Plasma Cell Leukemia Research Articles

RNASeq Analysis for Accurate Identification of Fusion Partners in Tumor Specific Translocations Detected by Standard FISH Probes in Hematologic Malignancies.

Fluorescence labeled DNA probes and in situ hybridization methods had shorter turn round time for results revolutionized their clinical application. Signals obtained from these probes are highly specific, yet they can produce fusion signals not necessarily representing fusion of actual genes due to other genes included in the probe design. In this study we evaluated discordance between cytogenetic, FISH and RNAseq results in 3 different patients with hematologic malignancies and illustrated the need to perform next generation sequencing (NGS) or RNASeq to accurately interpret FISH results. Bone marrow or peripheral blood karyotypes and FISH were performed to detect recurring translocations associated with hematologic malignancies in clinical samples routinely referred to our clinical cytogenetics laboratory. When required, NGS was performed on DNA and RNA libraries to detect somatic alterations and gene fusions in some of these specimens. Discordance in results between these methods is further evaluated. For a patient with plasma cell leukemia standard FGFR3 / IGH dual fusion FISH assay detected fusion that was interpreted as FGFR3-positive leukemia, whereas NGS/RNASeq detected NSD2::IGH. For a pediatric acute lymphoblastic leukemia patient, a genetic diagnosis of PDGFRB-positive ALL was rendered because the PDGFRB break-apart probe detected clonal rearrangement, whereas NGS detected MEF2D::CSF1R. A MYC-positive B-prolymphocytic leukemia was rendered for another patient with a cytogenetically identified t(8;14) and MYC::IGH by FISH, whereas NGS detected a novel PVT1::RCOR1 not previously reported. These are 3 cases in a series of several other concordant results, nevertheless, elucidate limitations when interpreting FISH results in clinical applications, particularly when other genes are included in probe design. In addition, when the observed FISH signals are atypical, this study illustrates the necessity to perform complementary laboratory assays, such as NGS and/or RNASeq, to accurately identify fusion genes in tumorigenic translocations.

Atypical Morphological Presentation of Neoplastic Plasma Cells: A Series of Five Cases

The diagnosis of Multiple Myeloma (MM) is made by demonstration clonal plasma cells in Bone Marrow (BM) aspiration/biopsy, in addition to assessing serum biochemical parameters, conducting radiological examinations, and considering the clinical presentation. In most cases, predominantly mature plasma cells are observed, along with scattered immature forms in the BM. Several morphological variants of plasma cells have been reported, including Auer rod-like inclusions, small lymphocyte-like cells, hairy cell-like cells, anaplastic variants, promonocyte-like cells, crystal-storing histiocytes, Burkitt-like cells, and blastoid cells. In this series of five cases, most showed a typical clinical presentation and laboratory findings suggestive of plasma cell dyscrasia. However, the morphology of each case exhibited unusual morphological variants, posing diagnostic challenges. These variants included Auer rod-like inclusions, small lymphocytes/lymph-plasmacytoid cells, hairy-like cells, multilobulated nuclei, and anaplastic variants mimicking dysplastic megakaryocytes, leading to various differential diagnoses. The age range of these cases was 57-76 years. Most of the cases presented with generalised dull aching body pain. Imaging studies revealed lytic lesions involving various parts of the bone, including the skull, ribs, vertebrae, and femur. Biochemical assays suggested the possibility of plasma cell dyscrasia. Two of the cases had primary Plasma Cell Leukaemia (PCL), which is a rare and highly aggressive plasma cell neoplasm. The anaplastic variant is associated with a poor prognosis, aiding in predicting treatment responses. However, due to the unusual morphological presentation, the diagnosis of MM or PCL was made after conducting ancillary studies such as Serum Protein Electrophoresis (SPEP), serum free light chain assay, Immunofixation Electrophoresis (IFE), and immunophenotyping through Immunohistochemistry (IHC) or flow cytometry

Leukemia cutis: a rare manifestation of an underlying primary plasma cell leukemia

Leukemia cutis: a rare manifestation of an underlying primary plasma cell leukemia

Primary plasma cell leukemia discovered during a case of acute anemia following gastrointestinal bleeding

Plasma cell leukemia can occur in undiagnosed patients with myeloma. The existence of anemic syndrome with intolerance symptoms following massive gastrointestinal bleeding can mislead the diagnosis. Careful reading of blood smears is essential, especially in regions of the world with a weak technical platform. In this case, abnormal plasma cells were found on the blood smear. The myelogram revealed a bone marrow infiltration by dysmorphic plasma cells. An immunophenotypic analysis discovered circulating plasma cells, which helped to establish the diagnosis. A methodical identification of the etiology of anemia is needed to discover causes of anemia more easily.

Allogeneic Stem Cell Transplantation in Multiple Myeloma: Risk Factors and Outcomes in the Era of New Therapeutic Options-A Single-Center Experience.

Despite major treatment advances, multiple myeloma remains incurable. The outcome of patients who are refractory to immunomodulatory agents, proteasome inhibitors, and anti-CD38 monoclonal antibodies is poor, and improved treatment strategies for this difficult-to-treat patient population are an unmet medical need. This retrospective, unicentric analysis included 38 patients with relapsed/refractory multiple myeloma or plasma cell leukemia who underwent allogeneic stem cell transplantation (allo-HSCT) between 2013 and 2022. Survival outcomes, relapse incidence, and non-relapse mortality were calculated according to remission status, date of allo-HSCT, cytogenetic risk status, timing, and number of previous autologous HSCTs. The median PFS was 13.6 months (95% CI, 7.7-30.4) and the median OS was 51.4 months (95% CI, 23.5-NA) in the overall cohort. The cumulative incidence of relapse at 3 years was 57%, and non-relapse mortality was 16%. The median PFS and OS were significantly longer in patients with very good partial remission (VGPR) or better compared to patients with less than VGPR at the time of allo-HSCT (mPFS 29.7 months (95% CI, 13.7-NA) vs. 6.5 months (95% CI, 2.6-17.0); p = 0.009 and mOS not reached vs. 18.6 months (95% CI, 7.0-NA); p = 0.006). For selected patients, allo-HSCT may result in favorable overall survival, in part by providing an appropriate hemato-immunological basis for subsequent therapies.

Real world analysis on the determinants of survival in primary plasma cell leukemia in the United States.

Real world analysis on the determinants of survival in primary plasma cell leukemia in the United States.

Distinct Genetic Features in Peripheral Blood Represent the Characteristics of Circulating Plasma Cells in Primary Plasma Cell Leukemia

