Marrow Plasmacytosis Research Articles

Long-term outcomes of renal AL amyloidosis patients undergoing autologous stem cell transplantation: Validating the performance of the renal staging system.

Renal AL amyloidosis can be complicated by end-stage renal disease (ESRD) requiring renal replacement therapy (RRT). In this study, we describe the long-term outcomes of renal AL amyloidosis patients undergoing autologous stem cell transplantation (ASCT) and assess the utility of the renal staging system. Retrospective study of renal AL patients (n = 697; Mayo Clinic, Boston University) who underwent ASCT between 2003 and 2020. Renal stage was assigned based on 24-h proteinuria and estimated glomerular filtration rate measurements. Renal survival was defined as the time from ASCT until initiation of RRT, while patients who were not placed on RRT were censored at their last follow-up. With a median follow-up of 10.4 years, RRT was required in 149 patients (21%). The median time from ASCT to ESRD was 3.4 years, with late events of progression to ESRD seen >10 years from ASCT. Pre-ASCT renal stage was significantly associated with the cumulative incidence of RRT: 3-year RRT rate was 3%, 10%, and 37% for renal stages I, II, and III, respectively. However, in the 2012-2020 period subset, a significant decrease in ESRD risk was noted across all renal stages (3-year RRT 0%, 5%, and 24%, respectively). In multivariate analysis, renal survival was independently associated with the pre-ASCT renal stage, lambda isotype, bone marrow plasmacytosis ≥20%, post-ASCT hematologic response, and year of ASCT. Long-term outcomes of renal AL amyloidosis treated with ASCT are presented. Renal stage reliably predicts renal outcomes in patients with AL undergoing ASCT, despite a reduction in the proportion of patients progressing to RRT in recent years.

#2622 Very late renal recovery in patient with light chain cast nephropathy: the prognostic value of renal biopsy

Abstract Background and Aims Renal biopsy is not necessary to assess LCCN (Light Chain Cast Nephropathy) in patients with laboratory features suggestive of the disease. However, it has been shown that the histological picture often correlates with renal outcome. We present the case of a 55-year-old man with no significant previous medical history that was evaluated in the emergency department for a stage 3 AKI (sCr 17.3 mg/dl, eGFR 3 ml/min/1.73 m2). Laboratory tests showed a Lambda Micromolecular Myeloma (K chains 44.6 mg/l, λ 4160 mg/l and K/ λ 0.01); Bence Jones not evaluable due to anuria. Bone marrow plasmacytosis was 70%. Method The patient started chemotherapy with Bortezomib and Dexamethasone and hemodialysis thrice a week with a PMMA hemofilter in order to improve the FLC (Free Light Chain) removal rate. After three months of treatment the patient achieved a complete hematologic response but he didn't reach any renal response. In order to assess a more precise renal prognosis a kidney biopsy was performed. The histopathological exam showed a Cast Nephropathy (< 5 casts/mm2) associated with low grade interstitial fibrosis and tubular atrophy (IFTA +1). After 5 cycles with Bortezomib and Dexamethasone, one year after onset, the patient underwent ASCT (Autologous Stem Cell Transplantation). Results In the following months, a progressive increase in renal function allowed us to perform a gradual reduction of dialysis rate, until discontinuation occurred 16 months after disease onset. To date, three years after onset, complete hematologic and renal remission persists with an eGFR of 20 ml/min/1.73 m2. Conclusion Renal biopsy, performed even several months after disease onset, could play a pivotal role in cases of LCCN with a discordance between hematologic and renal response. A low cast number and low IFTA grade are known to be positive prognostic factors for renal outcome and they can predict a renal recovery that sometimes could be exceptionally late.

Asymptomatic skin lesions as a diagnostic clue in multiple myeloma – A case report

Multiple myeloma (MM) is a rare cancer of plasma cells in the bone marrow. Cutaneous plasmacytoma is an uncommon but specific skin lesion in MM with an incidence of 2%. Cutaneous plasma cell infiltration in pre-existing MM is a very rare phenomenon, with approximately 100 cases described in the literature. Here, we report a case of a 61-year-old male who presented with asymptomatic skin nodules and plaques over the chest, abdomen, and back of the trunk for five months. Histopathological examination showed mononuclear cells with moderate cytoplasm and round to ovoid nuclei. Immunohistochemistry showed CD138 and kappa positivity and lambda and CD20 negativity, confirming the diagnosis of cutaneous plasmacytoma. Bone marrow biopsy and immunohistochemistry revealed bone marrow plasmacytosis with kappa light chain restriction. Serum free light chain ratio was 106.61 and fluorescence in situ hybridization showed del 13q. The clinical features and investigations fulfilled the diagnostic criteria for MM, and the patient was started on chemotherapy, following which the skin lesions improved. Development of skin lesions is seen in the advanced stages of MM and is considered a bad prognostic sign. However, they can also be seen as initial manifestations of the disease, as in this case. Hence, meticulous investigations and early diagnosis are of paramount importance.

Descriptive analysis and prognostic factors in cats with myeloma-related disorders: A multicenter retrospective study of 50 cases.

Myeloma-related disorders (MRDs) are rare and poorly documented neoplasms of cats. To describe clinical, clinicopathologic, and imaging findings, response to treatment, and survival time and to identify factors associated with shorter outcomes in cats with MRD. Fifty cats with a diagnosis of MRD. Cats with paraproteinemia confirmed by serum protein electrophoresis (SPE) and either intramedullary plasmacytosis >10%, marked cytonuclear atypia with intramedullary plasmacytosis that ranged between 5% and 10%, or cytologically or histologically confirmed visceral infiltration were retrospectively included from several veterinary referral centers. Bone marrow plasmacytosis and splenic or hepatic involvement were present in 17/27 cats (63%), 36/42 cats (86%), and 27/38 cats (71%), respectively. Anemia was reported in 33/49 cats (67%) and thrombocytopenia in 16/47 cats (34%). Some of the treatments that the cats received included melphalan and prednisolone (n = 19), cyclophosphamide and prednisolone (n = 10), chlorambucil and prednisolone (n = 4), prednisolone (n = 4), or other (n = 4). The overall response rates to melphalan, cyclophosphamide, and chlorambucil in combination with prednisolone were 87%, 90%, and 100%, respectively. Adverse events to melphalan or cyclophosphamide occurred in 65% and 23% of cats, respectively. Median survival time was 122 days (range, 0-1403) and was not significantly associated with chemotherapy protocol. Anemia (hazard ratio [HR], 3.1; 95% confidence interval [CI], 1.0-9.8) and thrombocytopenia (HR, 2.7; 95% CI, 1.2-6.0) were risk factors for shorter survival. Our study confirmed the guarded prognosis of MRD in cats and identified risk factors for shorter survival times.

