was 61 (17-87), race was self-identified as White (85.6%), Black (13.1%) other (1.3%). In multivariable analysis, patients who were 65 years or older were less likely to undergo a transplant (age 65-70: IRR=0.80, 95% CI: 0.72-0.89, p<0.001; age > 70: IRR 0.23, 95% CI: 0.18-0.30, p<0.001). When assessed by race, relative to White patients, Black patients were less likely to receive a MM transplant (IRR=0.85, 95% CI: 0.74-0.97, p=0.018). RUCA code showed no significant difference in receiving a transplant between the non-metropolitan v. metropolitan groupings (IRR 1.06, 95% CI: 0.97-1.16, p=0.186). Residence in higher SES areas (quartiles 2-4) was associated with higher rate of ASCT receipt compared to those in quartile 1 (IRR 1.16, 95% CI: 1.05-1.29, p=0.038). Among all MM patients median OS for age <65 was 9.0 years (95%CI 8.4-9.7); age 65-70, 7.0 years (95%CI 6.3-7.9); age>70, 4.7 years (95%CI 4.0-5.3). In multivariable analysis, hazard of death was lower for those who received a transplant (vs. no transplant, HR= 0.63, 95%CI 0.53-0.74, p<0.001), patients identified as Black (vs. White, HR=0.66, 95%CI 0.51-0.85, p=0.001), and those residing in higher SES areas (quartile 2-4 vs. quartile 1, HR=0.69, 95%CI 0.58-0.83, p<0.001). Advancing age was associated with higher hazard of death, age 65-70 HR=1.45 (95%CI 1.18-1.78, p<0.001); age >70 HR=2.03 (95%CI 1.65-2.49, p<0.001). Rurality was not associated with OS (HR 1.14, 95% CI 0.96-1.35, p=0.134). Conclusions: In a large MM population, age, race, and area-level socioeconomic status impact both the receipt of transplant and overall survival following MM diagnosis. Area-level SES could be an important driver of MM survival independent of transplant access.

Perturbation of the gut microbiome and association with outcomes following autologous stem cell transplantation in patients with multiple myeloma

The gut microbiome is an important feature of host immunity with associations to hematologic malignancies and cellular therapy. We evaluated the gut microbiome and dietary intake in patients with multiple myeloma undergoing autologous stem cell transplantation. Thirty patients were enrolled, and samples were collected at four timepoints: pre-transplant, engraftment, day +100 (D + 100), and 9–12 months post-transplant. Microbiome analysis demonstrated a loss of alpha diversity at the engraftment timepoint driven by decreases in Blautia, Ruminococcus, and Faecalibacterium genera and related to intravenous antibiotic exposure. Higher fiber intake was associated with increased relative abundance of Blautia at the pre-transplant timepoint. Lower alpha diversity at engraftment was associated with a partial response to therapy compared with complete response (CR) or very good partial response (VGPR) (CR/VGPR vs. PR, p < 0.05). We conclude that loss of bacterial diversity at engraftment may be associated with impaired response to stem cell transplantation in multiple myeloma.

Non-cryopreserved peripheral blood stem cells as a safe and effective alternative for autologous transplantation in multiple myeloma.

Autologous stem cell transplantation is the standard procedure for multiple myeloma and the grafts are usually cryopreserved. Previous studies reported advantages in the use of fresh peripheral blood stem cells (PBSC) autotransplantation compared to cryopreservation of the grafts. This study compared the transplant-related outcomes of two graft preservation methods: fresh storage (4°C/72 h) and cryopreservation (-80°C). We performed an analysis of 45 patients with multiple myeloma under autotransplantation (17 fresh and 28 cryopreserved) from 2017 to 2021. Fresh PBSC were maintained in the refrigerator for three days in a concentration up to 300 × 103 TNC/μL. Cryopreserved PBSC were concentrated by plasma reduction after centrifugation (950 g/10min/4°C) and an equal volume of cryoprotection solution was added for a final concentration of 300 × 103 TNC/μL, 5% DMSO, 6% hydroxyethyl starch, and 3% human albumin. Neutrophil engraftment was significantly faster with fresh PBSCs (10 vs. 11.5 days, p=0.045). Adverse effects were more common in cryopreserved PBSC transplantation (75% vs. 35.3% patients; p=0.013). Post transplantation hospital stay was 20 and 22 days for fresh and cryopreserved PBSCs respectively (p=0.091). There was no difference in platelet engraftment time (10.5 days for both; p=0.133), number of antibiotics used after transplantation (3 for fresh and 2.5 for cryopreserved; p=0.828), days of antibiotic use after transplantation (12.2 days for fresh and 13.3 days for cryopreserved, p=0.579), and overall survival (p=0.736). The infusion of fresh PBSC refrigerated for up to three days is effective and safe for autologous transplantation in patients with multiple myeloma, which is a useful alternative to cryopreserved PBSC.

