Primary Plasma Cell Leukemia Research Articles

Clinical Features and Prognosis of Multiple Myeloma Patients with Secondary Primary Malignancies

To explore the clinical characteristics and prognosis of multiple myeloma(MM) patients with secondary primary malignancies. The clinical data of newly diagnosed MM patients admitted to the First Affiliated Hospital of Zhengzhou University from January 2011 to December 2019 were retrospectively analyzed. The patients with secondary primary malignancies were retrieved, and their clinical features and prognosis were evaluated. A total of 1 935 patients with newly diagnosed MM were admitted in this period, with a median age of 62 (18-94) years old, of which 1 049 cases were hospitalized twice or more. There were eleven cases with secondary primary malignancies (the incidence rate was 1.05%), including three cases of hematological malignancies (2 cases of acute myelomonocytic leukemia and 1 case of acute promyelocytic leukemia) and eight cases of solid tumors (2 cases of lung adenocarcinoma, and 1 case each of endometrial cancer, esophageal squamous cell carcinoma, primary liver cancer, bladder cancer, cervical squamous cell carcinoma, and meningioma). The median age of onset was 57 years old. The median time between diagnosis of secondary primary malignancies and diagnosis of MM was 39.4 months. There were seven cases with primary or secondary plasma cell leukemia, the incidence rate was 0.67%, and the median age of onset was 52 years old. Compared with the randomized control group, the β2-microglobulin level in the secondary primary malignancies group was lower (P=0.028), and more patients were in stage I/II of ISS (P=0.029). Among the 11 patients with secondary primary malignancies, one survived, ten died, and the median survival time was 40 months. The median survival time of MM patients after the secondary primary malignancies was only seven months. All seven patients with primary or secondary plasma cell leukemia died, with a median survival time of 14 months. The median overall survival time of MM patients with secondary primary malignancies was longer than that of the patients with plasma cell leukemia (P=0.027). The incidence rate of MM with secondary primary malignancies is 1.05%. MM patients with secondary primary malignancies have poor prognosis and short median survival time, but the median survival time is longer than that of patients with plasma cell leukemia.

Improved Survival of Patients with Primary Plasma Cell Leukemia with VRd or Daratumumab-based Quadruplets: A Multicenter Study by the Greek Myeloma Study Group.

We evaluated the efficacy and prognostic impact of bortezomib-lenalidomide triplet (VRd) or daratumumab-based quadruplets (DBQ) vs. previous anti-myeloma therapies i.e., bortezomib standard combinations (BSC) or conventional chemotherapy (CT), in a large cohort of patients with primary plasma cell leukemia (pPCL), including those fulfilling the revised diagnostic criteria i.e. circulating plasma cells (cPCS): ≥5%; 110 pPCL patients (M/F: 51/59; median age 65 years, range: 44-86) out of 3324 myeloma patients (3%), registered in our database between 2001-2021, were studied; 37% had cPCS 5-19%; 89% received novel combinations including DBQ (21%), VRd (16%) and BSC (52%); 35% underwent autologous stem cell transplantation. 83% achieved objective response. Treatment with VRd/DBQ strongly correlated with higher complete response rate (41% vs. 17%; p=0.008). After a median follow up of 51 months (95% CI: 45-56), 67 patients died. Early mortality was 3.5%. Progression-free survival was 16 months (95% CI: 12-19.8), significantly longer in patients treated with VRd/DBQ vs. BSC/CT (25 months, 95% CI: 13.5-36.5 vs. 13 months 95% CI: 9-16.8; p=0.03). Median overall survival (OS) was 29 months (95% CI: 19.6-38.3), significantly longer in patients treated with VRd/DBQ vs. BSC/CT (not reached vs. 20 months, 95% CI: 14-26; 3-year OS: 70% vs. 32%, respectively; p < 0.001; HzR: 3.88). In the multivariate analysis VRd/DBQ therapy, del17p(+) and PLT <100.000/μL, independently predicted for OS (p < 0.05). Our study has demonstrated that in the real-world setting, treatment with VRd/DBQ induces deep and durable responses and is a strong prognostic factor for OS representing currently the best therapeutic option for pPCL. This article is protected by copyright. All rights reserved.