Mode of progression in smoldering multiple myeloma: a study of 406 patients

The approach to patients with high-risk smoldering multiple myeloma (SMM) varies among clinicians; while some advocate early intervention, others reserve treatment at progression to multiple myeloma (MM). We aimed to describe the myeloma-defining events (MDEs) and clinical presentations leading to MM diagnosis among SMM patients seen at our institution. We included 406 patients diagnosed with SMM between 2013–2022, seen at Mayo Clinic, Rochester, MN. The 2018 Mayo 20/2/20 criteria were used for risk stratification. Median follow-up was 3.9 years. Among high-risk patients who did not receive treatment in the SMM phase (n = 71), 51 progressed by last follow-up; the MDEs included: bone lesions (37%), anemia (35%), hypercalcemia (8%), and renal failure (6%); 24% met MM criteria based on marrow plasmacytosis (≥60%) and/or free light chain ratio (>100); 45% had clinically significant MDEs (hypercalcemia, renal insufficiency, and/or bone lesions). MM diagnosis was made based on surveillance labs/imaging(45%), testing obtained due to provider suspicion for progression (14%), bone pain (20%), and hospitalization/ED presentations due to MM complications/symptoms (4%). The presentation was undocumented in 14%. A high proportion (45%) of patients with high-risk SMM on active surveillance develop end-organ damage at progression. About a quarter of patients who progress to MM are not diagnosed based on routine interval surveillance testing.

Caseinolytic Mitochondrial Matrix Peptidase Proteolytic Subunit (CLPP) As a Novel Mediator of, and Target in High Risk Multiple Myeloma

Background: Up to 30% of newly diagnosed myeloma (NDMM) patients have high-risk disease characterized by increased proliferation, resistance to apoptosis, focal and bone marrow-independent growth, and intraclonal heterogeneity. High-risk can be defined by fluorescence in situ hybridization (FISH) features including 17p deletion, translocation (t)(4;14), t(14;16), or t(14;20), and gain of 1q. However, some standard risk patients also exhibit high-risk characteristics, indicating that identifying novel targetable mediators of this phenotype is of interest. Methods: We conducted single cell RNA-Sequencing (scRNA-Seq) of CD138 + monoclonal/neoplastic and polyclonal/normal plasma cells (PCs) from 72 individuals across the plasma cell dyscrasia spectrum and 3 healthy controls to identify differentially expressed genes associated with myeloma pathobiology. Also, we leveraged publicly available gene expression profiling (GEP) databases, and performed pre-clinical studies both in vitro and in vivo. Results: CLPP was expressed with increased frequency in NDMM and relapsed/refractory myeloma patients compared to the precursors monoclonal gammopathy of undetermined significance and smoldering myeloma (GSE6477; p=4.03x10 -14). Notably, CLPP is the proteolytic component, along with CLPX, of the CLP complex which cleaves peptides and proteins in an ATP-dependent manner and is associated with the inner mitochondrial membrane. The GEP data were confirmed in our scRNA-Seq database, which showed CLPP over-expression occurred preferentially in each patient's monoclonal versus their own polyclonal PCs. Moreover, analysis of the Broad Institute Cancer Cell Line Encyclopedia revealed MM cells had the highest mean CLPP expression of any tumor cell type. In the NDMM CoMMpass database, high CLPP levels were associated with markers of increased disease burden (beta-2-microglobulin (p<0.001), calcium (p=0.0027), circulating plasma cells (p<0.001), marrow plasmacytosis (p<0.001), and lactate dehydrogenase (p=0.0025)). Moreover, these patients showed a significantly shorter progression-free and overall survival (both p<0.0001), and did not cluster in any of the Arkansas GEP70-defined myeloma subtypes. In MM.1S and H929 myeloma cells, specific CLPP knockdown with an inducible shRNA decreased cell proliferation and activated apoptosis as shown by increased Annexin V positivity. Similarly, pharmacologic CLPP inhibition produced a time- and concentration-dependent induction of apoptosis in a panel of cell lines representing myeloma molecular subtypes and drug resistant phenotypes. Ectopic CLPP overexpression promoted myeloma organoid growth, while its suppression had the opposite effect. Functional analysis revealed that CLPP knockdown or inhibition impaired cell proteolytic activity, mitochondrial transmembrane potential, and reduced adhesion to stromal cells while inducing reactive oxygen species and autophagy. To further pursue the underlying molecular mechanisms, we first examined the net downstream effects of CLPP knockdown and inhibition by mass spectrometry followed by mapping to the KEGG database. Recurrently up-regulated pathways included the mitochondrial unfolded protein response (UPR mt), lysosome transport, and autophagy utilizing and metabolic processes. In contrast, down-regulated pathways included oxidative phosphorylation, c-Myc signaling, RNA polymerase I-directed transcription, DNA replication and elongation, and the G2M checkpoint. Next, our metabolomics analysis revealed a significant attenuation of the Warburg effect in myeloma cells upon CLPP inhibition consistent with reduced glycolysis and pentose phosphate pathway activity. Notably, mitochondrial ATP production was significantly reduced, as confirmed by a seahorse XF Real-time ATP Rate assay. Finally, in vivo experiments demonstrated that pharmacologic CLPP inhibition impaired myeloma growth in an MM.1S-based xenograft model ( Figure). Conclusions: These pre-clinical data support the hypothesis that CLPP represents a novel mediator of high-risk behavior in multiple myeloma, demonstrate that its targeting results in mitochondrial dysfunction that attenuates myeloma growth and survival, and support development of pharmacologic CLPP inhibitors to target myeloma.