Long-Term Responders After Autologous Stem Cell Transplantation in Multiple Myeloma

IntroductionMultiple myeloma (MM) is considered an incurable hematological neoplasm. For transplant-eligible patients, initial treatment includes an induction phase followed by an autologous stem cell transplantation (ASCT). Despite the introduction of several drugs in the past years, relapses still occur. Nevertheless, some patients achieve sustained responses after successful induction treatment and ASCT.MethodsWe retrospectively evaluated all patients diagnosed with MM in our institution who underwent induction treatment and ASCT between 1990 and 2015. The subset of patients who achieved a sustained response (any degree) for 5 or more years after ASCT without further treatment or signs of progression were distinguished as “long-term responders” (LTRs). In the non-LTR group, a cohort referred to as “prolonged responders” (PLRs) showed sustained response of at least 5 years after ASCT but eventually relapsed. We collected and analyzed clinical and laboratory data.ResultsTwo hundred and fifty patients were diagnosed with MM and received induction treatment and ASCT at our institution in the study period. Among them, 54 (21.6%) patients met the criteria for LTR. Some diagnostic features such as a younger age, female gender, ECOG performance status of 0, lower International Staging System (ISS) stage, lower bone marrow plasma cell infiltration, and lower serum levels of calcium, C-reactive protein, and lactate dehydrogenase (LDH) were found to be more prevalent in LTR. Female gender, an ECOG performance status of 0, a localized Durie-Salmon stage, an ISS of I–II, the absence of bone disease, and an LDH within normal range were also predictive of longer progression-free survival (PFS) and overall survival (OS) in the whole cohort. The depth of the response achieved after induction and ASCT as well as the administration of an IMID-based maintenance regimen may play a role in the differences observed on PFS between cohorts. A detectable M-protein with a monoclonal gammopathy of undetermined significance (MGUS)-like behavior was detected in one-third of LTR after ASCT. Although relapses continue to occur in patients who achieve a 5-year treatment-free period after ASCT, a plateau is observed in the survival curves at approximately 21 years of follow-up.

Complications of Autologous Stem Cell Transplantation in Multiple Myeloma: Results from the CALM Study.

Background: The main goal of this post hoc analysis of the Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study was to evaluate the rate of short- and long-term infectious and non-infectious complications occurring after ASCT in patients with multiple myeloma (MM). Methods: The analysis included all patients with MM from the CALM study who underwent ≥1 ASCT. The primary endpoint of the analysis was to determine the rate of infectious and non-infectious complications after ASCT and to compare them in three time periods: 0–100 days, 101 days–1 year, and >1 year after the first transplant. Results: The analysis included a total of 3552 patients followed up for a median of 56.7 months (range 0.4–108.1). Complication rates decreased with the time from ASCT with 24.85 cases per 100 patient-years from day 0 to 100 days after the transplant, and <2.31 cases per 100 patient-years from the 101st day. At 100 days after ASC T, 45.7% of patients had complications, with infectious events being twice as frequent as non-infectious complications. Bacterial infections (6.5 cases per 100 patient-years, 95% CI: 6.1–7.0) and gastrointestinal complications (4.7 cases per 100 patient-years, 95% CI: 4.3–5.1) were the most common early events. The pattern of complications changed with time from ASCT. The presence of complications after ASCT was not associated with overall survival. Conclusions: Our data provide a solid basis for comparing ASCT-related complications to those caused by emerging treatments in multiple myeloma, such as CAR T-cell therapy and other immunotherapies.