Secondary plasma cell leukemia: Case report

Plasma cell leukemia (PCL) is a rare lymphoproliferative disorder characterized by monoclonal proliferation of plasma cells in marrow and peripheral blood. It is defined by a blood plasma count greater than 2 G/l or a plasma cell count greater than 20% of white blood cells. There are two forms of PCL: primary PCL (primary plasma cell leukemia or PCL-P), which occurs de novo and is diagnosed by blood dissemination, and secondary PCL (secondary plasma cell leukemia or SPL), which is the result of the evolution of multiple myeloma (MM). We report an observation of secondary plasma cell leukemia in a 42-year-old female patient diagnosed at the hematology laboratory of the Mohamed VI University Hospital in Marrakech. The patient was being followed up for chronic end-stage renal failure in whom the etiological assessment of a hypercalcemia of fortuitous discovery revealed MM for which she was put on chemotherapy according to the Velcade-Thalidomide-Dexamethasone protocol with a good evolution after 6 courses. Two and a half years later, the patient presented with anemia and spinal pain. The biological work-up showed a normocytic normochromic anemia at 5.4 g/dl and hypercalcemia at 150 mg/l. The blood smear showed the presence of 22% of circulating plasma cells, the majority of which were dystrophic, in favor of secondary plasma cell leukemia. Patients diagnosed with multiple myeloma who have undergone treatment and have a stable disease should have regular surveillance, hence the interest of the blood smear examination in all multiple myeloma.

Primary plasma cell leukemia in Latin America: demographic, clinical, and prognostic characteristics. A study of GELAMM group

Primary plasma cell leukemia (pPCL) is an infrequent and aggressive plasma cell disorder. The prognosis is still very poor, and the optimal treatment remains to be established. A retrospective, multicentric, international observational study was performed. Patients from 9 countries of Latin America (LATAM) with a diagnosis of pPCL between 2012 and 2020 were included. 72 patients were included. Treatment was based on thalidomide in 15%, proteasome inhibitors (PI)-based triplets in 38% and chemotherapy plus IMIDs and/or PI in 29%. The mortality rate at 3 months was 30%. The median overall survival (OS) was 18 months. In the multivariate analysis, frontline PI-based triplets, chemotherapy plus IMIDs and/or PI therapy, and maintenance were independent factors of better OS. In conclusion, the OS of pPCL is still poor in LATAM, with high early mortality. PI triplets, chemotherapy plus IMIDs, and/or PI and maintenance therapy were associated with improved survival.

Is t(11;14)(q13;q32) good or bad for newly diagnosed multiple myeloma?

Is t(11;14)(q13;q32) good or bad for newly diagnosed multiple myeloma?

Primary Plasma Cell Leukemia Presenting Mainly with Negative CD38 Expression at Diagnosis

The loss of CD38 expression has been described in multiple myeloma (MM) patients with relapsed/refractory disease and patients receiving CD38 monoclonal antibodies. However, the loss of CD38 at diagnosis is extremely rare with very few reports describing such finding in newly diagnosed MM patients. Only two detailed case reports described CD38-negative clonal plasma cells at diagnosis. However, none of these cases was primary plasma cell leukemia (PCL). We describe an elderly patient with primary PCL presenting mainly with a negative CD38 expression, which, to the best of our knowledge, has never been described. The patient did not do well and died within 3 months of diagnosis. The loss of CD38 expression at diagnosis could indicate more aggressive disease biology.

Aberrant Cytomorphological Features of Primary Plasma Cell Leukaemia: A Case Series

Primary Plasma Cell Leukaemia (pPCL) is a rare but distinctive sub-type of Plasma Cell Myeloma (PCM) comprising approximately 2-4% of cases of PCM and characterised by short remissions and survivals. Apart from these clinical distinctions, this entity also demonstrates unique cytomorphological features. The authors here attempted to highlight this unusual spectrum of leukaemic plasma cells, posing diagnostic challenges in the blood and bone marrow examinations. The cases presented in this series (48 years old male, 72 years old male,68 years old male and 63 years old female) patients, showed presence of atypical cells in the peripheral smear with few cells portraying the characteristic “hairy cell” morphology, the fourth case in addition, showed small sized plasma cells resembling lymphocytes. Bone marrow biopsy in three cases showed haematopoetic cells replaced by sheets of atypical plasma cells. In addition, the fourth case showed atypical cells having convoluted and notched nuclei giving a differential diagnosis of lymphoplasmacytic lymphoma and small B-cell lymphoma with plasmacytic differentiation. As plasma cell neoplasm was not suspected clinically in all four cases, flow cytometry was sought for confirmation which showed atypical cells expressing CD38 (+), CD138 (+), CD56 (–) with Cykappa (+) in first case, Cylambda (+) in the second case and Cykappa (+) in the fourth case with aberrant expression of cyclin D1 thus confirming a diagnosis of PCL in first two cases and PCM-lymphocytic type with PCL in the fourth case. Immunophenotyping was not performed in the third case due to financial constraints. This case series showcases this mélange of cytomorphological variations of plasma cells ranging from cells masquerading as hairy cells to small sized plasma cells resembling lymphocytes, each posing a unique diagnostic dilemma. This has been rarely discussed in prior published case series. Aberrant morphological features rarely seen in PCL, could lead the pathologist astray from the diagnosis, therefore appropriate use of ancillary tests are essential to arrive at a correct diagnosis.