Teclistamab Induces Rapid Responses in Patients with Relapsed/Refractory AL Amyloidosis

Introduction Systemic light chain (AL) amyloidosis is a rare disorder characterized by tissue deposition of amyloid fibrils derived from immunoglobulin free light chains. While daratumumab in combination with cyclophosphamide, bortezomib and dexamethasone (Dara-CyBorD) is the standard for upfront treatment of AL, management of relapsed/refractory (R/R) disease is often challenging, particularly in context of multiorgan dysfunction. Teclistamab was recently approved for treatment of R/R multiple myeloma (MM) and showed an overall response rate (ORR) of 63% (N Engl J Med 2022;387:495). Notable adverse effects (AEs) included cytokine release syndrome (CRS), neurologic, renal and hematologic toxicities, and infections. Efficacy of teclistamab in AL has not been previously reported. Here, we present a series of three patients who received treatment with teclistamab for R/R AL and MM. Methods In this retrospective study, we included all patients with R/R AL and MM who received teclistamab at two US academic centers between October 2022 and July 2023. We recorded all standard metrics, including serologic and biomarker data. Hematologic and organ responses were evaluated based on standard consensus criteria. Toxicity assessment was performed in accordance with the NCI CTCAE v5.0, except for CRS and neurotoxicity, which were graded according to the 2019 ASTCT criteria (BBMT 2019;25:625). Results We identified 3 patients; baseline characteristics are provided in Table 1 and treatment data in Table 2. Median age was 67 years (range, 54-70). All patients were male, and 2 had AL λ-type. At the time of teclistamab initiation, the median number of prior therapies was 7 (5-10), with all patients being refractory to a bortezomib, lenalidomide and daratumumab. Median iFLC was 228 mg/L (45.5-1272) with 10% median bone marrow (BM) plasmacytosis. In one patient with rapidly progressive multiple myeloma, BM FISH showed high-risk cytogenetic changes, including gain 1q, del 1p and del 17p. All patients were hospitalized for treatment initiation and received escalating doses of 0.06 mg/kg, 0.3 mg/kg and 1.5 mg/kg during the ramp-up phase. Subsequent treatment with target dose of 1.5 mg/kg was continued in the outpatient setting on a weekly basis. Monitoring for cytokine release syndrome (CRS) and neurologic toxicity was performed in accordance with institutional protocols. At a median follow-up of 49 days (44-58), 2 patients achieved hematologic responses (HR), with 1 complete hematologic response (CR) and 1 low dFLC PR. Both hematologic responses occurred promptly within 3 weeks of treatment initiation, were deep with iFLC <10 mg/L, and were ongoing at the last follow-up. One patient with rapid renal progression prior to teclistamab also enjoyed a renal response by day 42. The most common toxicity was hematologic, with 1 patient experiencing grade 4 lymphopenia, grade 2 thrombocytopenia and hypogammaglobulinemia. There were no infectious complications or instances of febrile neutropenia, CRS or neurologic AEs. All patients received routine prophylaxis against VZV and PJP, as well as prophylactic IVIg. One patient with heavily pre-treated, high-risk MM had an aggressive clinical relapse with widespread osseous involvement within 6 months of an autologous stem cell transplant (ASCT) and experienced progressive disease as best response to teclistamab, necessitating discontinuation after 29 days in favor of cytotoxic chemotherapy. Conclusion In this series of 3 patients with heavily pre-treated, R/R AL and MM, teclistamab showed an impressive hematologic response rate of 67%. These responses were deep and occurred rapidly within 3 weeks of treatment initiation. One patient also enjoyed a renal response, whereas cardiac responses were non-evaluable in 2 patients. While the most common treatment-related toxicity was hematologic in nature, infections or febrile neutropenia were not observed, likely due to the institution of aggressive prophylactic measures. Importantly, no new safety signals were identified in AL patients. To our knowledge, this is the first report providing preliminary evidence for efficacy of teclistamab in R/R AL, highlighting the need to investigate this strategy in clinical trials.

Phase I/II Study of Belantamab Mafodotin, Cyclophosphamide, and Dexamethasone (BelCyd) in Relapsed/Refractory Multiple Myeloma

Background: We hypothesize that combining Belantamab (Bel) direct tumor kill with the immune modulatory properties of cyclophosphamide (Cy) will enhance cytokine profile, cytotoxicity & phagocytosis with improved overall response rate (ORR) & manageable toxicities. Methods: Phase 1 (dose escalation) evaluated 2 doses: Arm A: Bel 1.9 mg/kg IV Q3W; Arm B: Bel 2.5 mg/kg IV Q6W. On day 1, both arms included oral Cy 300 mg (A-1 & B-1) or 500 mg (A-2 & B-2) plus dexamethasone 40 mg. We report on phase I safety & efficacy; correlative studies: biomarkers [GM-CSF, Granzyme B, TNF, IFN-γ, IL-1, -2, -4, -5, -6, -7, -8, -10, -13,-17a, CXCL10 (IP-10), CCL2 (MCP-1), TGF-β1, MIP-1, & periforin] were measured in tears using BioLegend's LEGENDplex™ platform at baseline, during flare-ups & cycle 2 day 1. T cell subsets using antibodies from BioLegend's & BD Biosciences for the following markers [CD 3, -4, 8, -38, -14, -206, -183, -25, -185, -27, CCR 7 & 6, HLA DR, TCR gamma delta, 5, Treg, T-naive, TEM, Th1, NK cells & activated T cells] were assessed in peripheral blood at baseline & cycle 2 day 1. Results: 10 patients were treated on phase I; 2/3 patients on Arm A-1 developed DLT (corneal grade 3 with more than 8 weeks to resolution). Arm B-2 was selected for RP2D. Median age was 70 years old (range 56-72), 6 were white, 3 were black & 1 was Asian. Median time since diagnosis was 9 years with a median of 5 prior therapies (range: 4- 7) including Auto-SCT (n=7), Allo-SCT (n=1); all patients had received lenalidomide, pomalidomide, bortezomib, carfilzomib & daratumumab, 2 patients had BCMA CAR T cell therapy. All patients were refractory to last line of therapy. Six patients had high-risk cytogenetics, 5 had extramedullary plasmacytoma; median LDH was 398 units/L (range: 181-2303), median B2M was 3.5 (range: 2.7-5.6). median Marrow plasmacytosis was 40% (range: 20-100%); CD-138/BCMA staining ranged from 70-100%. There were no infusion related reactions, main adverse event was corneal toxicity (keratopathy or superficial epithelial changes) grade 3 (2 on arm A-1 & 1 arm B-2), grade 1-2 (1 arm A-1 & 6 on Arm B). recovery from corneal toxicity was protracted (up to 4 months) but without sequalae in all patients. Median cycles given was 3 (range 2-13); median time to best response was 42 days (range 21-196). All patients had reduction in M-spike; ORR was 50% [VGPR (n=1); PR (n=4)]. Five patients proceeded to CAR-T cell therapy (within 2-4 months of bel), none of them progressed on Bel. All 5 patients responded [sCR (n=3), VGPR (n=1) & PR (n=1)]. The two patients who relapsed (19 & 24 months) after prior BCMA- directed CAR-T therapy progressed within 2 months: 1 patient relapsing with extramedullary disease despite biomarker response to BelCyd. One patient remains on study & 2 discontinued therapy (1 PD & 1 patient preference). Correlative studies: Therapy evidently had an immune effect in peripheral blood & tears samples. In peripheral blood, percentage of CD3 + was lower on Cycle 2 day 1 than screening (average: 40%-30%); CD14 + / CD206 +CD14 + macrophages were higher (average: 34%-44% & 0.7%-1%, respectively). Interestingly, functionally active HLA-DR + NK cells doubled on C2 day-1 (average: 0.4%-0.8%); similar increase in HLA-DR +CD38 + CD8 + T cells was noted (Average: 7%-18%). In the tears, significantly higher levels of several proinflammatory cytokines (granzyme B, IL-7, IL-13, IP-10, MCP-1, MIP-1 alpha, TNF-beta) were found during symptomatic corneal disease compared with baseline (for e.g. granzyme B, cytotoxic T cell biomarker, increased from 65 pg/ml to 809 pg/ml in a patient with grade 3 corneal toxicity to 40 pg/ml after resolution of symptoms); Additional levels & correlation with corneal toxicity will be presented. Conclusion: The RP2D of BelCyd is 2.5 mg/kg Q6W plus Cy 500 mg & dexa 40mg; no new safety signal was seen. BelCyd activate NK, cytotoxic T cells & macrophages adding to Bel direct MM cytotoxicity. BelCyd did not negatively impact the efficacy of subsequent BCMA directed CAR-T cell therapy but does not seem effective as salvage after prior CAR-T therapy. Preliminary data suggest that in addition to direct impact of Belantamab on corneal epithelial cells, BelCyd modify the biomarkers of the tears suggestive of immune mediated changes, unclear if these are initiating events or secondary to epithelial damage. Phase 2 expansion is ongoing. This is an investigator-initiated trial supported by GSK; registered www.clinicaltrials.gov # NCT04896658