The impact of COVID-19 on autologous stem cell transplantation in multiple myeloma: A single-centre, qualitative evaluation study

Autologous stem cell transplantation (ASCT) is standard of care in biologically fit, newly diagnosed multiple myeloma (MM) patients, offering better therapeutic outcomes and improved quality of life (QoL). However, with the UK’s 1st national lockdown on 23/03/2020, several guidelines recommended deferring ASCT due to risks of infection, with resource limitations forcing some units to suspend ASCT entirely. Such changes to patients’ treatment plans inevitably altered their lived experience during these uncertain times with expected impact on QoL. We conducted a qualitative study using semi-structured interviews to gain insight into MM patients’ understanding of their disease, initial therapy and ASCT, and their response to therapy changes. A clinical snapshot of how COVID-19 affected the MM ASCT service in a single UK institution is also provided, including changes to chemotherapy treatment plans, timing, and prioritisation of ASCT. Framework analysis identified 6 overarching themes: (1) beliefs about ASCT, (2) perceptions of information provided about MM and ASCT, (3) high levels of fear and anxiety due to COVID-19, (4) feelings about ASCT disruption or delay due to COVID-19, (5) perceptions of care, and (6) importance of social support. Example subthemes were beliefs that ASCT would provide a long-remission/best chance of normality including freedom from chemotherapy and associated side-effects, disappointment, and devastation at COVID-related treatment delays (despite high anxiety about infection) and exceptionally high levels of trust in the transplant team. Such insights will help us adjust our service and counselling approaches to be more in tune with patients’ priorities and expectations.

Relapse with plasmacytoma after upfront autologous stem cell transplantation in multiple myeloma.

Plasmacytoma has been reported to be associated with a poor prognosis in patients with multiple myeloma (MM). In this study, we evaluated the incidence of relapse with plasmacytoma and survival outcomes after upfront autologous stem cell transplantation (ASCT). This study retrospectively analyzed the data of 303 patients with MM who underwent upfront ASCT between April 2000 and April 2018 at eight institutes in the Republic of Korea. In total, 52 patients (17.1%) had plasmacytoma at MM relapse after upfront ASCT, of whom, 27 had paramedullary plasmacytoma (PMD) and 25 had extramedullary plasmacytoma (EMD). Patients with initial plasmacytoma were more likely to have plasmacytoma at MM relapse than those without initial plasmacytoma (37.1% vs. 11.2%). Over a median follow-up of 66.0months, patients with plasmacytoma at relapse had significantly inferior overall survival (OS) than those without plasmacytoma (43.9 vs. 100.7months, P < 0.001), but the OS did not significantly differ between patients with EMD and those with PMD (42.2 vs. 56.6 months, P = 0.464). After MM relapse, all patients received salvage therapy, and progression-free survival after relapse was significantly shorter in patients with plasmacytoma than in those without (6.4 vs. 12.4months, P = 0.007). This study showed that plasmacytoma frequently developed at MM relapse after upfront ASCT in patients with plasmacytoma at the time of diagnosis. Plasmacytoma at relapse was significantly associated with a poor prognosis.

Current Role of Allogeneic Stem Cell Transplantation in Multiple Myeloma.

Major progress in the treatment of multiple myeloma has been made in the last several years. However, myeloma remains incurable and patients with high-risk cytogenetics or advanced stage disease have an even worsen survival. Only allogeneic transplantation may have curative potential in some patients. However, the high non-relapse mortality and incidence of chronic graft-versus-host disease have raised controversy regarding this procedure. In this review, we will address the role of upfront and delayed allogeneic transplant.

Feasibility of Outpatient Stem Cell Transplantation in Multiple Myeloma and Risk Factors Predictive of Hospital Admission.

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) remains the standard of care for multiple myeloma (MM) patients. Although outpatient ASCT has been shown to be safe and feasible, the procedure is overall rare with most patients in the US undergoing inpatient ASCT. Furthermore, hospitalization rates for patients that undergo outpatient ASCT remain high. Adequate markers that predict hospitalization during outpatient ASCT are lacking, yet would be of great clinical value to select patients that are suited to outpatient ASCT. In this study we aimed to elucidate differences between planned outpatient and inpatient ASCT and further evaluated clinical characteristics that are significantly associated with hospitalization during planned outpatient hospitalization. Factors that were significantly associated with a planned inpatient ASCT included an advanced MM disease stage, worse performance status as well as non-Caucasian race, while low albumin levels and female gender were significantly associated with hospitalization during outpatient ASCT. The results of this analysis provide crucial knowledge of factors that are associated with planned inpatient ASCT and hospitalization during outpatient ASCT and could guide the treating physician in decision-making and further facilitate outpatient transplantation.