Clonal plasma cells in peripheral blood (PB) are crucial for diagnosing plasma cell neoplasm. The diagnostic criteria for plasma cell leukemia (PCL) have recently been revised to 5% or more circulating plasma cells (CPCs) in PB. Considering that CPCs are an independent worse prognostic factor in multiple myeloma (MM), elucidating how many CPCs are sufficient for distinguishing patients between PCL and other plasma cell neoplasm is important yet uncertain. These CPCs have been recently discussed in MM, characterized by more immature phenotype, clonogenic potential, and high expression of cancer stem cell (CTC) markers. Though the exact mechanism of peripheral circulation still needs further studies, MM CTCs are considered subclones of bone marrow (BM) plasma cells. On the other hand, previous studies regarding PB plasma cells in primary PCL (pPCL) have been mainly focused on similar characteristics to BM plasma cells. Considering significant prognostic differences based on CPCs, PB from PCL patients should have distinct features. Previous studies on PCL revealed that high genetic heterogeneity and accumulation of diverse high-risk genetic abnormalities eventually led to the disease. Therefore, we aimed to investigate the genetic profile of CPCs in PCL to exhibit proper evidence for diagnostic criteria and improve the current practices. We retrospectively identified patients diagnosed with PCL from 2015 to 2017 at Seoul National University Hospital. Our study population included 4 pPCL and 2 secondary PCL (sPCL) patients. We retrospectively collected patients' clinical information and laboratory test results and performed targeted sequencing using the NGS panel of 647 genes related to hematologic malignancies. In all analyzed samples, 51 in PB and 40 variants in BM were detected in pPCL. The median number of variants in pPCL patients was 11 per patient (range 5-25) in PB and 10 per patient (range 3-17) in BM. When comparing variant allele frequency (VAF) between the paired samples, there was a moderate correlation (R=0.44, P<0.05). Similarly, a moderate correlation was observed in both pPCL (R=0.41, P<0.05) and sPCL (R=0.47, P<0.05) groups. When comparing paired variants between PB and BM, 38 were commonly detected in both samples in pPCL patients. Fifteen variants were identified in only one of the two samples, 12 in PB and 3 in BM. Most variants showed a heterogeneous distribution of genes. We checked the paired samples using an Integrative genomics viewer. As a result, twelve pPCL and thirteen sPCL variants were identified in the paired samples. These variants were initially excluded in the filtering process because of low VAF. Consequently, three unique variants were identified in each pPCL and sPCL group, which were considered truly unique. In pPCL patients, MED12, VPS13B variant from PB, and ZMYM3 variant from BM were identified in one of the paired samples. In sPCL patients, unique variants were identified in ARID1A, FANCE, and TP53. In addition, we determined that PB VAF is higher than BM VAF in shared variants of pPCL patients. Conversely, BM VAF tended to be higher than PB VAF in sPCL. However, plasma cell% was generally higher in BM than PB, regardless of pPCL or sPCL. Therefore, the differences in the percentage of plasma cells between PB and BM samples cannot explain the unique variants detected in only one of the paired samples. pPCL is an aggressive disease characterized by a markedly high diversity of heterogeneous mutation distribution and high mutational burden. The clinical outcomes of pPCL are still poor in the novel agent era. There is an urgent need to improve the current diagnosis and treatment strategy. As shown in this study, CPCs in pPCL are not simply part of the malignant plasma cells shed from the BM but have characteristics distinct from them. In this study, we exhibited that PB variants had higher VAF than BM variants, and some unique variants were identified only in the PB samples. Conversely, in sPCL, more diverse variants were detected mainly in BM samples, and VAF was also higher in BM than PB. Considering unique variants detected in PB and the high genetic heterogeneity of the disease, PB should be included in the diagnosis of PCL to determine the exact genetic profile.

Prevalence of Exclusion Criteria in Multiple Myeloma Randomized Controlled Trials: A Systematic Review

Introduction: Patients with the most aggressive, hardest-to-treat, and rarer forms of multiple myeloma (MM), such as patients with severe renal impairment, central nervous system (CNS) disease, extramedullary disease, and plasma cell leukemia, have the greatest need of novel therapeutic approaches. Strict eligibility criteria for randomized controlled trials (RCTs) both deny access to clinical trials to these patients in greatest need, and also limit generalizability of trial results. We thus systematically assessed newly diagnosed MM RCT's from 2006 to 2023 to ascertain the prevalence of restrictive eligibility criteria, and their trends over time. Methods: We searched MEDLINE/PubMed, Embase, and the Cochrane Registry of Controlled Trials to measure the prevalence of restrictive inclusion criteria MM RCTs. We included all published newly-diagnosed MM RCTs from 2006-2023. Restrictive eligibility criteria evaluated included 1) age exclusions, 2) projected life expectancy requirements, 3) performance status 4) requiring thresholds of “secretory disease”, 5) CNS disease, 6) plasma cell leukemia, 7) hepatic and/or 8) renal function requirements, 9) hematological thresholds, 10) prior malignancy, 11) history of neuropathy, and 12) exclusion of extramedullary disease. We searched manuscripts, clinicaltrials.gov listings, and individual protocols whenever publicly available to ascertain these criteria. We ascertained what proportion of trials had each of these twelve restrictive criteria and assessed trends over time. A logistical regression was used to compare these variables over time. Results: 85 RCTs were included (Table 1). Exclusion criteria included: age in 43 (51%); projected life expectancy in 20 (24%); performance status in 74 (87%); thresholds of “secretory or measurable” disease in 47 (55%), , hepatic function in 64 (79%), renal function in 63 (74%), hematological thresholds in 50 (59%), prior malignancy (various time windows) in 68 (80%), neuropathy in 50 (59%) (various grades), plasma cell leukemia in 16 (18.8%), extramedullary disease in 4 (4.7%) and CNS disease in 9 (10.6%). Trends in exclusion criteria were assessed over time (Figure 1) showing all criteria (other than performance status) have failed to improve from 2006 to 2023, and there has been an increase in exclusionary criteria pertaining to plasma cell leukemia, extramedullary disease, CNS involvement and pre-existing neuropathy. Specific definitions of secretory disease varied with trials that required secretory disease (n=47), with 24 (51%) of these trials requiring a serum monoclonal protein of 1 g/dL or 0.5 if IgA/IgD/IgE/IgM MM, 2 (4.3%) requiring serum monoclonal protein of 2 g/dL regardless of MM subtype, 3 (6.4%) requiring serum monoclonal protein of 0.5 regardless of MM subtype, 11 (23.4%) requiring a serum free light chain of 10 mg/dL, and one (2.1%) requiring a serum free light chain of 5 mg/dL. Conclusion: The majority of MM RCTs have restrictive eligibility criteria that limit enrollment of the sickest MM patients and subsequent external validity of these trials, which perpetuates the status quo where limited data are available to guide the treatment of these challenging MM subtypes. It is very likely our methodology under-estimates the true prevalence of exclusionary criteria, as protocols were not universally available, and a trial was considered as having an exclusionary criteria only if explicitly listed. The presence of these restrictive eligibility criteria has failed to decrease over time.

High Efficacy and Safety of Nanobody Based Anti-BCMA CAR-T Cell Therapy in Treating Patients with Relapsed or Refractory Multiple Myeloma