A Comparative Study of Clinical Characteristics, Cytogenetic Abnormalities and Outcomes Among Multiple Myeloma, Primary Light-Chain Amyloidosis and Multiple Myeloma with Concurrent AL Amyloidosis

Introduction: Multiple myeloma (MM) and light-chain (AL) amyloidosis are both plasma cell dyscrasias and may coexist in the same patients, contributing to distinct clinical outcomes. Although they share a similar spectrum of cytogenetic abnormalities (CA), the distribution and prognostic value of these aberrations are varied. The use of fluorescence in situ hybridization (FISH) in predicting outcomes for MM is well established, while the prognostic value of CA in AL amyloidosis, notably in MM with concurrent AL amyloidosis, is still evolving. This study aimed to evaluate the outcomes of patients with MM, AL amyloidosis and coexistence of the two disorders, and address the landscape and prognostic implication of CA in patients with these 3 types of plasma cell dyscrasias. Methods: A total of 902 consecutive patients with newly diagnosed MM between January 2007 and October 2021 or AL amyloidosis between January 2007 and June 2023 were retrospectively included. Patients were classified as MM alone, MM with coexistent AL amyloidosis (MM-AL) or primary AL amyloidosis alone (pAL-alone). The presence of symptomatic MM was based on the International Myeloma Working Group (IMWG) criteria and the diagnosis of AL amyloidosis was confirmed by Congo-red-positive biopsy and immunoelectron microscopy study of the amyloid. Demographic and clinical characteristics, FISH results, along with real-world effectiveness outcomes including best hematologic response, overall survival (OS), and progression free survival (PFS) were assessed. Results: Of the 902 patients enrolled, 658 patients were in the MM-alone group, 99 in the MM-AL group and 145 in the pAL-alone group. The three groups share a similar incidence rate of CA, while the prevalence of t(11;14) was significantly higher in pAL-alone group than MM-AL and MM-alone group (41.0% vs. 24.5% vs. 16.6%, p<0.001), and the prevalence of del13q14, gain1q21 and IMWG high-risk cytogenetic abnormalities [HRCA, including t(4;14), t(14;16) and del17p] decrease in turn in MM-alone, MM-AL and pAL-alone group(del13q14, 46.4% vs. 38.1% vs. 29.7%, p=0.005; gain1q21, 52.6% vs. 46.4% vs. 27.8%, p<0.001; HRCA, 27.5 % vs. 17.2 vs. 7.6%, p<0.001) (Table). In patients with AL amyloidosis with or without coexisting MM, presence of del13q14 was associated with higher level of baseline bone marrow plasmacytosis and difference in involved and uninvolved free light chain (dFLC). Compared with the MM-alone group, a significantly lower proportion of the MM-AL group achieved hematologic response (90.4% vs. 67.7%, p<0.001) and very good partial remission (VGPR, 44.6% vs. 68.9%, p<0.001). The OS of patients with MM-AL was significantly inferior to patients with MM-alone (median, 25.2 months vs. 96.8 months, p<0.001) or pAL-alone (median, 25.2 months vs. not reached, p<0.001 )(Figure B), while patients with MM-alone has shorter PFS than AL amyloidosis irrespective of the presence or absence of MM (MM-alone vs. pAL-alone: median, 56.8 months vs. not reached, p=0.007; MM-alone vs. MM-AL: median, 56.8 months vs. not reached, p=0.515) (Figure A). Other than MM-alone group, no significant difference in PFS and OS was found between pAL patients with and without HRCA, as well as the MM-AL group, indicating the difference in prognostic implications of common HRCAs among the three groups. When stratified by the type of plasma cell disorders and status of t(11;14) (a CA that strongly related to poor outcome of pAL), patients with MM-AL and t(11;14) presented the worst OS (median, 8.2 months, p<0.001) (Figure C). Conclusion: This comparative study presented an apparent discrepancy in distribution and prognostic role of CA in different plasma cell dyscrasias. Comparing with patients with MM-alone and pAL-alone, MM-AL patients, notably with the presence of t(11;14), had the poorest survival.