To transplant or not to transplant in multiple myeloma

Multiple myeloma (MM) is the second most common hematologic cancer resulting from proliferation and accumulation of abnormal plasma cells (myeloma cells) with a preferential homing in the bone marrow. It causes significant morbidity including lytic bone lesions, renal insufficiency, anemia, and infections, to name just a few. Although MM remains largely incurable, it is a chemo-sensitive disease. The use of high-dose intravenous melphalan (100-140 mg/m2) in the treatment of MM was first studied almost 4 decades ago.Subsequently, the dose of melphalan was increased and was followed by autologous hematopoietic stem cell to decrease the aplasia-associated toxicity. Results from phase 3 studies comparing chemotherapy alone to chemotherapy followed by high-dose melphalan and autologous stem cell transplantation appeared in the mid-90s with the publication of the IFM-90 study demonstrating significant clinical benefits on response rate, event-free survival and even overall survival in a cohort of two hundred previously untreated patients under the age of 65 years. This landmark study was followed by confirmatory studies in the early 2000’s. Within the last 2 decades, although improvement in the treatment of transplant-eligible patients is mostly the result of better induction regimens and due to the addition of maintenance therapies, autologous stem cell transplantation remains a cornerstone treatment for MM patients. Indeed, despite novel and more effective treatments for MM, autologous stem cell transplantation continues to demonstrate clinical benefits (Table 1). Moreover, tandem autologous transplantation has demonstrated progression-free survival and overall survival benefits for some patients with poor risk cytogenetics.&#x0D; In 2022, with better knowledge of MM, awareness of potential consequences of high-dose melphalan and with novel and more effective treatment modalities, the role of autologous stem cell transplantation is certainly becoming a question for debate. The purpose of this article is to present the pros and cons of autologous stem cell transplantation in our Canadian reality (Figure 1). This article aims to better assess its role as a therapeutic option considering our health system’s limited resources in which many novel drugs will not be available/accessible in Canada for several more years to come.

561 - Tandem Autologous Stem Cell Transplantation in Patients with Persistent Bone Marrow Minimal Residual Disease Post First Transplantation in Multiple Myeloma

561 - Tandem Autologous Stem Cell Transplantation in Patients with Persistent Bone Marrow Minimal Residual Disease Post First Transplantation in Multiple Myeloma

14 - Biologic Basis of the Impact of Autologous Hematopoietic Cell Transplantation in Multiple Myeloma Treated with Quadruplet Therapy

14 - Biologic Basis of the Impact of Autologous Hematopoietic Cell Transplantation in Multiple Myeloma Treated with Quadruplet Therapy

Autologous Stem Cell Transplantation in Multiple Myeloma: Where Are We and Where Do We Want to Go?

The introduction of high-dose therapy in the 1990s as well as the development of drugs such as thalidomide, lenalidomide, and bortezomib in the 2000s led to an impressive improvement in outcome of patients with multiple myeloma (MM) eligible for autologous stem cell transplantation (ASCT). Clinical trials conducted in the first ten years of the twenty-first century established as standard therapy for these patients a therapeutic approach including induction, single or double ASCT, consolidation, and maintenance therapy. More recently, incorporating second-generation proteasome inhibitors carfilzomib and monoclonal antibody daratumumab into each phase of treatment significantly improved the efficacy of ASCT in terms of measurable residual disease (MRD) negativity, Progression Free Survival (PFS), and Overall Survival (OS). The availability of techniques such as multiparameter flow cytometry (MFC) and next-generation sequencing (NGS) for MRD assessment allowed the design of MRD-based response-adjusted trials that will define, in particular, the role of consolidation and maintenance therapies. In this review, we will provide an overview of the most recent evidence and the future prospects of ASCT in MM patients.