Introduction Refractory or relapsed (R/R) multiple myeloma (MM) is often associated with a poor prognosis following chemotherapy or even transplantation. BCMA-targeted CAR-T therapy has demonstrated notable efficacy in R/R MM. In the past, the overall response rate (ORR) was relatively low at around 60%, but in recent years, advancements in the manufacturing of BCMA-CAR-T products have led to a substantial improvement in efficacy. Here we explore the efficacy and safety of nanobody-based anti-BCMA CAR-T cell therapy in R/R MM from a clinical trial (https://clinicaltrials.gov NCT04447573). Methods Autologous peripheral blood lymphocytes were collected from patients, who subsequently underwent intravenous fludarabine (30mg/m 2/d) and cyclophosphamide (300mg/m 2/d) lymphodepletion chemotherapy from day-5 to day -3. The SL-BCMA CAR molecule, an anti-BCMA CAR-T cell product generated by Senlang Biotechnology, features a structure that includes dual nanobody VHHs targeting BCMA (dVHHs), CD8α hinge region, CD8α transmembrane domain (TMD), co-stimulatory domain (4-1BB), and CD3 zeta domain (CD3ζ). Among them, dVHHs consist of two different VHHs connected by short peptides. The CD8α hinge region provides an effective spatial architecture for the binding of dVHHs and BCMA protein. The first signal of CAR-T cell activation is completed along with the intracellular CD3ζ domain. The 4-1BB intracellular co-stimulatory domain provides co-stimulatory signals for the activation of CAR-T cells. Under the dual signal stimulation, CAR-T cells are activated and expanded. After the BCMA CAR-T cells infusion on day 0, patients underwent evaluations, including immunoglobulin fixed electrophoresis, free light chains in blood and urine, bone marrow penetration, and whole-body PET CT to evaluate the efficacy at the first month, second and third month, and every three months thereafter. Results From April 2021 to May 2023, 21 R/R MM patients in our hospital were treated with SL-BCMA CAR-T, including 10 males and 11 females. The median age is 57 years (30-73 years). Among them, there were 2 cases with Plasma cell leukemia, 10 had extramedullary multiple lesions, and 2 had paralysis caused by central nervous system infiltration. Pre-CAR-T, 11 patients had a prior transplant history including 10 who relapsed after autologous transplantation and 1 who relapsed after allogeneic transplantation. One patient had a rare type of anaplastic Plasma cell tumor. Seven patients presented high-risk factors characterized by FISH abnormalities such as t (4; 14) (p16; q32), t (14; 16) (q32; q23), and 3 had TP53 mutations. The median BCMA expression rate among 19 patients was 53.3% (range: 18.5% -100%), while the remaining 2 patients displayed non-BCMA expression. The median BCMA CAR-T cell dose was 1*10 6/Kg (0.3-2*10 6/Kg). One month following BCMA-CAR-T cell infusion, the ORR was 95%(20/21), and the CR rate was 38% (8/21). The patient who initially showed no response achieved a partial response following a second infusion of BCMA-CAR-T cells. One died at about 2.5 months due to lung infection. Evaluations conducted at the three-month mark showed an ORR of 95% (19/20) and a CR rate of 80% (16/20). One patient relapsed at the second month and underwent salvage allogeneic hematopoietic stem cell transplantation. For the long follow-up data, the median duration of remission was 11 months. Of the 7 deaths, 2 were attributed to infection during disease control, and 5 were due to disease progression. (Figure 1) In terms of side effects, 6 patients developed grade 2 cytokine release syndrome (CRS), and only 1 patient developed grade 3 CRS. Only one patient had grade 1 neurotoxicity. Conclusions The clinical trial demonstrated that BCMA CAR-T therapy, composed of dual nanobody VHHs targeting BCMA (dVHHs), exhibits a high ORR with a manageable safety profile in treating R/R MM patients. This extends even to high-risk patients, such as those with extramedullary lesions, cytogenetics high-risk groups, and patients with plasma cell leukemia or anaplastic plasma cell tumor.

Management of Bone Marrow Transplants in Incarcerated Patients with Plasma Cell Dyscrasias: A Case Series

Background The U.S.' incarcerated population aged 55 years or older is expected to increase to 400,000 by 2030. This aging population faces intensifying health issues, including an increase in cancer diagnosis rates without adequate healthcare infrastructure and access. Studies show that individuals who received a cancer diagnosis while incarcerated, or within one year of release, had higher rates of cancer-related and all-cause mortality, compared to the general population. Our research seeks to assess how a cohort of patients with plasma cell dyscrasias (myeloma, amyloidosis, plasma cell leukemia) were treated and managed while incarcerated. Methods We performed a retrospective chart review of three patients with plasma cell dyscrasias in the incarcerated population who have undergone bone marrow transplants. Patients' disease characteristics, treatment sequences and details, and clinical outcomes were described qualitatively. Results Case 1: a 48-year-old Black man diagnosed with multiple myeloma in 2019. He was treated with 5 cycles of CyBorD at an outside hospital and had a favorable response. Stem cells were collected but never transplanted and patient was lost to follow-up due to incarceration. In April 2021, he presented to us with bilateral lower extremity paralysis and difficulty walking while in prison. He received emergent radiation to spine, then underwent both DCEP and VDPAC. The patient was discharged for physical rehabilitation in prison with ixazomib maintenance and monthly lab work. 6 months later, he was sent to another outside hospital with acute renal failure and then transferred to us. He demonstrated relapsed myeloma, received DV-AC, and was discharged back to prison while we awaited banked stem cells from 2019. He was admitted a month later for melphalan and auto-SCT, which was well-tolerated. We were ultimately able to arrange lenalidomide maintenance with prison. Case 2: a 65-year-old Black man with abnormal cardiac imaging and lymph node biopsy concerning for amyloid in 2020 while in prison. No treatment was given at the time. In 2021, an outside hospital conducted a bone marrow biopsy showing monoclonal plasma cells consistent with primary amyloidosis. 3 months later, the patient began CyBorD but completed subsequent cycles at another outside hospital. Correctional authorities indicated transplant would ultimately need to occur at our facility. Patient began stem cell mobilization and was admitted to us for melphalan and auto-SCT in March 2022. Patient was discharged back to corrections but there was a delay in acquiring lenalidomide for maintenance therapy, which was not started until August 2022. Case 3: a 44-year-old Black man was diagnosed with plasma cell leukemia in 2009. That year, he received an auto-SCT and then an allo-SCT from his HLA-matched sister at an outside hospital. In 2016, he received radiation for a large mass in his brain, as well as lenalidomide and dexamethasone. Since then, records indicate limited follow-up until he presented to us in 2022 with leg pain and imaging showing progressing myeloma while in prison. He was given 1 cycle of DCEP, was discharged back to a correctional facility, and subsequently refused 2 nd cycle. He sought a second opinion from an outside hospital for CAR-T therapy but was told eligibility required failure of daratumumab. In January 2023, he was offered Dara-Pom-Dex-Carfilzomib though declined the pomalidomide portion. He has responded well and is continuing maintenance. The CAR-T center offered to see him for treatment if he progresses on this regimen. Discussion Our research suggests that incarcerated patients face multiple obstacles that delay or hinder treatment, including siloed care, poor record-keeping, lack of follow-up, and difficulty obtaining appropriate medications. All three patients were frequently transferred between correctional facilities, outside hospitals, and our institution, which led to incomplete records. Additionally, patients went months or even years without follow-up monitoring after initial treatment and would often re-enter the healthcare system only upon presenting with severe symptoms from relapsed disease. Correctional facilities faced issues procuring expensive medications only available through restricted distribution programs. Further analysis is warranted to understand the generalizability of our results and identify solutions to support this population.

Will Survival Improve By Treating Multiple Myeloma Patients at MRD Relapse? the Remnant Study