Identifying Early Suboptimal Hematological Response in Patients with AL Amyloidosis Treated with Bortezomib-Based Chemotherapy

Background: Achievement of rapid and deep hematological responses is critical in the treatment of AL amyloidosis, particularly for those patients with advanced cardiac involvement. The timing and depth of FLC reduction that defines suboptimal response and the need to switch to second-line therapy is uncertain. We aimed to determine the impact of hematological response after 2 months of bortezomib-based therapy on subsequent best hematological and organ responses and survival in patients with and without advanced cardiac disease. Methods: The cohort was derived from three amyloidosis centres in Australia (Brisbane, Perth and Sydney). Patients were identified with a diagnosis of AL amyloidosis, symptomatic organ involvement and initial treatment with a bortezomib-based regimen. The impact of hematological response after 2 months of treatment on subsequent best hematological, cardiac and renal response was assessed using Fisher's exact test. The impact on OS was assessed by landmark analysis using log-rank or Cox regression analysis. Organ involvement and response criteria were as per International Society of Amyloidosis recommendations. Results: 190 patients with AL amyloidosis were identified: Median age was 66 yrs and 38% were male. 74% of cases were lambda restricted, the median dFLC was 170mg/L, the median bone marrow plasmacytosis was 11% and 7% had symptomatic myeloma. Mayo 2004 cardiac stage was: 1 (14%), 2 (47%), 3A (23%) and 3B (16%). 69% had renal involvement with a median eGFR of 70mls/min and median proteinuria of 1.9g/d , with 7% dialysis dependent at presentation. Liver involvement was present in 16% and peripheral neuropathy in 27%. Bortezomib regimens were: VCD (75%), VCD+daratumumab (13%), MDV (5%), VD (5%) and VRD (2%), with a median of 6 cycles delivered (range 1-16). Median OS was 6.2 years which was adversely associated with more advanced cardiac disease: stage 1 (not reached), stage 2 (90 months), stage 3A (74 months) and stage 3B (24 months)(p=0.0001). Hematological response after 2 months of bortezomib-based induction was: CR (17%), VGPR (39%), PR (19%) and less than PR (13%). 9% of patients died prior to the 2 month response assessment and 5 patients (2%) had missing data. Failure to achieve PR by 2 months was associated with a low chance of achieving deep responses, with only 16% going on to achieve VGPR or better (p<0.001). Similarly, failure to achieve PR by 2 months predicted a low likelihood of improving organ function with less chance of cardiac (6% vs 56%, p=0.001) and renal (30% vs 46%, p=0.097) responses. In a landmark analysis, failure to achieve PR after 2 months predicted worse OS (median 31 vs 88 months, p=0.001), a finding confirmed in multivariate analysis including cardiac stage and age. Failure to achieve VGPR by 2 months was also associated with a lower likelihood of achieving subsequent deep hematological responses and organ responses but 38% still managed to achieve VGPR or better by the completion of therapy and 31% a cardiac response. When analysed among patients with Mayo Stage 3A or 3B cardiac disease (i.e. advanced cardiac involvement), however, failure to achieve VGPR by 2 months was associated with reduced likelihood of cardiac response (25% vs 61%, p<0.001) and worse overall survival (median OS 30 vs 72 months, p<0.001). In contrast, among patients with cardiac stage 1 or 2 disease, failure to achieve VGPR by 2 months was associated with a trend to reduced cardiac responses (35% vs 58%, p=0.083) but not overall survival (median 78 vs 96 months, p=0.224) Conclusion: Failure to achieve hematological PR after 2 months of bortezomib-based therapy defines a high chance of therapeutic failure in AL amyloidosis and such patients should be switched to alternate salvage therapy. In patients with advanced cardiac stage 3A and 3B disease rapid, deep responses are required and failure to achieve VGPR after 2 cycles also predicts poor cardiac response and survival and defines a suboptimal response. Failure to achieve VGPR by 2 months in patients with cardiac stage 1 or 2 disease, however, was not associated with therapeutic futility.

A prospective, multicenter study on hematopoietic stemcell mobilization with cyclophosphamide plus granulocyte colony-stimulating factor and 'on-demand' plerixafor in multiple myeloma patients treated with novel agents.

High-dose melphalan plus autologous stem cell transplantation (ASCT) is a standard of care for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM), and adequate hematopoietic stem cell (HSC) collection is crucial to ensure hematologic recovery after ASCT. In this prospective, observational study we evaluated HSC mobilization with granulocyte colony-stimulating factor (G-CSF), cyclophosphamide, and 'on-demand' plerixafor (in patients with <20×106 CD34+ cells/L after at least 4 days of G-CSF or failing to collect ≥1×106 CD34+ cells/kg after the first apheresis) in NDMM patients treated with novel agent-based induction therapy. The primary endpoint was the rate of poor mobilizers (patients collecting <2×106 CD34+ cells/kg or requiring plerixafor rescue to reach an adequate HSC harvest). Secondary endpoints included the rate of patients collecting ≥2×106 CD34+ cells/kg after plerixafor administration and the identification of factors predicting mobilization failure or plerixafor need. Overall, 301 patients (median age 60 years) were enrolled. Two hundred and eighty-seven of 301 (95%) and 274 of 301 (93%) patients collected ≥2×106 and ≥4×106 CD34+ cells/kg, respectively, with a median of 9.9×106 CD34+ cells/kg collected. Poor mobilizers were 48 of 301 (16%): 34 of 301 (11%) required plerixafor rescue, and 14 of 301 (5%) failed HSC collection regardless of plerixafor. Thirty-four of 38 (90%) patients receiving plerixafor collected ≥2×106 CD34+ cells/kg. Bone marrow plasmacytosis at diagnosis >60% (odds ratio [OR]=4.14), lenalidomide use (OR=4.45), and grade 3-4 hematologic toxicities during induction (OR=3.53) were independently associated with a higher risk of mobilization failure or plerixafor need. Cyclophosphamide plus G-CSF and 'on-demand' plerixafor is an effective strategy in NDMM patients treated with novel agents, resulting in a high rate of HSC collection and high HSC yield (clinicaltrials gov. identifier: NCT03406091).

Lysosomal Associated Membrane Protein Family Member 5 (LAMP5) As a Novel Mediator of, and Target in High Risk Multiple Myeloma (MM)