A Rare Presentation of Primary Plasma Cell Leukemia: A Case Report and Review of Literature

Background: The primary plasma cell leukemia (pPCL) is an aggressive plasma cell neoplasm. It is diagnosed by the presence of an absolute plasma cell count of &gt;2 × 109/L or 20% plasma cells in the peripheral blood. pPCL is rare and reported to be &lt;1 in a million. Hence, our case report is a rare opportunity to describe clinical presentation and management of pPCL. Case Details: A 72-year-old male patient with benign prostatic hyperplasia, presented to the hospital for cough, breathlessness, and intermittent fever of one month. On arrival, he was tachypnoeic with altered sensorium and rales in his chest. Laboratory examination showed anemia, leucocytosis, and thrombocytopenia. The peripheral blood smears revealed 25-30% circulating atypical plasmacytoid cells. Flow cytometry on the peripheral blood revealed 58.7% lymphoid cells. Out of the total lymphoid cells, 73.6 % cells were characterized by expression of CD38, CD138, CD19, CD49d, CD43, CD27, CD81 (96.9% dim positives) CD 56 with dim kappa light chain restriction suggestive of PCL. Furthermore, serum protein electrophoresis and serum immunofixation showed an M-band (0.53g) of IgG kappa subtype. However, the patient developed lower respiratory tract infections with multi-organ dysfunction and he succumbed to the same.Conclusion: The prognosis of pPCL is very poor and the high risk of infective complications. Early diagnosis and optimal chemotherapy would be the key to the management. Detailed peripheral blood film examination and characterization of abnormal cells with immune phenotyping are of utmost importance in diagnosing pPCL.

Validation of the revised diagnostic criteria for primary plasma cell leukemia by the Korean Multiple Myeloma Working Party

The International Myeloma Working Group has recently revised the diagnostic criteria for primary plasma cell leukemia (PCL) to circulating plasma cells (CPCs) ≥ 5% in a peripheral blood smear. The present study validated new criteria in patients with multiple myeloma or PCL diagnosed using the previous diagnostic criteria, who were administered immunomodulatory drugs or proteasome inhibitors as induction therapy. We analyzed the medical records of 1357 patients from eight hospitals in South Korea. The median age of the all patients was 64 years, and 187 (13.8%) had CPCs at diagnosis. Only 79 (5.8%) of the patients had ≥ 5% CPCs. The median overall survival (OS) of patients with CPCs ≥ 5% and ≥ 20% was similar, but had significantly inferior median progression-free survival (PFS) and median OS than those with CPCs < 5% (13.1 vs. 21.5 months, P < 0.001, and 21.5 vs. 60.9 months, P < 0.001, respectively). Primary PCL diagnosed using the revised criteria presented with higher total calcium levels and serum creatinine levels, lower platelet counts and frequent organomegaly and plasmacytoma at diagnosis. Univariate and multivariate analyses demonstrated that the presence of plasmacytoma and elevated serum β2-microglobulin were significantly associated with OS in primary PCL. In conclusion, the revised criterion of CPCs ≥ 5% in a peripheral blood smear is appropriate for PCL diagnosis.

Improved Survival of Patients with Primary Plasma Cell Leukemia with VRD or Daratumumab-Based Quadruplets: A Multicenter Study By the Greek Myeloma Study Group