Background: Although many new treatment options have become available, multiple myeloma (MM) is still considered an incurable disease. The importance of achieving minimal residual disease (MRD) negativity in MM patients has become clearer in recent years. Multiple studies show that bone marrow based MRD assessment is one of the strongest prognostic factors, and deeper responses correlate with more favorable outcomes. The REMNANT study will evaluate if treating at MRD relapse after first line (1.L) treatment prolongs progression-free survival (PFS) and overall survival (OS) in MM patients. Methods: The REMNANT study (RElapse from Mrd Negativity As iNdication for Treatment) is an academic, multicenter, open-label, randomized phase 2/3 study of newly diagnosed (ND) MM patients eligible for autologous stem cell transplant (ASCT). The study has a population-based approach with few exclusion criteria, implying that patients with kidney failure, amyloidosis, plasma cell leukemia and other comorbidities are enrolled. To increase enrollment in part 2, patients who have received 1.L treatment outside the REMNANT study can be enrolled directly if they are >CR/MRD negative. 391 NDMM patients (age 18-75 years) eligible for ASCT will be enrolled in part 1 (phase 2) of the study and receive standard of care Norwegian 1.L treatment; 4 pre-transplant induction and 4 post-transplant consolidation cycles of bortezomib, lenalidomide and dexamethasone (VRd). After induction, patients will undergo tandem or single transplant, depending on toxicity and response to first transplant. All patients receive lenalidomide maintenance. Following 1.L treatment 176 patients achieving MRD negative (Euroflow NGF 10 -5) complete response will be enrolled in part 2 (phase 3) of the study. Patients will be randomized in a 1:1 ratio to receive second line treatment (2.L) at MRD relapse in arm A or at PD in arm B. At loss of MRD negativity in arm A or at PD in arm B, 2.L treatment will be daratumumab, carfilzomib and dexamethasone until PD. The primary endpoint of part 1 (phase 2) of the study is the number of patients who achieve MRD negative (Euroflow NGF 10 -5) complete response 30-45 days post consolidation. Secondary endpoints includes response rates, safety evaluations and patient-reported outcome. The co- primary endpoints in part 2 (phase 3) are PSF and OS from randomization to progressive disease or death on 2.L treatment. We will also compare different methods for measuring MRD: NGF Euroflow, Next Generation Sequencing, mass spectrometry and PET-CT. We want to evaluate how the different methods compare when it comes to sensitivity and outcome (PFS and OS). Results: As of July 18 th 2023, 291 patients are enrolled in part 1 and 97 in part 2 (23 directly enrolled). Baseline characteristics, safety summary and preliminary results can be found in Table 1. The ORR on first line treatment is 95% and 65 of 152 patients (45%) were >CR and MRD negative at the post-consolidation visit. Patients achieving > VGPR but not CR MRD negativity post consolidation are followed for up to 24 months on lenalidomide maintenance, and 11 of 74 patients (15%) in follow-up have converted to >CR/MRD negativity at a median time of seven months (range 2-16). Nine patients have started 2.L treatment in part 2 (phase 3), eight in arm A (MRD guided) and one in arm B (control arm). Median time to loss of MRD negativity among the eight patients in arm A was four months (range 1-6). The most common adverse events were infections, occurring in 24% of patients (any grade). During 1.L treatment, 61 patients have left the study. Seven patients have died, 27 discontinued due to disease progression, 12 patients have withdrawn from the study and seven discontinued due to adverse events. 59% of the patients who progressed during 1. L treatment had high-risk cytogenetics (with gain1q and/or del17p and/or t(4;14)). Conclusion: Standard of care Norwegian first line treatment has an ORR of 95%. The MRD negativity rate among patients who have finished 1.L treatment was 43% (65 of 152). The median time to loss of MRD negativity in arm A (MRD guided) was 4 months.

Incidence of Second Primary Malignancies in Medicare-Insured Patients in the US with Triple-Class Exposed Relapsed/Refractory Multiple Myeloma

Background As therapeutic advances have increased life expectancy for patients (pts) with relapsed/refractory (RR) multiple myeloma (MM), second primary malignancies (SPMs) have become an increasingly important safety consideration. Prior studies have demonstrated that treatment with alkylators, autologous stem cell transplantation, and immunomodulatory drugs (IMiDs), specifically lenalidomide, are associated with increased risk of SPM. Pts who are triple-class exposed (TCE), defined as prior exposure to an IMiD, a proteasome inhibitor (PI), and an anti-CD38 monoclonal antibody (mAb), represent an increasingly large subgroup of RRMM pts. The objective of this study was to describe the incidence and characteristics of SPMs in Medicare-insured pts with TCE RRMM initiating a new line of therapy (LOT). Methods Adult pts with an incident diagnosis (Dx) of MM (≥2 outpatient Dx 30-365 days apart OR ≥1 inpatient Dx AND 6 months of continuous eligibility prior to initial Dx) during the study period (Nov 14, 2006-Dec 31, 2020) who were TCE (≥1 claim each for an IMiD, a PI, and an anti-CD38 mAb) were selected from the Center for Medicare and Medicaid Services Chronic Conditions Data Warehouse (TCE pts were assumed to have RRMM based on exposure). The first LOT after TCE was defined as the index LOT and the associated date of initiation was defined as the index date. Pts with SPMs prior to the index date were excluded. SPMs were identified based on having ≥2 outpatient Dx of SPM (of the same cancer type) 30-365 days apart OR ≥1 inpatient Dx of SPM. Dx of SPM included Dx of invasive malignancies or myelodysplastic syndromes (MDS), excluding MM, Waldenström macroglobulinemia, plasma cell leukemia, non-melanoma skin cancers, or primary bone malignancies that were preceded by a Dx of bone metastases. The incidence of SPM was calculated per 100 person years (PY) of follow-up, considering only the first SPM for each pt. Cumulative incidence of SPM (with death as a competing risk) was also calculated. For pts who experienced SPM, overall survival (OS) and measures of healthcare resource utilization (HRU) and costs (in 2021 USD, on a per patient per month [PPPM] basis) were calculated. Results A total of 3,088 TCE RRMM pts were identified, of whom 989 had no evidence of SPM prior to the index date (Table). These 989 pts had a mean age of 75.2 years, a mean of 2.9 prior LOTs and a mean of 3.1 years since MM Dx. Over a median follow-up of 7.1 months, 166 pts (19.3 per 100 PY) experienced an SPM, including 93 (10.8 per 100 PY) with a solid tumor and 73 (8.5 per 100 PY) with a hematologic malignancy. The latter included 27 (3.1 per 100 PY) with acute myeloid leukemia (AML) and 18 (2.1 per 100 PY) with MDS. The cumulative incidence of SPM (95% confidence interval [CI]) at 12, 24, and 36 months was 15.2% (12.8-17.9%), 19.7% (16.8-22.8%), and 23.8% (20.2-27.6%), respectively (Figure). Median (95% CI) OS from SPM Dx was 7.9 months (5.4-10.9). Kaplan-Meier estimated probability of survival (95% CI) at 12, 24, and 36 months following SPM Dx was 40.3% (31.6-48.9%), 27.6% (18.6-37.4%), and 9.5% (2.1-23.8%), respectively. Mean (95% CI) total costs after SPM were $22,514 ($19,105-$26,404) PPPM. Conclusions The incidence of SPM in Medicare-insured TCE RRMM pts is high. Many SPMs in these pts, such as AML, are life-threatening and may interfere with or prevent MM treatment. Pts with SPMs have poor survival and high HRU and costs. With increasing OS for RRMM pts due to therapeutic advancements, there is a need for effective treatments that are not associated with increased risk of SPMs.

Single Nuclei Multiomics Analysis of Transcriptional and Chromatin Accessibility of Tumor Cells Uncovers Molecular Signatures and Regulatory Elements of Malignant Clonal Evolution in Multiple Myeloma