Prognostic impact of natural killer cell recovery on minimal residual disease after autologous stem cell transplantation in multiple myeloma

IntroductionNatural killer cells are a potent effector lymphocyte subset that can induce cytotoxicity without the need for antigen sensitization or presentation. NK cells are a tempting target –for immune therapy, monoclonal antibody, or genetic engineering-to enhance immune surveillance mechanisms against myeloma cells. Materials and methodsWe hypothesized an association between natural killer cell recovery after autologous stem cell transplantation (ASCT) and disease outcomes in multiple myeloma patients.We concluded a prospective study that started enrolling patients in January 2020 to identify the association between absolute NK cell count two to three after ASCT and disease outcomes after autologous stem cell transplantation in multiple myeloma using univariate and multivariate analysis. ResultsNatural killer cell recovery was evaluated during the third month after ASCT, day +60 to +90 post-ASCT. Our patients had a mean NK cell count of 90.53, ranging from 14 to 282 Cell/μL (Std Dev 84.64 Cell/μL). The odds of having a minimal residual disease (MRD-positivity) among patients with partial remission before transplantation is four times higher than patients with very good partial response or better (95% confidence interval 0.45–35.79). Our patients were classified into two groups based on MRD status after ASCT, an MRD-negative group of eight participants and an MRD-positive group of seven participants. The mean absolute NK cell count was significantly higher in the MRD-negative cohort, 131.38 Cell/μL, versus 43.86 Cell/μL in the MRD-positive group (p = 0.049). ConclusionWe conclude that for multiple myeloma patients treated with ASCT, high absolute NK cell counts two to three months after ASCT is an independent predictor for MRD negativity.

Autologous NK cells as consolidation therapy following stem cell transplantation in multiple myeloma

SummaryFew approaches have been made toward exploring autologous NK cells in settings of cancer immunotherapy. Here, we demonstrate the feasibility of infusing multiple doses of ex vivo activated and expanded autologous NK cells in patients with multiple myeloma (MM) post-autologous stem cell transplantation. Infused NK cells were detected in circulation up to 4 weeks after the last infusion. Elevations in plasma granzyme B levels were observed following each consecutive NK cell infusion. Moreover, increased granzyme B levels were detected in bone marrow 4 weeks after the last infusion. All measurable patients had objective, detectable responses after NK cell infusions in terms of reduction in M-component and/or minimal residual disease. The present study demonstrates that autologous NK cell-based immunotherapy is feasible in a setting of MM consolidation therapy. It opens up the possibility for usage of autologous NK cells in clinical settings where patients are not readily eligible for allogeneic NK cell-based immunotherapies.

Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma with Renal Impairment

Aim. To study the efficacy and adverse event spectrum of high-dose chemotherapy with subsequent autologous hematopoietic stem cell transplantation (auto-HSCT) in multiple myeloma (MM) patients with acute renal impairment, including hemodialysis (HD) dependence. Materials &amp; Methods. The retrospective single-center study enrolled 64 MM patients (30 men and 34 women) with renal impairment, aged 19-65 years (median 54 years), who received auto-HSCT in the period from 2013 to 2019. Newly diagnosed patients had a median creatinine of 462 nmol/L and a median glomerular filtration rate of 10 ml/min/1,73 m&lt;sup&gt;2&lt;/sup&gt; (CKD-EPI). HD dependence was reported in 23 (36 %) patients on diagnosis date. As a result of the induction therapy, in 13 (57 %) out of 23 patients HD could be discontinued. Prior to auto-HSCT, overall antitumor response was 91 % (complete remission was 45 %), overall renal response was 80 % (complete renal response was 28 %). In the course of auto-HSCT 10 patients remained HD dependent. Two groups were analyzed: “HD-” (program HD-independent patients during auto-HSCT, n = 54) and “HD+” (program HD-dependent recipients of auto-HSCT, n = 10). Results. Herpes virus infection reactivation and reversible toxic encephalopathy were observed significantly more often in “HD+” than in “HD-” group (30 % vs. 6 %, p = 0.04 and 20 % vs. 0 %, p = 0.02, respectively). HD-dependent patients required red blood cell transfusion significantly more often than HD-independent patients (100 % vs. 35 % of cases; p = 0.0001). In 100 days after auto-HSCT, overall antitumor response increased from 91 % to 96 %, the rate of complete remission increased from 45 % to 64 %. After auto-HSCT the rate of complete renal response increased from 28 % to 34 %, however, overall renal response remained within the range of 80 %. After auto-HSCT, in a single case HD was discontinued. As a result of the treatment, 14 (61 %) patients became HD-independent. Transplantation-associated mortality was not reported. During median follow-up of 48 months, 5-year overall survival was 70 % and 5-year disease-free survival was 42 %. Conclusion. Auto-HSCT is a feasible, safe, and effective treatment of MM patients with acute renal impairment. Induction therapy with subsequent auto-HSCT resulted in less need for HD which was 36 % at MM onset and 14 % on completing the treatment.