Primary plasma cell leukemia (pPCL) is a rare plasma cell disorder with poor outcome. Recently, the International Myeloma Working Group revised its definition proposing cPCS of ≥5% as the new cut-off value. There is still limited information regarding the impact of novel effective anti-myeloma combinations, i.e., bortezomib-lenalidomide triplet (VRd) or daratumumab-based quadruplets (DBQ) on pPCL outcome. Therefore, considering the lack of prospective trials, our aim was to compare retrospectively treatment approaches, and to evaluate prognostic factors of overall survival (OS) in an extended cohort of pPCL patients including those fulfilling the new criteria, in the real-world setting. We analyzed the medical records of 110 pPCL patients (M/F: 51/59; median age 65 years, range: 44-86; IgG: 47, IgA: 17, light-chain: 32, IgD: 3, IgM: 2, non-secretory: 9; ISS1: 9, ISS2: 32, ISS3: 69) out of 3324 myeloma patients (3%), registered in our database, between 2001-2021; 51% of patients were ≤65 years; Eastern Cooperative Group (ECOG) was ≥2 in 46%; 65% had advanced bone disease and 15% had bone/soft tissue plasmacytomas; 72% had Bence-Jones proteinuria, 45% had abnormal LDH, 27% had hypercalcemia, 72% had hemoglobin <10 g/dL and 24% had estimated glomerular filtration rate <30ml/min/1.73m2. High-risk molecular abnormalities i.e., del17p, t(4;14), t(14;16) and 1q21+ tested by FISH hybridization were detected in 56%; 30% had t(11;14). Revised ISS (RISS) was distributed as follows: RISS1: 4%, RISS2: 58%, RISS3: 38%. Median cPCs % was 11% (range: 5-71%), in line with multiparameter flowcytometry findings (10%; range: 4,5-71%). Immunophenotype of PCs was similar in bone marrow and peripheral blood in 92% of patients; CD56(-) and CD27(+) cPCs was found in 52% and 35%, respectively. 37% had cPCS 5-20%; Patients' characteristics did not correlate with cPCs %, except from platelets (PLT) that were significantly lower in patients with >20% cPCs; 89% of patients received novel therapies; DBQ: 21%, VRd: 16%, bortezomib standard combinations (BSC): 52%, conventional chemotherapy (CT): 11%; 35% underwent autologous stem cell transplantation (ASCT). Regarding response to treatment 83% achieved objective response (≥PR); 24% had very good partial response (vgPR), and 26% had complete response (CR). Median time to response was one month (range 1-5). Treatment with VRd/DBQ or ASCT strongly correlated with higher CR rates (45% vs. 19%; p=0.007; 52% vs. 11%; p<0.001, respectively). After a median follow up of 51 months (95% CI: 45-56), 67 patients died (progression: 42, infection: 20, other: 5) and 43 patients remain alive. Early mortality (≤1 month) occurred in 4/67 deceased patients; 51/110 (46%) patients received 2nd line therapy (lenalidomide-based: 17, proteasome inhibitor-based: 12, daratumumab-based: 9, pomalidomide-based: 4, CT: 9). Median number of treatment lines was 1 (range: 1-5). Progression-free survival was 16 months (95% CI: 12-19.8), significantly longer in patients treated with VRd/DBQ vs. BSC/CT (25 months 95% CI: 13.5-36.5, vs. 13 months 95% CI: 9-16.8; p=0.03). Median OS was 29 months (95% CI: 19.6-38.3), significantly longer in patients treated with VRd/DBQ vs. BSC/CT (not reached vs. 20 months, 95% CI: 14-26; 3-year OS: 70% vs. 32%, respectively; p<0.001; HR: 3.88). Median survival after pPCL progression was 8 months (95% CI: 3.5-13.5). In the univariate analysis, ECOG ≥2, PLT <100.000/μL, cPCs (5-20% vs >20%), del17p(+), upfront treatment with VRd/DBQ, ASCT and CR were independent prognostic factors for OS; treatment with VRd/DBQ, del17p(+) and PLT <100.000/μL, significantly predicted for OS in the multivariate analysis (p<0.05). Median OS for patients with del17p(+) vs. del17p(-) was 17 months (95% CI: 11.7-22) vs. 48 months, respectively (95% CI: 27.8-68) (p=0.01, HR: 3.1). Median OS for patients with PLT <100.000/μL vs. ≥100.000/μL was 16 months (95% CI: 9-23) vs. 46 months (95% CI: 28-64) respectively (p=0.01; HzR: 0.34). These real-world data, based on the largest reported national multicenter series of pPCL incorporating the new criteria, has shown that treatment with VRd or antiCD38-based quadruplets induces deep and durable responses and is one of the strongest prognostic factors for OS representing currently the best therapeutic approach for pPCL; ASCT maintained its therapeutic value. Del17p (+) and thrombocytopenia were negative predictors for OS.

Extended Intensified Post-ASCT Consolidation with Daratumumab, Bortezomib, Lenalidomide and Dexamethasone (Dara-VRd) for Ultra-High Risk (UHiR) Newly Diagnosed Myeloma (NDMM) and Primary Plasma Cell Leukemia (pPCL): The UK Optimum/Muknine Trial