Category Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational Introduction Multiple myeloma (MM) is a hematological cancer resulting from abnormal proliferation of plasma cells (PC) in bone marrow. The progression of the disease from Monoclonal Gammopathy of Undetermined Significance (MGUS), Smoldering Multiple Myeloma (SMM), to MM involves multiple drivers and dynamic interactions of premalignant/malignant cells. In the advancement of single-cell technologies, the same-cell readouts of nucleus RNA sequencing (snRNA-seq) and Assay for Transposase-Accessible Chromatin sequencing (snATAC-seq) provide a less biased measurement of gene expressions and chromatin accessible regions. Profiling and analyzing both omics data at different stages of MM may reveal essential molecular signatures and regulatory elements for microenvironmental modification and evolution. These insights could benefit MM patients as novel targets for early therapeutic intervention at different stages of progression. Methods Bone marrow aspirates were collected from 33 individuals: Healthy donors (n=3), patients with MGUS (n=2), SMM (n=5), MM (n=21), and Plasma Cell Leukemia (PCL; n=2). Viable mononuclear cells underwent CD138+ sorting and nuclei isolation prior to library preparation. Libraries were prepared with the Chromium Multiome kit (10X Genomics) and sequenced on NovaSeq S4 flow cells at UAMS. The clonal V(D)J arrangements of each sample and expression level from HD samples were used to distinguish malignant (MM) from normal plasma cells (PC). The MM data from snATAC-seq and snRNA-seq were integrated using Signac with the weighted nearest neighbor methods from Seurat. All inter- and intra-tumor clusters were evaluated for markers of high-risk disease, differential gene expression, differentially accessible regions, and transcription factor activities. Results We performed snRNA-seq and snATAC-seq sequencing to generate multi-stage, molecular classified-specific chromatin accessibility and transcriptional profiles of plasma cell neoplasms comprising 439,134 cells across 33 samples. The malignant plasma cells for each sample were extracted by the unique clonotypic signature of the immunoglobulin gene rearrangement. Of these, we detected the highest clonality in MGUS samples, suggesting clonal competition at the premalignant stage. Based on our primary microarray data, we detected the overexpression of molecular signatures for most cells in each sample, confirming the intratumor cell heterogeneity. Furthermore, we used the ratio of 70-gene signature of aggressive disease and proliferation signatures to investigate the clonal composition of MM cells corresponding to the risk of relapse. Surprisingly, the proportion of high-risk cells increased respectively from low to high-risk samples. The expansion of high-risk clonality might exhibit competition among malignant cell subpopulations regarding microenvironmental adaptation. The multiomics integration generated less distinct clusters between MGUS and SMM, indicating the gradual complex alterations of subclonal gene expression and chromatin accessibility in malignant transformation. Interestingly, most accessible regions were found in intronic/distal intergenic regions implying the long-range gene regulation from cis-regulatory elements. Based on the positive/negative correlation of binding motifs within differentially accessible regions, we identified unique enriched transcription factors for each disease stage, suggesting the mechanism patterns in the evolutionary process of malignant cells. Conclusion In the largest multiomics study to date of CD138+ cells, we demonstrate the malignant clonal evolution using gene expression and chromatin accessibility profiling from patients with early-stage disease to highly aggressive form. Throughout the time of disease progression, we found an increase in the proportion of malignant cells with high-risk signatures. Also, we uncover unique signatures of chromatin accessibility for each molecular classification that can further refine our understanding of functional heterogeneity in multiple myeloma. Collectively, our joint single nuclei profiling reveals additional insights into the malignant clonal evolution and investigates novel regulatory elements involved in disease progression.

An Indirect Comparison of Elranatamab's Progression-Free Survival and Overall Survival from Magnetismm-3 Versus Real-World External Control Arms in Triple-Class Refractory Multiple Myeloma

BACKGROUND Elranatamab(ELRA) is a BCMAxCD3 bispecific antibody being investigated for the treatment of relapsed/refractory multiple myeloma (MM). The phase 2 MagnetisMM-3 (MM-3; NCT04649359) trial was single-armed; the aim of this study was to contextualize the efficacy data from MM-3 with two real-world (RW) external control arms. METHODS We conducteda retrospective cohort study to indirectly compare the efficacy observed in MM-3 Cohort A (BCMA-naïve; N=123) from the March 2023 data cut (approximately 15 months of follow-up) with two US-based oncology electronic health record databases, COTA and Flatiron Health (FH), as external controls. MM-3 inclusion (eg, prior MM diagnosis, ECOG≤2, refractory to ≥1 PI, ≥1 IMiD, and ≥1 anti-CD38) and exclusion (I/E) criteria (eg, plasma cell leukemia, smoldering MM) were applied to each RW database to obtain comparable patient populations across sources. After imposing MM-3 I/E criteria, we conducted comparisons between data sources on progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier estimators or Cox proportional hazard models (“unweighted analyses”) and restricted mean survival time (RMST) analyses in instances where the proportional hazards assumption was violated. We used additional Cox proportional hazard models, Kaplan-Meier estimators, or semi-parametric models implementing inverse probability of treatment weighting (IPTW), doubly robust, and propensity score (PS) matching analyses to adjust for any remaining imbalances across cohorts on confounding variables (eg, age, comorbidities, Eastern Cooperative Oncology Group (ECOG) score, International Staging System (ISS), prior lines/refractoriness, cytogenetic risk, extramedullary disease [COTA only], lab values). RESULTS N=123 patients from MM-3 Cohort A were compared with the 239 and 152 patients identified from the COTA and FH databases, respectively. Treatment regimens in the RWD sources included various combinations of PIs (carfilzomib- and bortezomib-based regimens were each used by 43% and 15% of patients, respectively), IMiDs (lenalidomide- and pomalidomide-based regimens were used by 9% and 41% of patients, respectively), and mAbs (daratumumab- and isatuximab-based regimens were used by 32% and 1% of patients, respectively), among other agents (eg, selinexor-based regimens were used by 5% of patients). Across unweighted, IPTW, doubly robust, and PS matching analyses, ELRA was associated with significantly longer PFS than RW physicians' choice of treatment from both COTA and FH (hazard ratios [HRs] ranged from 0.37 to 0.57; see Table 1). Similarly, across unweighted, IPTW, doubly robust, and PS matching analyses, ELRA was associated with significantly longer OS than RW physicians' choice from COTA (HRs ranging from 0.46 to 0.65) and longer OS across unweighted (RMST difference at 15 months = 1.70) and PS matching analyses (HR = 0.60) than RW physicians' choice from FH. IPTW and doubly robust methods indicated only directionally longer OS for ELRA than RW physician's choice from FH (RMST difference at 15 months = 0.72 and HR = 0.66, respectively). CONCLUSIONS Among BCMA-naïve patients who resemble those enrolled in the MM-3 trial, those treated with ELRA exhibit significantly longer PFS and OS compared with real-world treatments.

Safety and Efficacy Outcomes for Patients with High-Risk Multiple Myeloma Receiving Idecabtagene Vicleucel: The MD Anderson Experience