Background: Our recently published studies of single cell clonotypic and transcriptional evolution of multiple myeloma precursor disease (Dang et al. Cancer Cell, 2023), as well as related multi-omic studies of more advanced disease, identified a number of genes as potential contributors to progression. Among these is LAMP5, a gene on chromosome 20 that is markedly and specifically overexpressed in the malignant, monoclonal plasma cells in a high proportion of patients. As LAMP5 expression has also been associated with osteolytic bony disease in myeloma, we sought to delineate its potential contributions to the pathobiology of myeloma, which remain incompletely understood. Methods: The impact of LAMP5 knockdown and over-expression was studied using myeloma cell line models both in vitro and in vivo. Moreover, we generated a monoclonal antibody to LAMP5 after finding it was exposed on the myeloma cell plasma membrane, and converted this agent into an antibody drug conjugate (ADC) linked to monomethyl auristatin E (MMAE) or pyrrolobenzodiazepine ( PBD) dimers. Finally, we used the sequence of the single-chain variable fragment to generate LAMP5-targeted chimeric antigen receptor (CAR)-guided T-cells. Results: Analysis of the Multiple Myeloma Research Foundation's CoMMpass SM database indicated that high LAMP5 expression (defined as in the top quartile) in newly diagnosed myeloma patients was significantly associated with markers of increased disease burden, including a higher beta-2-microglobulin (p = 0.047), C-reactive protein (p = 0.0399), serum calcium (p &amp;lt; 0.0001), marrow plasmacytosis (p &amp;lt; 0.001), and a trend towards increased circulating plasma cells (p = 0.075). Moreover, high LAMP5 expression correlated with a shorter progression-free (p = 0.0006) as well as overall survival (p = 0.0006). Similarly, analysis of the University of Arkansas for Medical Sciences gene expression data indicated LAMP5 was increased in the hyperdiploid and proliferative groups that are associated with a poor prognosis. Inducible shRNA-mediated LAMP5 knockdown in myeloma cell lines conferred a survival disadvantage and activated apoptosis. RNA-sequencing analysis identified multiple dysregulated Hallmark pathways, including the G2M checkpoint, the mitotic spindle, apoptosis, mTORC1 signaling, and the unfolded protein response. Proteomic consequences of LAMP5 knockdown included Caspase-7, -8, and -3 cleavage, and increased abundance of Smac, Bim, and PUMA. By contrast, many G2M checkpoint proteins were down-regulated, including Aurora A, Checkpoint-1, Cell division cycle-6, and WEE1 kinases, and decreased levels of phospho-S807/S811 Rb protein were seen. Also, RNA-sequencing revealed mTORC1 pathway dysregulation, and proteomic studies showed decreased activity of AKT and AKT2, mTOR, and p70 S6 kinase. Notably, LAMP5 suppression was associated with reduced levels of expression of an RFP-LC3 fusion protein consistent with a role for LAMP5 in autophagy. In contrast, high LAMP5 expression was associated with improved colony formation in vitro ( A), and promoted disease progression in vivo. Since the LAMP5 promoter had consensus retinoic acid sites, we tested all-trans retinoic acid and found it suppressed LAMP5 protein expression, and reduced in vitro clonogenicity. Finally, since other LAMPs can under some circumstances be found at the plasma membrane, we performed flow and LAMP5 was indeed detected on the surface of unpermeabilized LAMP5-positive myeloma cells. We thus developed a panel of monoclonal antibodies that recognized the extracellular domains of LAMP5, and converted one of these into antibody drug conjugates (ADCs) linked to either MMAE or PBD. Both ADCs reduced the viability of LAMP5-positive myeloma cells in a time- and concentration-dependent manner ( B), activated immunogenic cell death in vitro, and also showed anti-tumor activity in vivo. Importantly, LAMP5-directed CAR T-cells similarly and specifically eliminated only LAMP5-positive myeloma cells with efficacy that was comparable to that of B-cell maturation antigen-targeted CAR T-cells. Conclusions: These pre-clinical in vitro and in vivo data support the possibility that LAMP5 represents a novel mediator of myeloma clonogenicity and high-risk behavior, and that it could serve as a rational therapeutic target leveraging immune therapies that recognize the extracellular domains of cell surface LAMP5.

Patterns of Response to 200 Mg Linvoseltamab in Patients with Relapsed/Refractory Multiple Myeloma: Longer Follow-Up of the Linker-MM1 Study

Background Linvoseltamab, a B-cell maturation antigen (BCMA)×CD3 bispecific antibody, demonstrated promising efficacy and generally manageable safety as therapy for relapsed/refractory multiple myeloma (RRMM; Lee et al. ASCO 2023). Here we report additional analysis of efficacy, including response pattern over time, and safety. Methods To enroll into LINKER-MM1 (NCT03761108) patients (pts) had to have multiple myeloma (MM) that either progressed on/after ≥3 lines of therapy including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody; or that was ≥triple-class (PI/IMiD/anti-CD38 antibody) refractory. Pts received intravenous linvoseltamab once a week through week 14, then once every two weeks. In the 200 mg phase 2 expansion cohort, pts achieving very good partial response (VGPR) or better received linvoseltamab once every four weeks after week 24. Primary endpoint was objective response rate (ORR). Key secondary endpoints included progression free survival (PFS) and overall survival. Treatment-emergent adverse events (TEAEs) reported are those that occurred from first dose until 30 days after the end of study treatment. Results As of February 28, 2023, 117 MM pts enrolled into the 200 mg cohort; median age was 70 (range: 37-91) with 26% ≥75, 26% were non-white, 14% had extramedullary (excluding paramedullary) plasmacytomas ≥2 cm, 36% had a high-risk cytogenetics, 22% had bone marrow plasma cells ≥50%, and 74% were ≥triple-class refractory. Median duration of follow-up was 5.6 months (interquartile range [Q1-Q3]: 3.02-8.34) ORR was 71% with ≥complete response (CR) rate of 30%. Responses deepen over time: median time to ≥partial response (PR) was 0.95 months (Q1-Q3: 0.76-1.87); median time to ≥VGPR was 1.87 months (0.79-3.55); and median time to ≥CR was 5.32 months (3.71-7.69). Moreover, high ORR and high rates of ≥CR were observed in many subgroups of difficult-to-treat MM pts. Specifically, ORR and ≥CR rates were: 70% and 29% in pts with ≥triple-class refractory disease; 68% and 26% in pts ≥75 years old; 62% and 26% in pts with high cytogenetic risk; and 47% and 18% in pts with International Staging System stage III. High rates of overall response and ≥CR were also observed in patients with high tumor burden as determined by various measures including bone marrow plasmacytosis ≥50% (50% and 31%) and soluble BCMA at baseline ≥ 0.4mg/L (55% and 25%). Kaplan-Meier (KM) estimated median duration of response was not reached (NR) (95% confidence interval [CI] non-evaluable [NE], NE), and probability of response at 12 months was 79% (95% CI 63, 89). KM estimated median PFS was NR (95% CI NE, NE) and probability of PFS at 12 months was 66% (95% CI 52, 77). TEAEs occurred in all patients with Grade [Gr] ≥3 in 79%. The most common TEAE was cytokine release syndrome (any grade: 45%, Gr3-4: 1%, Gr5: 0; tocilizumab was utilized to treat these symptoms in 16 [13.7%] pts). Other common TEAEs were cough (33%, 0, and 0), neutropenia (32%, 31%, and 0), diarrhea (32%, 2%, and 0), and fatigue (32%, 0, and 0). Rate of infections of any grade was 59.8% with ≥Gr3 in 36.8%. The most common infections were pneumonia (any grade 17.1%, ≥Gr3 13.7%), upper respiratory tract infection (12.0%, and 2.6%), and COVID-19 (12.0%, 5.1%). Opportunistic infections (any grade) were observed in 9 (7.7%) pts including 7 (6.0%) pts ≥Gr3. Twenty-six of 117 (22%) pts were treated with intravenous immunoglobulin. Conclusions Linvoseltamab 200 mg induced deep responses in patients with RRMM including those with high-risk myeloma and high tumor burden, and deepened responses over time while maintaining a generally manageable safety profile. More mature data with longer follow-up will be reported at the meeting.