Allogeneic Stem Cell Transplantation in Multiple Myeloma.

Simple SummaryDue to its graft-versus-myeloma effect, allogeneic hematopoietic stem cell transplantation (allo-SCT) can enable long-term survival or even cure in carefully selected patients with multiple myeloma (MM), but remains controversial due to its relevant treatment-related toxicity. Current data suggest that allo-SCT should be considered in young MM-patients without relevant comorbidities in case of a high-risk constellation according to cytogenetics or stage, primarily as part of a tandem approach with autologous-SCT followed by allo-SCT and early in the course of the disease. Prospective studies are warranted, due to a suspected synergism especially those including new immunotherapeutic approaches for induction, conditioning and maintenance therapy.The development of new inhibitory and immunological agents and combination therapies significantly improved response rates and survival of patients diagnosed with multiple myeloma (MM) in the last decade, but the disease is still considered to be incurable by current standards and the prognosis is dismal especially in high-risk groups and in relapsed and/or refractory patients. Allogeneic hematopoietic stem cell transplantation (allo-SCT) may enable long-term survival and even cure for individual patients via an immune-mediated graft-versus-myeloma (GvM) effect, but remains controversial due to relevant transplant-related risks, particularly immunosuppression and graft-versus-host disease, and a substantial non-relapse mortality. The decreased risk of disease progression may outweigh this treatment-related toxicity for young, fit patients in high-risk constellations with otherwise often poor long-term prognosis. Here, allo-SCT should be considered within clinical trials in first-line as part of a tandem approach to separate myeloablation achieved by high-dose chemotherapy with autologous SCT, and following allo-SCT with a reduced-intensity conditioning to minimize treatment-related organ toxicities but allow GvM effect. Our review aims to better define the role of allo-SCT in myeloma treatment particularly in the context of new immunomodulatory approaches.

Application of Conditioning Regimen with Busulfan and Cyclophosphamide in Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma

To evaluate the safety and efficacy of BUCY (busulfan and cyclophosphamide) conditioning regimen for autologous hematopoietic stem cell transplantation (ASCT) in patients with multiple myeloma (MM). The clinical data of 72 MM patients received transplantation in the Hematology Department of the First Affiliated Hospital of Soochow University from May 2012 to June 2015 were retrospectively analyzed. Among them, 36 patients received BUCY conditioning regimen while the others received high-dose melphalan (HDM) conditioning regimen. The complication, post-transplantation hematopoietic reconstitution and efficacy between the two groups were compared. There were no significant differences in sex, age, isotype, stage, induction therapy, mobilization method and proportion of conditioning regimen with Bortezomib between the two groups. The median time of neutrophil engraftment for the patients in BUCY and HDM groups was 10 (8-17) and 10 (9-13) d (P=0.046), and the median time of platelet engraftment was 10 (8-18) and 11 (9-47) d (P=0.017), respectively. The transplant related mortality of the patients in both groups was 2.7%. The CR rates of the patients after ASCT (38.9% and 50.0%) were higher than those before ASCT (27.8% and 19.4%) in the two groups. For the patients in BUCY group, the median follow-up time was 45 (0-61) months. Fifteen patients (41.7%) achieved disease progression. While for the patients in HDM group, the median follow-up time was 52(0-75) months. Twenty-two patients (61.1%) achieved disease progression. The BUCY conditioning regimen is a safe and effective therapy for ASCT in patients with MM. Besides, in terms of safety and efficacy, BUCY regimen is not inferior to HDM regimen. BUCY regimen may replace HDM regimen as a standard conditioning regimen for ASCT in MM.