Background: There is a paucity of data regarding the impact of high-risk features on the efficacy and safety of B-cell maturation antigen (BCMA)-directed autologous chimeric antigen receptor (CAR)-T therapy in patients with multiple myeloma (MM). Methods: In this retrospective single-center study we included all MM patients who received idecabtagene vicleucel (ide-cel) between 12/2019-10/2022, either in the setting of a clinical trial (i.e. KarMMa-2 and KarMMa-3) or as a standard of care (SOC). We evaluated the impact of high-risk disease features on the efficacy and safety outcomes. Patients with high-risk MM (HRMM) were defined as having at least one of the following: high-risk cytogenetic abnormalities prior to CAR-T infusion (deletion 17p, translocation (t)(4:14), t(14:16) or 1q gain/amplification (1q+)), extramedullary disease (EMD), plasma cell leukemia and Revised International Staging System (R-ISS) stage 3. Minimal residual disease (MRD) was evaluated using 8-color next-generation flow cytometry (NGF), with a sensitivity of 1/10-5 cells (0.001%) based on the acquisition and analysis of at least 2 million events. Efficacy outcomes included response rates, progression free survival (PFS) and overall survival (OS). Safety outcomes included incidence/grade of cytokine release syndrome (CRS), Immune effector cell-associated neurotoxicity syndrome (ICANS), hematological toxicity and infections. Results: A total of 74 patients were included in our analysis, 49 received SOC ide-cel and 25 were treated on clinical trial. The median age was 65.3 (range 37.9-90.3) years, and 49 patients (66%) were male. Median number of previous lines of therapy was 6 (range 1-18). The HRMM group included 52 patients (70%), and the most prevalent high-risk features were high-risk cytogenetic abnormalities (43%, most often 1q+ (n=26, 81%), followed by del17p (n=17, 33%), t(4:14) (n=9, 17%) and t(14:16) (n=4, 8%)) and EMD (19%). Seventy five percent of patients who received SOC ide-cel had HRMM compared to 25% of those who received ide-cel on clinical trial (p=0.014). Compared to patients with standard-risk MM (SRMM), those with HRMM more often had disease refractory to proteasome inhibitors (p=0.042) or anti-CD38 antibodies (p=0.01), and more often received bridging therapy prior to CAR-T infusion (p=0.021). After bridging therapy, 43% of HRMM patients had progressive disease, compared to 20% of SRMM patients (p=0.21). Sixty seven percent of the entire cohort received prior BCMA-directed therapy before ide-cel, without a significant difference between the two risk groups (p=0.80) ( Table 1). For the entire cohort, overall response rate was 85%, and 51% achieved ≥CR at best response. There was no significant difference between the HRMM and SRMM groups in response rates or in rates of MRD negativity at day 30 and at 3/6/9 months after CAR-T infusion, yet fewer HRMM had MRD negativity at 12 months after CAR-T (50% vs. 100% of evaluable patients, p=0.019). The 6-months PFS for the HRMM group and the SRMM group was 64% and 81%, respectively (p=0.11) ( Figure 1A), and the 6-months OS was 80% and 90%, respectively (p=0.067) ( Figure 1B); Thirty-nine patients in the HRMM group developed CRS (83% of evaluable patients), including one grade 3 and one grade 5 CRS, compared to 15 (75%, p=0.65) in the SRMM group (all grade <3). Eight patients in the HRMM group developed ICANS (17%), including two grade 4 ICANS, compared to 3 (15%, p=0.93) in the SRMM group (all grade <3). We did not observe a difference in rates of neutropenia (p=0.63), anemia (p=0.75) or thrombocytopenia (p=0.53) by day 30, and also not in the rates of infection (p=0.16) between the two groups. In multivariate analysis on the entire cohort, receiving <4 prior lines of therapy (HR 0.06, 95% CI 0.004-0.71, p=0.026) and ECOG≤2 (HR 0.07, 95% CI 0.08-0.53, p=0.01) were associated with superior OS. Conclusions: Patients with HRMM receiving ide-cel had mostly comparable response rates compared to those with SRMM. HRMM patients had numerically worse PFS and OS compared to patients with SRMM, though not reaching statistical significance. Overall rates of CRS/ICANS were comparable between the two groups, yet only patients with HRMM had grade ≥3 of these complications. Patients who received ide-cel after less than four previous lines of therapy had better overall survival.

Mitoxantrone Hydrochloride Liposome, Bortezomib, and Dexamethasone- Based Regimen in Multiple Myeloma Patients with Extramedullary Plasmacytoma: A Pilot Study

Background Extramedullary plasmacytoma (EMP) is frequently presented in multiple myeloma (MM), especially in relapsed/refractory MM (RRMM), indicating a high-risk state of disease with inferior survival. Even in novel agent era, most anti-myeloma therapeutics demonstrated limited efficacy in EMP. Since there are no randomized controlled studies specifically addressing this complicated situation, standard treatment recommendations still lacked in this setting. Mitoxantrone hydrochloride liposome (Lipo-MIT) has shown higher concentration in tumor tissues and extended half-life, which exhibited clinical benefits in leukemia and solid tumors. Herein we designed a pilot study to explore the efficacy and safety of Lipo-MIT, bortezomib, and dexamethasone (MVD)- based regimen in MM with EMP. Methods MM patients with measurable EMP were enrolled in this study. Patients were planned to receive a maximum of 8 cycles of Lipo-MIT, bortezomib, and dexamethasone (MVD)- based regimen. Other combination agents were chosen based on previous treatments and the tolerance of patients, according to the clinician's decision. For patients who were refractory or intolerant to bortezomib, carfilzomib could be an alternative option. The dose of Lipo-MIT was 12mg/m 2 on the first day of every cycle. Both hematological response and EMP response were assessed by the International Myeloma Working Group (IMWG) criteria. Results Between Nov 4, 2022 and Jun 25, 2023, fifteen patients were enrolled from Beijing Chaoyang Hospital, with a median age of 65 years (range: 46-77). All patients had at least one kind of EMP, of which 12 (80.0%) patients had paraskeletal plasmacytoma, 7 (46.7%) had soft-tissue plasmacytoma, and 4 (26.7) had plasma cell leukemia. Four (26.7%) patients were newly diagnosed MM (NDMM), three (20.0%) were first relapse, and eight (53.3%) were previously heavily treated (2-12 lines). All of the 11 RRMM patients had been previously treated with proteasome inhibitors and immunomodulatory drugs (IMiDs), seven of them (46.7%) had been treated with CD38 antibodies, five (33.3%) had been treated with anthracyclines, and three (20.0%) had received CAR-T therapy (Table 1). By the data cut-off date of July 30, 2023, enrolled patients received a median of 2 cycles of Lipo-MIT treatment (range: 1-4). Specific regimens included: Lipo-MIT- bortezomib/carfilzomib- dexamethasone (MVD) triplet regimen (20.0%), MVD plus lenalidomide regimen (M-VRD) (20.0%), MVD plus IMiDs and etoposide regimen (M-VTED) (40.0%), and MVD plus other cytotoxic drugs (cyclophosphamide or cisplatin) (20.0%). The overall response rate (ORR) of EMP was 53.3%. Among the 9 patients who had measurable hematological disease at baseline, the hematological ORR was 77.8% (22.2% ≥VGPR, 33.3% PR, 22.2% MR) (Table 1). The most common adverse effects (AEs) at all grades (incidence >10%) were myelosuppression, including leukocytopenia (80.0%) and thrombocytopenia (53.3%), as well as respiratory infection (46.7%), diarrhea (13.3%), blue skin (13.3%), dizzy (13.3%), and fatigue (13.3%). Common grade ≥3 AEs including leukocytopenia (46.7%), thrombocytopenia (26.7%) and respiratory infection (26.7%) (Table 2). Median follow-up time was 4.5 months. Five patients had died, among which 3 died of disease progression, 1 died of severe respiratory infection, and 1 died of Covid-19 infection. Median PFS and OS have not been reached in this cohort. Conclusion This study revealed promising results of early response and efficacy of MVD-based regimen in MM with EMP, which could be further explored in prospective phase 2 studies.

Outcomes of Salvage VDT-PACE-like Regimens in Relapsed-Refractory Multiple Myeloma: 10-Year Experience of a Large Academic Institution