Background: Outcome for patients with ultra-high risk (UHiR) newly diagnosed multiple myeloma (NDMM) or primary plasma cell leukemia (pPCL) remains unsatisfactory. Recent results from MASTER (NCT03224507) and other trials unfortunately confirmed the sustained risk of post-ASCT relapse for UHiR MM patients in context of contemporary combination induction therapy, including relapse from undetectable minimal residual disease (MRD). The OPTIMUM/MUKnine (NCT03188172) trial was designed to reduce (pre- and) post-ASCT relapse risk in UHiR patients by continued Dara-VR(d) consolidation for 18 cycles, followed by Dara-R maintenance. We report here outcomes for OPTIMUM patients until end of consolidation therapy and contextualise results with outcomes of UHiR MM patients treated in the Myeloma XI (ISRCTN49407852) trial. Methods: In OPTIMUM, patients identified to have UHiR NDMM (≥2 high risk lesions: t(4;14), t(14;16), t(14;20), gain(1q), del(1p), del(17p) or SKY92 risk signature) or with pPCL (circulating plasmablasts >20%) through central molecular screening of an all-comer population received up to 6 cycles of Dara-CVRd induction and V-ASCT. All patients then received 18 cycles of post-ASCT consolidation, of which 6 cycles Dara-VRd (Cons1) and 12 cycles Dara-VR (Cons2), before moving to monthly Dara-R maintenance until progression. OPTIMUM recruited 107 UHiR patients, including 9 pPCL, from 472 screened patients with suspected NDMM from 39 UK NHS hospitals between Sep 2017 and Jul 2019. We previously reported the OPTIMUM primary endpoint analysis, which demonstrated improved PFS at 18 months post start of induction for OPTIMUM in a pre-specified comparison against UHiR patients treated in the Myeloma XI (MyXI) trial. We report here a planned analysis of OPTIMUM patient PFS and safety data after all patients completed consolidation. Results are contextualised with outcome for UHiR patients treated in MyXI with carfilzomib/cyclophosphamide-Rd (KCRd) or CRd induction, ASCT and lenalidomide maintenance or observation. Further analyses including overall survival are underway and will be presented at the meeting. Results: With median follow-up of 40.0 months (95% CI: 37.3-42.7), median PFS was not reached for OPTIMUM patients. The PFS estimate at the end of consolidation, 30 months from start of induction therapy, was 77.0% (95% CI: 68.8-85.1). For context, PFS at 30 months for UHiR patients in Myeloma XI was 39.8% (95% CI: 30.7-48.9) for the overall group, and specifically 49.7% (95% CI: 33.2-66.2) for MyXI patients randomised to KCRd and 34.1% (95% CI: 23.4-44.8) for those randomised to CRd treatment arms (Figure 1). We observed a progressive separation of PFS curves over time between OPTIMUM and MyXI, suggesting a sustained beneficial effect of ongoing post-ASCT consolidation for UHiR patients (Figure 1). Of the 85 OPTIMUM patients who received at least one cycle of consolidation post-ASCT, 80 patients completed Cons1 and 74 patients Cons2. Progressive disease was the commonest reason for trial discontinuation. Most frequent CTCAE grade 3/4 adverse events (AEs) during Cons2 included neutropenia (43.8%), thrombocytopenia (27.5%) and infection (15%). Grade 4 events were rare (≤5%) for all categories; there were no treatment-related deaths. Peripheral neuropathy rate grade ≥2 was 13.8% (Grade ≥3: 2.5%) for Cons2; no cumulative increase from Cons1 was noted. Of the initial 107 patients who started therapy in OPTIMUM, 47 had an MRD test result available at end of Cons2 at time of abstract submission. Of these, 44 (93.6%; 41.1% of overall trial population) had undetectable MRD at 10-5 sensitivity by flow cytometry. In the majority of patients undetectable MRD was sustained since ASCT. Conclusions: Prevention of relapse remains a key challenge in the treatment of UHiR MM/PCL patients, including for patients achieving undetectable MRD. OPTIMUM outcomes for extended Dara-VR consolidation in UHiR/PCL patients demonstrate 30 months PFS of 77% and compare favourably with MyXI, but also results from the MASTER trial, which recently reported 24-month PFS of 58% for UHiR patients defined by same criteria (JCO 2021). Safety data demonstrate manageable side effects with extended Dara-VR consolidation. Our results support extended, risk stratified post-ASCT therapy for UHiR MM/PCL patients. Figure Legend: PFS Kaplan-Meier plot for UHiR/PCL patients treated in OPTIMUM and Myeloma XI. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Treatment of Primary Plasma Cell Leukemia with Carfilzomib and Lenalidomide-Based Therapy: Results of the Final Analysis of the Prospective Phase 2 EMN12/HOVON-129 Study for Patients Aged 18-65 Years