P-127 Bone marrow plasmacytosis >5% at time of autologous transplant influences survival outcomes in patients with standard risk cytogenetics

P-127 Bone marrow plasmacytosis >5% at time of autologous transplant influences survival outcomes in patients with standard risk cytogenetics

Predictors of treatment response and survival outcomes in patients with advanced cardiac AL amyloidosis

AbstractPatients with advanced cardiac immunoglobulin light chain (AL) amyloidosis have a poor prognosis. Early hematologic and cardiac responses can prolong survival, but predictors of these outcomes have yet to be clarified. We report on 142 patients with newly diagnosed stage IIIb AL amyloidosis. After a median follow-up of 60 months, the median overall survival (OS) was 9 months. Independent baseline factors associated with shorter OS were symptom onset to diagnosis >6 months (hazard ratio [HR], 1.94; P = .003); bone marrow plasmacytosis ≥ 10% (HR, 1.98; P = .01); troponin I > 0.635 ng/mL (HR, 1.62; P = .04); New York Heart Association class III or IV (HR, 1.67; P = .04); and 6-minute walk test distance < 200 m (HR, 1.85; P = .01). Early hematologic (within 1 month) and cardiac (within 3 months) responses were significantly associated with longer survival. In a 1-month landmark analysis, patients with a hematologic very good partial response, partial response, and no response had a median OS of 47, 25, and 5 months, respectively (P < .0001). Patients with cardiac response at 3 months had significantly longer OS (47 vs 11 months; P < .0001). On multivariable modeling, bortezomib use was associated with early hematologic and cardiac responses and longer OS. Symptom onset to diagnosis duration of >6 months and difference between the involved and uninvolved free light chain > 350 mg/L were independently associated with lower odds of an early cardiac response. This study identified factors predictive of treatment outcomes and survival in advanced cardiac AL amyloidosis.

PB1997: DARATUMUMAB, LENALIDOMIDE, BORTEZOMIB, AND DEXAMETHASONE FOR TRANSPLANT-ELIGIBLE NEWLY DIAGNOSED MULTIPLE MYELOMA: OUTCOME AND SAFETY PROFILE FROM A REAL-WORLD SINGLE CENTER EXPERIENCE

Background: lenalidomide, bortezomib, and dexamethasone (RVd) followed by autologous stem cell transplant is standard frontline therapy for transplant eligible newly diagnosed multiple myeloma (MM).The addition of daratumumab (D) to RVd improve the depth of response (Stringent complete remission and MRD negativity). RVd-D combination is now being suggested as first-line treatment. Real-word data is lacking. Aims: We aim to share our experience regarding clinical response and safety profile of D-RVd for treatment of newly diagnosed transplantation eligible MM patients. Methods: We conducted a retrospective study with medical review of all patients diagnosed with multiple myeloma and treated with D-RVd at The National Center for Cancer Care and Research (NCCCR) in Qatar between January 2019 to December 2021. Overall response rate and safety profile were evaluated. All analyses were descriptive and exploratory in nature. Results: Fifteen newly diagnosed MM patients had received D-RVd in the time period of the study. The median age of patients was 58 year (range, 36-68 years) and the majority 12 (80 %) were male. The immunoglobulin (Ig) subtypes were IgG 9 (60%), IgA 3 (20%), free light chain 3 (20%). At diagnosis, 14 patients had bone lesions and 4 had extramedullary plasmacytoma. Anemia, hypercalcemia (serum calcium > 2.6 mmol/L) and/or renal impairment (serum creatinine > 133µmol/L) was present in 66%, 66% and 33% of patients respectively. Bone marrow plasmacytosis more than 60% on bone marrow examination was reported in 11/14 (78%) of patients. The proportion of patients at ISS stage I, II, and III were 1 (7%), 6 (40%), 8 (53%) respectively. Cytogenetic abnormalities detected via karyotyping and/or FISH were present in 9 of 12 evaluated patients. The average number of D-RVd were 4 cycles. The overall response rate (ORR) post induction therapy was evaluated in 14 patients (one patient was not evaluated for response due to early death), 9 (64%) patients had a complete response (CR), 4(29%) had very good partial response (VGPR) and one had partial response (PR). No myeloma progression while receiving induction therapy occurred. So far, seven patients have undergone autologous stem cell transplant. Median CD 34+ cell yield was 5,2 million cells per kg body weight, plerixafor were used in 5 patients and 5 patients required more than one apheresis session. Survival data to be collected and reported after a longer follow up period. The most common adverse events (AEs) were hematological toxicities; grade 3/4 neutropenia was detected in 6 patients (40%), thrombocytopenia in 3 patients (20%), lymphopenia in 4 patients (27%) and leukopenia in 2 patients (13%). Infusion reactions occurred in 2 patients (13%), one of them experienced anaphylactoid reaction that required infusion interruption. Non-hematological AEs where uncommon and included grade 2 hepatotoxicity in one patient and venous thrombosis in one patient. None of the AEs lead to treatment discontinuation. One death occurred early during the second cycle due to streptococcus pneumoniae meningitis. Image:Summary/Conclusion: Our real-world results show a high response rate (CR/VGPR) to D-RVd as first-line treatment in transplantation eligible patients with MM. However, the feasibility and safety of this treatment regimen needs to be confirmed in larger prospective studies.