Introduction: Rapidly evolving therapies for multiple myeloma (MM) have drastically changed the treatment landscape over the last decade. Despite the introduction of novel agents into clinical practice, MM remains challenging to treat in the setting of aggressive relapse and/or multi-refractory disease, accompanied by high tumor burden and extramedullary sites. Intensive chemotherapy with VDT-PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide)-like regimens may be used for a limited number of cycles as a bridging regimen to quickly achieve cytoreduction. This study aimed to evaluate outcomes of patients treated with VDT-PACE-like regimens (VPRs) for relapsed-refractory MM (RRMM) at our center. Methods: We retrospectively analyzed medical records of patients with RRMM who were treated with VPRs at our institution between 1/1/2013 and 6/1/2023. Responses including complete response (CR), very good partial response (VGPR), partial response (PR) and minimal response (MR) were measured according to the International Myeloma Working Group (IMWG) criteria. Baseline characteristics were outlined by descriptive analysis. Kaplan-Meier method was used for progression free survival (PFS), and overall survival (OS) calculations. Patients were censored in PFS analysis if they started another therapy before progression. Results: A total of 93 patients with RRMM were included in this analysis. Median age was 59 (range 42-84) years, 41% were female and 82% were White. The median number of prior lines of therapy was 6 (range 1-17) and median percentage of bone marrow plasma cells prior to VPRs initiation was 70%. Of the entire cohort, 60% of patients had high risk cytogenetics and 27% had plasma cell leukemia; other baseline patient and disease characteristics are summarized in Table 1. Patients received a median of 1 cycle (range 1-4) of VPRs; 37% received >2 cycles of treatment. After completion of cycle 1, VGPR or better, PR, and MR were achieved in 25 (27%), 30 (32%) and 11 (12%) patients, respectively. The estimated median PFS was 4 months (95% Cl, 2.8 - not reached [NR]) and the estimated median OS was 7 months (95% Cl, 5-8) from VPRs initiation (Figure 1). Among the 72 patients who received further treatment post VPRs completion, 19% underwent autologous hematopoietic cell transplant (AHCT), 70% were switched to another plasma cell-directed therapy, and 11% received chimeric antigen receptor T (CAR T)-cell therapy as the next line of therapy. The remaining 21 patients were transitioned to hospice immediately following VPRs, or died prior to receiving next line of therapy due to disease progression. Thirty-eight patients (41%) were readmitted after cycle 1 due to complications; median number of readmissions was 1 (range 1-4), and median cumulative duration of inpatient hospital stay was 7.5 (range 1-42) days. Severe neutropenia (defined as neutrophilic count <500 x10 9/L) and severe thrombocytopenia (defined as platelet count <25 x10 9/L) were seen in 57 (61%) and 43 (46%) patients, respectively after cycle 1, and 28 (30%) patients developed neutropenic fever. Conclusion: VPRs are feasible salvage treatment options in RRMM patients with aggressive and multi agent-refractory disease. Most patients responded to VPRs bridge therapy and were able to transition to autologous hematopoietic cell transplant, CAR T-cell therapy or other less toxic plasma-cell directed regimens. Despite that, the median overall survival of the entire cohort was short indicating that VPRs might not be able to reverse the poor prognosis of highly aggressive RRMM disease.

A Phase I Trial of Activated Donor-Derived Marrow Infiltrating Lymphocytes to Treat Relapsed Hematologic Malignancies after Allogeneic Transplantation with Post-Transplantation Cyclophosphamide As Graft-Versus-Host Disease Prophylaxis

Background: Donor lymphocyte infusion (DLI) or a second allogeneic transplant (HCT) are the only curative treatments for hematologic malignancies relapsing after initial HCT. Both approaches lack significant efficacy and may cause considerable toxicity. Post-transplant cyclophosphamide (PTCy) used as graft-versus-host disease (GVHD) prophylaxis eliminates alloreactive T cells and enriches for tumor-specific T cells in the bone marrow. We hypothesized that expanded, donor-derived marrow infiltrating lymphocytes (alloMILs) collected post-HCT could restore antitumor immunity in relapsed recipients without the additional GVHD and toxicity seen with DLI or second HCT. Methods: We conducted a phase I dose-escalation trial (NCT02342613) of expanded alloMILs to treat bone marrow infiltrating hematologic malignancies relapsing after HCT with PTCy. Key inclusion criteria were age ≥ 18 years; relapsed hematologic malignancy ≥ 6 months after HLA matched or mismatched HCT with PTCy; donor CD3 + chimerism ≥ 30% in the peripheral blood; and lack of immunosuppressant use for 2 weeks prior to alloMILs harvest. Enrolled patients underwent salvage chemotherapy prior to or after alloMILs harvest to control the disease during the expansion process. Harvested bone marrow mononuclear cells were co-incubated with anti-CD3/CD28 beads and IL-2 for 7 to 14 days until the target CD3 + dose was reached. Given the differential risk of GVHD with matched versus mismatched DLI, dosing progressed from 1 x 10 7 to 5 x10 7 CD3 + cells/kg for matched HCT recipients and 1 x 10 6 to 5 x10 7 CD3 + cells/kg for mismatched HCT recipients. The primary endpoint was the feasibility of the product, defined as: successful harvest; expansion; infusion; and absence of grade III-IV acute GVHD for 90 days after infusion. Evaluation for HLA loss was performed using next-generation sequencing (NGS) of HLA loci. Single cell RNA sequencing (scRNAseq) was performed using 10x Genomics technology, Cell Ranger (v6.0.2), and Seurat (v4.3.0). Results: Thirty-two patients enrolled and underwent bone marrow harvest. Two patients were inaspirable, and five patients were not expanded due to low cell counts or high tumor volume. Twenty-five patients underwent alloMILs expansion, of which five failed to expand. Twenty patients received an infusion and six received a second infusion. Of the twenty patients receiving an infusion, eleven had multiple myeloma (MM) or plasma cell leukemia; five had acute myeloid leukemia (AML); one had chronic myeloid leukemia in blast phase; and three had chronic lymphocytic leukemia. Harvest, expansion, and infusion were well tolerated with minimal adverse events. No patient developed acute or chronic GVHD after infusion. Dosing advanced to the highest level of 5 x10 7 CD3 + cells/kg in both the mismatched and matched HCT cohorts. At day 60, the overall response rate (composite of complete (CR) and partial responses) was 40 percent (8/20) in the entire cohort; 33.3 percent (2/6) in the myeloid cohort (Figure 1A); 30 percent (3/10 evaluable patients) in the MM cohort; and 66.7 percent (2/3) in the lymphoid cohort. One MM patient achieved sustained > 2 years long CR and one AML patient is in ongoing CR, both of whom received alloMILs with no or minimal disease followed by maintenance therapy. HLA loss analysis was performed on pre-expansion samples from three AML patients receiving a mismatched HCT and alloMILs. Both non-responders in this cohort had loss of the host mismatched HLA haplotype. ScRNAseq on pre-expansion samples from ten AML patients, eleven MM patients, and four AML patients in remission after HCT (control) yielded 197 522 total cells and 32 587 CD8 + T cells. CD8 + T cells expressing a senescent-like gene signature previously associated with dysfunctional tumor killing in AML patients (Mazziotta et al ASH 2022) were associated with non-response primarily in AML patients (observed log2 fold change -2.48 compared with responders; FDR = 0.0017) (Figure 1B). Conclusions: AlloMILs demonstrated feasibility, a favorable safety profile, and early evidence of clinical activity in patients with measurable residual disease. The maximum dose of 5 x10 7 CD3 + cells/kg was reached, and no patient developed acute or chronic GVHD. HLA loss and CD8 + T cell senescence may be associated with non-response in AML patients. A clinical trial utilizing alloMILs as maintenance therapy for patients with measurable residual disease is in development.

Teclistamab Induces Favorable Responses in Patients with Relapsed and Refractory Multiple Myeloma after Prior BCMA-Directed Therapy