Introduction. Primary plasma cell leukemia (pPCL) is a rare and aggressive plasma cell disorder with a very poor prognosis. The median PFS for transplant-eligible patients (pts) is approximately 9 months. The aim of the EMN12/ HOVON-129 study was to improve the outcome of pPCL by incorporating carfilzomib and lenalidomide in induction, consolidation, and maintenance. The trial enrolled 61 pts aged 18 years and older, with different treatment for those aged 18-65 (n=36) and ≥66 years (n=25). Here we report the results of the final analysis for pts aged 18-65 years. Methods. The EMN12/HOVON-129 study is a prospective, non-randomized, phase 2, multicenter study, for previously untreated pPCL pts. Inclusion criteria were newly diagnosed pPCL (defined as >2x109/L circulating monoclonal plasma cells or plasmacytosis >20% of the differential white cell count) and WHO performance status 0-3. Main exclusion criteria were severe cardiac or pulmonary dysfunction; and creatinine clearance of <15 ml/min. There were no restrictions based on blood counts. Pts aged 18-65 years were treated with induction therapy with four 28-day cycles of carfilzomib-lenalidomide-dexamethasone (KRd; carfilzomib 20/36 mg/m2 on days 1,2,8,9,15,16; lenalidomide 25 mg days 1-21; dexamethasone 20 mg on days 1,2,8,9,15,16,22,23). KRd induction was followed by tandem autologous stem cell transplantation (ASCT), 4 cycles of KRd consolidation, and then maintenance with carfilzomib (27 mg/m2 on days 1,2,15,16) and lenalidomide (10 mg on days 1-21/28 days) until progression. Pts who were eligible for allo-SCT, could also receive one ASCT, followed by 2 KRd consolidation cycles, reduced-intensity conditioning allo-SCT, and carfilzomib/lenalidomide maintenance. The primary endpoint was PFS, and secondary endpoints were response rate, OS, and toxicity. Results. From October 2015 till August 2021, we enrolled 36 pts with pPCL aged ≤65 years. Median age was 60 years; 67% had bone disease; and WHO performance status was ≥2 in 33% of pts. Pts had a high tumor burden with a median plasma cell percentage in BM of 80%. The median peripheral blood plasma cell count was 4.1x109/L (range 1.6-60.0); median platelet count was 111x109/L (range 20-517); and median eGFR was 54.0 ml/min (range 15.0-123). Pts had high-risk disease as evidenced by elevated LDH in 58%; and high frequency of high-risk genetic lesions (del(17p) in 47%, t(4;14) in 9%, t(14;16) in 19%, gain/ampl(1q) in 61%). Two or more high-risk cytogenetic abnormalities were present in 38%. The frequency of t(11;14) was 26%. In addition, 17% of pts had extramedullary plasmacytomas. ISS stage 3 was present in 64%, and revised ISS stage 3 in 50%. Response to induction was ≥PR in 72%, ≥VGPR in 64%, and ≥CR in 14%. Twenty-four pts (67%) received high-dose melphalan (HDM)/ASCT; 12 pts (33%) underwent a second course of HDM/ASCT; and 5 (14%) received allo-SCT after first HDM/ASCT. Eighteen pts (50%) received maintenance treatment. Best response on protocol was ≥PR in 83%, ≥VGPR in 81% and ≥CR in 50%; 10 (28%) pts achieved MRD-negative (10-5) CR. With a median follow-up of 40.8 months (range 8-2-74.5), the median PFS was 15.5 months (95% CI 9.4-38.4), which was sufficient to reject our null hypothesis (median PFS=9 months). With 19 pts having died (14 due to disease progression, 4 due to infections, and 1 due to cardiac disorder), median OS was 28.4 months (95% CI 15.1-not reached). In exploratory analyses, the presence of elevated LDH, t(14;16), and del(17p) were associated with both inferior PFS and OS. For patients who underwent first HDM/ASCT, median PFS and OS were 32.9 and 34.1 months from date of ASCT, resp. Adverse events mainly occurred during the first cycle of KRd, and decreased thereafter. Overall, grade ≥3 adverse events were observed in 67% of pts, including infections (25%) and cardiovascular disorders (14%). One patient developed a second primary malignancy (MDS). As of July 24 2022, 25 pts (69%) pts discontinued protocol treatment, mainly because of progression, but none because of treatment-related toxicity. Conclusions. KRd induction provides efficient and rapid disease control, which allows two-thirds of pts to undergo a first course of HDM/ASCT. Toxicity occurred mainly during the first cycle of induction, and was manageable with appropriate interventions. However, median PFS and OS remain low in pPCL, compared to MM. This trial was registered at https://trialsearch.who.int as NTR5350 Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Carfilzomib and Lenalidomide for the Treatment of Primary Plasma Cell Leukemia: Final Results of the Prospective Phase 2 EMN12/HOVON-129 Study for Patients Aged ≥66 Years