Reactive bone marrow plasmacytosis: A common denominator with diverse etiology

Background and Aims: Reactive plasmacytosis (RP) is characterised by the diffuse distribution of mature polyclonal plasma cells in the bone marrow (BM) and it is known to occur in various disorders. These need to be differentiated from the clonal plasma cell dyscrasias (PCD). We aim to study the morphological features of RP and to help differentiate them better from PCD. Materials and Methods: We analysed 1409 consecutive BM aspirates for the percentage of plasma cells along with the associated clinical findings. The study group included cases with BM RP and the polyclonality being supported by serum protein electrophoresis or by kappa/lambda immunohistochemistry on BM biopsy. The clinical records, haemogram and BM aspiration findings were retrieved and reviewed in all cases. Morphological features of RP cases were analysed in detail. Further, these cases were compared with 10 confirmed cases of PCD in an attempt to distinguish between the two on morphology. Results: A total of 210 BM aspirates showed increased plasma cells (>3.5%). Clonality could be proven in 135 cases, of which 98 cases were polyclonal and 37 were PCD. Majority of RP cases were >40 years with male predominance. The plasma cell concentration in RP ranged from 4% to 25%. The associated diseases included infections followed by autoimmune diseases. On the morphology, RP unveiled scattered, non-aggregated mature plasma cells while in PCDs, there was a mixture of both immature and mature forms including plasmablasts with frequent clustering. Conclusion: A number of diseases show increased percentage of plasma cells in BM raising suspicion of PCD. It may be difficult to distinguish reactive from neoplastic conditions as there is an overlap both in cell counts and morphology. Assessment of subtle morphological features along with associated clinical and laboratory findings are cardinal for making a correct diagnosis.

Belantamab Mafadotin in Patients with Relapsed/Refractory AL Amyloidosis with Myeloma

Belantamab Mafadotin in Patients with Relapsed/Refractory AL Amyloidosis with Myeloma

Fixed duration vs. prolonged duration treatment after first line therapy in patients with systemic light chain amyloidosis

Background The main objective of treatment in systemic light chain amyloidosis (AL amyloidosis) is to achieve the best hematological response. Deeper responses are associated with better organ responses and survival. In this study, we analysed the efficacy of prolonged duration treatment after first line in patients with AL amyloidosis. Methods Retrospective analysis that included patients older than 18 years with AL amyloidosis. We excluded patients with more than 30% marrow plasmacytosis or concurrent multiple myeloma. Two cohorts identified accordingly if they received or not prolonged treatment after the first line. Survival analysis regarding progression free survival (PFS) and overall survival (OS) estimated with Kaplan–Meier and comparisons between groups with log-rank. Results Thirty-eight patients were included in the analysis with a median age of 55 years. Twenty-one patients received prolonged duration treatment and 17 did not. In the prolonged duration group, after a median duration of 12 months, the median PFS was 58.8 months. In the fixed duration treatment group, PFS was 30.6 months. The difference was significant with p = .0045 favouring prolonged duration treatment. Organ response was sustained for a longer period in the prolonged duration treatment group. For OS, the difference was not significant. Conclusions Prolonged duration treatment in patients with systemic light chain amyloidosis correlated with better PFS and deeper organ responses. Prospective studies are needed to analyse this further.

Pomalidomide (Pom) Dexamethasone (D) With Or Without Oral Weekly Cyclophosphamide (Cy) For Lenalidomide Refractory Multiple Myeloma (LRMM): A Multicenter Randomized Phase II Trial

IntroductionPomD results in an overall response rate of 30% and median PFS of 3.8 months in patients with prior lenalidomide (L) and bortezomib (Vij et al. ASCO 2012). We thought to investigate the addition of oral weekly Cy to PomD in patients with LRMM. We have previously reported that the recommended phase II dose of Cy with standard dose Pom D was 400 mg PO D1, 8, 15. We herein report aggregated results of the phase I/II trial. PatientsEligible patients had relapsed and refractory myeloma after at least 2 prior therapies and were L refractory. Patients had a platelet count≥50,000/ mm3 and ANC≥1,000/mm3 (patients with ≥50% bone marrow plasmacytosis were allowed if platelet count ≥30,000/mm3 and ANC could be supported with GCSF during screening and therapy). In the phase II portion, patients were randomized (1:1) to receive pomalidomide 4mg PO D1-21, dexamethasone 40 mg PO D1,8,15,22 (20mg if older than 75 years) with or without oral cyclophosphamide 400 mg PO D1, 8, 15 of a 28 days cycle. Patients randomized to PomD were allowed to cross over to the PomCyD in the event of disease progression. Thromboprophylaxis was mandated with aspirin, warfarin or LMWH. Responses were assessed per the IMWG criteria with the addition of minimal response (MR, ≥25% decrease in serum component). ResultsBetween 1/2012 and 7/2013, 70 patients were enrolled (10 in the phase I portion) and 30 patients were randomized to the PomCyD and 30 to PomD. The median age was 65 years (range 44-80) and 41 (58%) were male. The median number of prior therapies was 5 (range 2-14). All patients were lenalidomide refractory and 55 (79%) were refractory to proteasome inhibitors. 19 patients (27%) had high risk cytogenetics (del 17p, t(4;14), t(14;16)) of which 12 patients (17%) had del 17p. In addition, 15 (21%) had 1q21 trisomy or tetrasomy. Aggregated responses are reported for the cohort. Of the 66 patients evaluable for response, 1 achieved a CR, 10 achieved a VGPR (15%), 21 achieved a PR (32%), 13 achieved a MR (20%) and 11 achieved SD (16%). The overall response rate (PR and better) was 48.5% and the clinical benefit rate (MR and better) was 68.2%. The median progression free survival (PFS) was 6.4 months (95% CI 2.6-10.2). Patients with ≥PR had a median duration of response of 10.4 months (95% CI 6.1-14.7). The most common grade ¾ adverse event regardless of attribution were neutropenia (30% of patients), febrile neutropenia (13%), pneumonia (13%), thrombocytopenia (11%) while grade 3/4 thromboembolic events were noted in 4%. ConclusionThe aggregate response rates (≥PR in 48%) and PFS of this all oral regimen compare favorably with published results using PomD in LRMM. Enrollment on the randomized phase II trial continues. Per protocol and to avoid alpha-spending, non-aggregated results of the two arms will be presented at the meeting. Disclosures:Baz:Sanofi: Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Bristol Myers Squibb: Research Funding; Millenium: Research Funding; Celgene: Research Funding. Off Label Use: pomalidomide dexamethasone in combination with cyclophosphamide for relapsed refractory myeloma. Alsina:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Shain:Celgene: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding. Wolf:Celgene: Honoraria, Research Funding; Millenium: Honoraria; Onyx: Honoraria. Mahindra:millenium: Membership on an entity's Board of Directors or advisory committees. Chari:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees. Jagannath:Millennium: Honoraria; Celgene: Honoraria.