Introduction: Teclistamab (TEC) received regulatory approval for the treatment of patients with Relapsed/Refractory Multiple Myeloma (RRMM) after ≥ 3 prior lines of therapy based on the results of the pivotal MajesTEC-1 trial in which such patients achieved an overall response rate (ORR) of 63%, ≥ complete response (CR) of 39%, and median progression free survival (PFS) of 11.3 months (Moreau et al. N Engl J Med 2022). Patients who had received a prior B-cell maturation antigen-targeted therapy (BCMA-TT) were excluded from MajesTEC-1 trial. Data on the efficacy of TEC in patients who have received and relapsed after prior BCMA targeted therapy is lacking. Several studies have shown reduced efficacy of both FDA approved BCMA targeted chimeric antigen receptor T cell therapies (CAR-T) for myeloma, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), when administered after BCMA targeted bi-specific antibodies. There is a paucity of data on the efficacy of TEC when administered in patients who progress after ide-cel or cilta-cel. We evaluated the real-world outcomes of patients treated with standard of care (SOC) TEC after having previously received a BCMA-TT. Methods We performed a retrospective chart review to find patients treated at our center that were > 30 days from first dose of commercial TEC, received at least one prior BCMA-targeted therapy, and were consented to an IRB approved registry protocol. Cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) were graded per ASTCT consensus criteria, while responses were graded based on the International Myeloma Working Group (IMWG) response criteria. Results: A total of 22 patients who had received prior BCMA-TT and TEC were evaluable for response, safety, and survival analyses. Median age was 66 years (range 48-81), 59% were male, and 13% had an ECOG PS ≥2. Beside prior BCMA-TT, other exclusion to MajesTEC-1 would have been cytopenias (27%), performance status ≥2 (9%), creatinine clearance <40 mL/min (5%), and plasma cell leukemia (5%). Eleven pts (50%) had high risk cytogenetics (defined as del17, t(4;14), t(14;16)), and 13 pts (59%) had gain 1q. Patients were heavily pretreated with a median of 8 (5-13) prior lines of therapy, 45% had R-ISS III, 14% had extramedullary disease (EMD), 27% had a high marrow burden (≥60% PCs in the marrow) and 11 (50%) were penta-class refractory. Sixty-eight percent (n=15) had received prior Chimeric Antigen Receptor T-cell Therapy (CAR-T), 9% (n=2) prior Antibody Drug Conjugate (ADC), and 23% (n= 5) both CAR-T and ADC, all BCMA-TT. Median time from prior BCMA-TT to TEC was 12.3 (1.3-33.5) months. With a median follow up of 4.16 (1.07-7.27) months, the best overall and ≥ CR response rates were 63% and 36% (N=8), respectively. Of those who had achieved a ≥ CR, 3 were MRD negative by clonoSEQ® (10 −6). Thirteen (57%) pts received TEC as the next line of therapy from prior BCMA-TT. Thirteen of 14 pts tested for BCMA expression were positive by IHC, with 9 expressors responding to TEC; the non-expressor responded to TEC. Toxicity was comparable to that seen in MajesTEC-1. Cytokine release syndrome (CRS) of any grade occurred in 16 (73%) pts. All events occurred during step-up and cycle 1 doses. All events of CRS were grade 1 (n=13; 59%) and 2 (n=3; 14%). The median time to onset of CRS was 3 (1-12) days after the most recent dose, and the median duration was 3 (1-9) days. Tocilizumab was administered to 4 (18%) pts. Only 1 patient had ICANS, grade 3 and requiring steroids. Infections were seen in 12 (55%) pts, including viral (10), bacterial (1), and fungal (1). 6 (50%) infections were deemed severe and required hospitalization. Prior to TEC, 13 (59%) pts had hypogammaglobulinemia (IgG< 400). After TEC, 6 pts developed new hypogammaglobulinemia. 11 (50%) pts had treatment delays, mainly due to CRS and infections. Four pts died due to progression of disease. Conclusions: This single center study in patients with heavily pretreated and prior BCMA-TT demonstrated favorable ORR (63%) and CR (36%) rates, comparable to pts in the MajesTEC-1 trial, without prior BCMA-TT exposure. No new safety signals were identified. Results on progression free survival (PFS) and overall survival (OS) will be reported with continued follow up and will be presented in the meeting.

Randomized Phase 3 Study of Pomalidomide Cyclophosphamide Dexamethasone (PCD) Versus Pomalidomide Dexamethasone (PD) in Relapse or Refractory Myeloma: An Asian Myeloma Network (AMN) Study

Introduction Patients with multiple myeloma (MM) who relapse or are refractory to (RRMM) lenalidomide and bortezomib have survival of less than 1 year. Pomalidomide (pom) is an immunomodulatory drug shown to improve survival in this group of patients 1. Optimal drugs to combine pom with are not known; patients tend to be triple class refractory by the time they require pom. We aim to compare pom, cyclophosphamide and dexamethasone (PCD) with pom and dexamethasone (PD) in Asian patients with RRMM 2. Methods This was a randomized, two arm, multicentre, multinational, prospective phase 3 study. RRMM patients with prior exposure to proteasome inhibitor (bortezomib, carfilzomib or ixazomib) and lenalidomide were recruited. Other inclusion criteria were: measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, satisfactory organ function (neutrophil count ≥ 1 000/mm 3, platelet ≥ 50 000/mm 3, bilirubin ≤ 1.5 x upper limit of the normal range (ULN), alanine aminotransferase and aspartate aminotransferase ≤ 3 x ULN and creatinine clearance ≥ 30ml/min). Patients with plasma cell leukaemia, > 6 lines of treatment or prior exposure to pom were excluded. Patients were randomized in a 1:1 ratio to receive PCD or PD. Dosing schedule was 4-weekly: pom 4mg day 1 - 21, dexamethasone 40mg twice a week and, for patients on PCD, cyclophosphamide 400mg weekly for 3 weeks. Patients received treatment until disease progression, unacceptable toxicity determined by treating physician, consent withdrawal or death. A modified intention-to-treat population was used for analysis, which included all randomized patients receiving at least 1 dose of study drug. Primary endpoint was progression free survival (PFS), defined as time from start of treatment to disease progression or death from any cause. Secondary endpoints were overall response rate (ORR, percentage of patients achieving partial response (PR) or better), overall survival (OS), duration of response (DOR, time from first evidence of PR or better till disease progression or death, whichever occurred first) and safety, assessed by frequency and percentage of adverse events by severity. PFS, OS and DOR were presented using Kaplan-Meier curves. Comparison between 2 arms was performed by Cox proportional hazard model for PFS, OS and DOR, using generalized linear model with binomial distribution for ORR. Results 124 patients were recruited, of whom 122 received at least 1 dose of study drug (62 PCD, 60 PD). Baseline characteristics were comparable between treatment arms (Table 1). Median age was 68.5 (range 47 - 88) years in the PCD arm; 67.2 (range 48 - 85) years in the PD arm. Patients in both arms received median of 3 (range 1-6) prior lines of treatment. At a median follow-up of 13.5 (IQR 8.7 - 24.0) months, median PFS was 10.9 months (95% CI, 7.1 - 27.7) in the PCD arm versus 5.8 months (95% CI, 4.4 - 6.9) in the PD arm (hazard ratio (HR) 0.43, 95% CI, 0.27-0.69); p < 0.001). ORR was 55.4% (95% CI, 41.0 - 69.7) in the PCD arm and 32.0% (95% CI, 19.5 - 44.5) in the PD arm; difference 23.3% (95% CI, 6.5 - 40.2, p = 0.007). Median DOR was 12.0 months (95% CI, 7.2 - not reached, NR) in the PCD arm and 5.7 months (95% CI, 3.7 - 9.7) in the PD arm (HR 0.41, 95% CI, 0.20 - 0.87). Although not statistically significant, median OS was numerically greater in the PCD arm (41.5 months, 95% CI, 24.5 - NR) in comparison with the PD arm (27.5 months, 95% CI, 27.5 - NR). Median treatment duration for pom was 7.8 (IQR 4.4 - 13.4) months in the PCD arm and 5.1 (IQR 2.8 - 8.7) months in the PD arm. Adverse events rates were similar in both arms. 51 patients (82.3%) in the PCD arm had 346 treatment emergent adverse events (TEAEs); 164 (47.4%) relating to study treatment. 49 patients (81.7%) in the PD arm had 241 TEAEs; 136 (56.4%) relating to study treatment. Most common grade 3/4 TEAEs in both arms were neutropaenia, anaemia and pneumonia. 34 deaths occurred during the study (17 PCD, 17 PD), 12 (35.2%) were due to disease progression. 3 (1 PCD, 2 PD) were deemed to be related to study treatment (2 infections, 1 fluid overload). Conclusion This study demonstrated that PCD significantly prolonged PFS, improved ORR, and DOR over PD in patients with RRMM and previous exposure to a proteasome inhibitor and lenalidomide. PCD treatment presents a therapeutic option in this population of patients, with acceptable and manageable safety profile.