Introduction. Primary plasma cell leukemia (pPCL) is a rare and aggressive plasma cell disorder with a very poor prognosis, requiring urgent action to prevent early mortality and to control the disease and complications. The EMN12/HOVON-129 study assessed the efficacy of carfilzomib and lenalidomide as part of first-line therapy in pPCL. The trial enrolled patients (pts) aged 18 years and older, with different treatment for those 18-65 and ≥66 years. Here we report the results for pts in the age-group ≥66 years. Methods. The EMN12/HOVON-129 study is a prospective, non-randomized, phase 2, multicenter study for previously untreated pPCL pts. Inclusion criteria were newly diagnosed pPCL (in this study defined as >2x109/L circulating monoclonal plasma cells and/or plasmacytosis >20% of the differential white cell count) and WHO performance status 0-3. Main exclusion criteria were severe cardiac or pulmonary dysfunction and creatinine clearance <15 ml/min. There were no restrictions based on blood counts. Pts ≥66 years received induction therapy with eight 28-day cycles of carfilzomib-lenalidomide-dexamethasone (KRd; carfilzomib 20/36 mg/m2 on days 1,2,8,9,15,16; lenalidomide 25 mg on days 1-21; dexamethasone 20 mg on days 1,2,8,9,15,16,22,23), followed by maintenance with carfilzomib (27 mg/m2 on days 1,2,15,16 for the first twelve cycles; then 56 mg/m2 on days 1,15) and lenalidomide (10 mg on days 1-21/28 days) until progression. The primary endpoint was progression-free survival (PFS); secondary endpoints were response rate, overall survival (OS), and toxicity. Results. From October 2015 to August 2021, we enrolled 61 pts with pPCL: 36 aged ≤65 years and 25 aged ≥66 years. Among the 25 pts aged ≥66 years, median age was 71 years (range 66-84); 68% had bone disease; and WHO performance status was 2 in 24% and 3 in 16% of pts. Median plasma cell percentage in bone marrow biopsy was 80% (10-100). Median peripheral blood plasma cell count was 3.8x109/L (range 2.0-52); median platelet count was 142x109/L (range 13-384); and median GFR was 56 ml/min (range 24-95). Most of pts had high-risk disease features, as proved by elevated LDH in 52% and high frequency of poor-risk genetic lesions (del(17p) in 20%, t(4;14) in 4%, t(14;16) in 4%, and gain/amp(1q) in 48%). In addition, 12% of pts had extramedullary plasmacytomas. ISS stage III was present in 68% and Revised ISS stage III in 40%. At the data cut-off (July 1, 2022), among the 25 pts, 17 (68%) received the planned 8 cycles of induction treatment, achieving ≥partial response (PR) in 80%, ≥very good (VG)PR in 68%, and ≥complete response (CR) in 32% of pts. Sixteen pts (64%) received maintenance treatment. Best response on protocol was ≥PR in 80%, ≥VGPR in 68% and ≥CR in 36%; 3 out of 4 pts in CR who could be evaluated for minimal residual disease (MRD) achieved MRD negativity (10-5) by flow cytometry. With a median follow-up of 24.6 months (range 7.9-59.6), the median PFS was 13.8 months (95% CI 9.2-35.5), which was sufficient to reject our null hypothesis (median PFS=6.5 months). With 16 pts having died (8 due to disease progression, 2 unknown, 1 pneumonia, 1 sepsis, 1 systemic aspergillus infection, 1 small intestinal SPM, 1 disseminated intravascular coagulation, 1 respiratory failure due to COPD exacerbation), median OS was 24.8 months (95% CI 14-not reached [NR]; Figure). Adverse events mainly occurred during the first two cycles of KRd and decreased thereafter. Overall, 36% of pts had grade (G)3 and another 36% G4 adverse events. G3 and G4 hematologic toxicity rates were 8% and 12%, respectively. Infections (20% and 16%) and respiratory events (16% and 4%) were the most common G3 and G4 non-hematologic toxicities. Twenty-two pts (88%) discontinued protocol treatment, mainly because of progression (13 pts, 59%). Conclusions. KRd is a potent treatment strategy to control disease in pPCL pts over 65 years of age, with not negligible, but generally manageable, treatment-related toxicities. Of note, along with a significant improvement of PFS, median OS substantially doubled compared to what has been reported in recent retrospective studies and, particularly, in the only other prospective trial (with the doublet lenalidomide-dexamethasone) so far conducted in transplant ineligible, elderly pts with pPCL (Musto P et al. Leukemia. 2014;28:222-5). This trial was registered at www.trialregister.nl (until June 2022) and https://trialsearch.who.int/ as NTR5350. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Bortezomib-Decp Alternating with Daratumumab-Vpd Plus Stem Cell Transplantation, Followed By Maintenance with VP in Ultra-High Risk (UHiR) Newly Diagnosed Multiple Myeloma (NDMM) and Primary Plasma Cell Leukemia (pPCL): A Multicenter, Prospective Phase 2 Pilot Trial (DRAGON CATCHER TRIAL)

Bortezomib-Decp Alternating with Daratumumab-Vpd Plus Stem Cell Transplantation, Followed By Maintenance with VP in Ultra-High Risk (UHiR) Newly Diagnosed Multiple Myeloma (NDMM) and Primary Plasma Cell Leukemia (pPCL): A Multicenter, Prospective Phase 2 Pilot Trial (DRAGON CATCHER TRIAL)

More Than 2% of Circulating Tumor Plasma Cells Defines Plasma Cell Leukemia-Like Multiple Myeloma.