Factors Affecting Natural Killer Cell Recovery after Autologous Stem Cell Transplantation in Multiple Myeloma

Introduction:Natural killer (NK) cells are large granular lymphocytes, very potent effector lymphocytes that can induce cytotoxicity against a vast array of tumors without the need for antigen sensitization or antigen presentation by MHC class I. NK cells are believed to play important role in immune surveillance for cancer, limiting neoplastic progression, and effectors of anti-tumor therapies -by introducing Abs that block NK cell inhibitory receptors yielding improved NK cell-mediated lysis-Retrospective studies demonstrated a significant correlation of NK cell recovery after autologous stem cell transplantation (ASCT) in multiple myeloma (MM) and disease outcomes. Higher absolute NK cell count one month after ASCT is associated with longer progression-free survival (PFS) and decreased risk of relapse. We aimed at investigating factors affecting NK cell recovery after ASCT in patients with multiple myeloma.Method:We designed a prospective cohort study, evaluating the potential factors that could affect NK cell recovery after ASCT. We included participants undergoing frontline ASCT for MM. We excluded participants with non-secretory myeloma or other malignancies that require active treatment, or with autoimmune disorders.All participants received conditioning regimen consisted of melphalan 200 mg/m2 on day -2. In patients older than 65 years old given 100mg/m2 for 2 days. Dose reduction to 140 mg/m2 for patients with serum creatinine > 2.0 mg/dL. Hematopoietic growth factor (peg-filgrastim 6 mg once subcutaneously) was given on day +1.Absolute NK cell count (CD3-, CD56+ cells) was determined using flow cytometric immunophenotyping of peripheral blood two-three months after ASCT. To determine variables that affected NK cell recovery after ASCT, absolute NK cell count was dichotomized to less than the lower limit of normal “NK < 76” and normal “NK > or equal 76” following institutional normal reference range which is consistent with ARUP NK cell enumeration reference. Statistical analysis was performed using Fisher-Exact test for categorical variable and Wilcoxon rank test for continuous variables.Results:We analyzed the results of fifteen patients treated with frontline ASCT for multiple myeloma. With a median age at diagnosis of 60 years, ranging from 47 - 70 years. Of which 53 percent females and 47 percent males. Patients' baseline characteristics are described in Table 1Our data showed that 63 percent of patients with post-transplantation ALC > 1000 (5 of 8 patients), and 73 percent for ALC > 500, (8 of 11 patients), had normal absolute NK cell count; with a correlation coefficient of 0.3 (Pearson Correlation Coefficients), suggesting a moderate linear correlation between absolute NK cell count and ALC two-three months after ASCT.Patients' gender, age at ASCT, and comorbidity index (SORROR score) did not differ between the two groups of patients, P-value= 0.6193, 0.8454, 0.1721, respectively. Additionally, disease burden at the time of diagnosis, presence of CRAB criteria, involved free light chain and monoclonal immunoglobulins; all did not differ between the two cohorts. (Table 2)Medications received before ASCT did affect the absolute NK cell count with a higher proportion of normal absolute NK cell count, and higher mean absolute NK cell in the cohort received double-class (PI plus IMiDs) when compared to triple-class (PI plus IMiDs plus Anti-CD 38 mAb) therapy before transplantation (mean NK cell count 125 and 53 Cell/μL, respectively), with marginal statistical significance P-value= 0.0667 (Fisher's Exact Test).Discussion:Our study showed that the addition of anti-CD38 mAb to myeloma induction regimen, associated with compromised NK cell recovery. Casneuf et al reported similar findings, in daratumumab-treated myeloma patients, total and activated NK-cell counts reduced rapidly in peripheral blood after the first dose, remained low throughout treatment, and recovered after treatment ended. Similar reductions were observed in the bone marrow.Conclusion:Medications received before transplantation potentially affect NK cell recovery in multiple myeloma patients. Although, the addition of anti-CD38 mAb to the myeloma induction regimen is associated with deeper response, its impact on immune reconstitution needs to be investigated on a larger sample size. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.