Primary plasma cell leukemia (PCL) is the most aggressive monoclonal gammopathy. It was formerly characterized by ≥ 20% circulating plasma cells (CTCs) until 2021, when this threshold was decreased to ≥ 5%. We hypothesized that primary PCL is not a separate clinical entity, but rather that it represents ultra-high-risk multiple myeloma (MM) characterized by elevated CTC levels. We assessed the levels of CTCs by multiparameter flow cytometry in 395 patients with newly diagnosed transplant-ineligible MM to establish a cutoff for CTCs that identifies the patients with ultra-high-risk PCL-like MM. We tested the cutoff on 185 transplant-eligible patients with MM and further validated on an independent cohort of 280 transplant-ineligible patients treated in the GEM-CLARIDEX trial. The largest published real-world cohort of patients with primary PCL was used for comparison of survival. Finally, we challenged the current 5% threshold for primary PCL diagnosis. Newly diagnosed transplant-ineligible patients with MM with 2%-20% CTCs had significantly shorter progression-free survival (3.1 v 15.6 months; P < .001) and overall survival (14.6 v 33.6 months; P = .023) than patients with < 2%. The 2% cutoff proved to be applicable also in transplant-eligible patients with MM and was successfully validated on an independent cohort of patients from the GEM-CLARIDEX trial. Most importantly, patients with 2%-20% CTCs had comparable dismal outcomes with primary PCL. Moreover, after revealing a low mean difference between flow cytometric and morphologic evaluation of CTCs, we showed that patients with 2%-5% CTCs have similar outcomes as those with 5%-20% CTCs. Our study uncovers that ≥ 2% CTCs is a biomarker of hidden primary PCL and supports the assessment of CTCs by flow cytometry during the diagnostic workup of MM.

P-151: Primary plasma cell leukemia in Latin America: demographic, clinical, and prognostic characteristics. A study of GELAMM group

P-151: Primary plasma cell leukemia in Latin America: demographic, clinical, and prognostic characteristics. A study of GELAMM group

P-165: The clinical characteristics and prognosis of patients with primary plasma cell leukemia (pPCL) according to the new IMWG definition criteria

P-165: The clinical characteristics and prognosis of patients with primary plasma cell leukemia (pPCL) according to the new IMWG definition criteria

P-142: Validation of new diagnostic criteria of primary plasma cell leukemia: a study of the Korean Multiple Myeloma Working Party (KMMWP-2003 study)

P-142: Validation of new diagnostic criteria of primary plasma cell leukemia: a study of the Korean Multiple Myeloma Working Party (KMMWP-2003 study)

Causes of death in primary plasma cell leukemia differ from multiple myeloma: A STROBE-compliant descriptive study based on SEER database.

The primary plasma cell leukemia (pPCL) is a rare but aggressive variant of multiple myeloma (MM). Few studies have focused on the differences in the causes of death between pPCL and MM. This study aimed to compare and evaluate the causes of death of patients with pPCL and MM.The data were collected from the Surveillance Epidemiology, and End Results (SEER) database. The demographic characteristics, survival, and causes of death in pPCL and MM patients were evaluated and compared. The competing risk regression model was performed to predict the cause of death.Between 1975 and 2009, the overall mortality rate was 96.13% and 88.71% for pPCL and MM, and the median survival was 9 and 26 months, respectively. In pPCL, leukemia caused 45.05% of the deaths, followed by myeloma (38.83%). In MM, myeloma was the leading cause of death, accounting for 74.89% of the deaths. Older age at diagnosis was a risk factor for dying of leukemia in pPCL patients (HR = 1.49, 95% CI: 1.16–1.91), while older age at death was associated with reduced risk (HR = 0.67, 95% CI: 0.52–0.86). Although the survival of pPCL patients increased with time periods of diagnosis since 1975 to 2009, the risk of dying of leukemia increased with the periods. For MM, most of the demographic characteristics were found to have independently predicting influence on the cause of death.Patients with pPCL and MM had distinct causes of death. Leukemia was the leading and the most serious cause of death in pPCL patients. The demographic factors could not predict the causes of death in pPCL. More large-scale and multi-center studies are needed to evaluate the effect of novel agents in pPCL patients, especially for patients who have progressed to leukemia.

The clinical characteristics and prognosis of patients with primary plasma cell leukemia (pPCL) according to the new IMWG definition criteria

Recently, the definition of primary plasma cell leukemia (pPCL) has been revised as the presence of circulating plasma cells (CPCs) ≥5% in peripheral blood smear. Consequently, the clinical features and prognosis of this aggressive disease can be truly identified by the larger patient cohort. Herein, we identified 158 new-defined pPCL patients among 2,266 MM patients (7.0%), and such prevalence doubled the previous estimate. Our study firstly provided solid support for the application of the new definition. We also found that cytopenias and adverse prognostic biomarkers were more common in new-defined pPCL compared with MM (p < 0.05). Besides, the patients receiving proteasome inhibitors based regimen in combination with stem cell transplantation could experience a considerable survival benefit. Strikingly, we showed that the presence of conventional high-risk cytogenetic abnormalities in pPCL didn’t exert a great prognostic effect like MM, while elevated LDH reflecting tumor cells proliferation rate was the only independent predictor.