KD-PACE Salvage Therapy for Aggressive Relapsed Refractory Multiple Myeloma, Plasma Cell Leukemia and Extramedullary Myeloma.

BACKGROUND: Patients with advanced/aggressive multiple myeloma have limited treatment options to achieve rapid disease control. In eligible patients, bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide is often used. However, many patients are refractory to or have toxicities from bortezomib and there is a need for bridging therapy. We have used a modified regimen incorporating the second-generation proteasome inhibitor carfilzomib (carfilzomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide [KD-PACE]) instead of bortezomib for relapsed/refractory multiple myeloma. PATIENTS AND METHODS: This 2-center retrospective study included consecutive patients receiving KD-PACE for relapsed or refractory multiple myeloma, plasma cell leukemia, or extramedullary myeloma. The primary outcome was the feasibility of KD-PACE as a bridging therapy to a more definitive treatment option. RESULTS: Fifty-two patients were included. The median age was 57 years, and 67% were male. Thirty-one patients were bridged with KD-PACE to autologous hematopoietic stem cell transplant (29%), allogenic hematopoietic stem cell transplant (27%), or a clinical trial (12%). Patients bridged to autologous hematopoietic stem cell transplant, allogenic hematopoietic stem cell transplant, or a clinical trial had a superior progression-free survival (8.3 months vs 2.3 months in the nonbridged group; P < .001) and overall survival (median, 16.7 months vs 4.3 months in the nonbridged group; P < .001). No unexpected toxicities occurred from the treatment regimen. CONCLUSION: KD-PACE is a promising treatment option for select patients with advanced/aggressive forms of myeloma requiring rapid disease control before a more definitive salvage therapy such as auto/allotransplantation or a clinical trial.

Hematopoietic cell transplantation utilization and outcomes for primary plasma cell leukemia in the current era.

The outcomes of patients with primary plasma cell leukemia (pPCL) after undergoing hematopoietic cell transplantation (HCT) in the novel agent era are unknown. We report outcomes of 348 patients with pPCL receiving autologous (auto-) HCT (n = 277) and allogeneic (allo-) HCT (n = 71) between 2008 and 2015. Median age was 60 years and 56 years for auto- and allo-HCT respectively. For auto-HCT, the 4-year outcomes were: non-relapse mortality (NRM) 7% (4-11%), relapse (REL) 76% (69-82%), progression-free survival (PFS) 17% (13-23%), and overall survival (OS) 28% (22-35%). Karnofsky performance status (KPS) > 90 and ≥very good partial response (VGPR) predicted superior OS in multi-variate analysis for auto-HCT. For allo-HCT, the 4-year outcomes were: NRM 12% (5-21%), REL 69% (56-81%), PFS 19% (10-31%), and OS 31% (19-44%). Compared with prior CIBMTR pPCL patients (1995-2006), inferior survival was noted in the current cohort (3-year OS, 39% vs. 38% in allo-HCT, and 62% vs. 35% in auto-HCT) respectively. However, we noted an increased HCT utilization, from 12% (7-21%) in 1995 to 46% (34-64%) in 2009 using SEER data (available till 2009). Despite modern induction translating to higher proportion receiving HCT, the outcomes remain poor in pPCL patients, mainly derived by high relapse rates post-HCT.

Bortezomib, Thalidomide and Lenalidomide: Have They Really Changed the Outcome of Multiple Myeloma?

Treatment of multiple myeloma (MM) has significantly improved, although the disease remains incurable. Prospective clinical trials evaluating the impact on outcome of new drugs such as proteasome inhibitors or immunomodulating agents are limited since they are not able to reflect the clinical routine and available retrospective data are not detailed enough to directly evaluate the value of new drugs. To address these information gaps, we performed a retrospective real-life analysis. We retrospectively assessed 949 patients treated for multiple myeloma or plasma cell leukemia at three Italian cancer centers in the years 1979-2014. Clinical features at the time of diagnosis were consistent with what was observed in clinical routine. A total of 39% of patients underwent high-dose chemotherapy followed by autologous stem cell transplantation (ASCT). The median overall survival (OS) of the whole group was 5.4 years and ranged from 3.4 years for patients who did not receive at least one of the new drugs compared to 5.9 years in the other patients (p<0.001). The improvement in OS due to administration of new drugs was also observed among different prognostic sub-groups such as age, Durie and Salmon stage, international staging system and renal impairment. Availability of new drugs significantly improved survival of patients who underwent ASCT and also those who did not. In conclusion, we provided evidence that the advent of the new drugs drastically improved the outcome of patients with MM, also in cases with poor risk at the time of diagnosis. ASCT is still of major importance in the treatment of this disease. Nevertheless, MM remains incurable and new therapeutic approaches are warranted.

Therapeutic advances in the treatment of primary plasma cell leukemia: a focus on hematopoietic cell transplantation.

Primary plasma cell leukemia (pPCL) is an uncommon but aggressive plasma cell malignancy associated with frequent extramedullary involvement, high-risk cytogenetic abnormalities, and frequent organ dysfunction, ultimately resulting in poor prognosis. Here we review recent advances in our understanding of the molecular and biological aspects of PCL and summarize therapeutic progress occurring over the past 2 decades. pPCL is distinguished from secondary PCL arising from multiple myeloma. The molecular and immunophenotypic changes of pPCL are often distinct from those seen in secondary PCL and multiple myeloma. The availability of novel agents (ie, proteasome inhibitors and immunomodulatory agents) and the increasing use of hematopoietic cell transplantation strategies have resulted in better outcomes, although long-term survival remains poor. Development of complex treatment algorithms that combine novel agents as induction therapy, as part of conditioning regimens for hematopoietic cell transplantation (autologous or allogeneic), or as post-transplantation remission strategies are logical and may translate into improved survival in patients with PCL.

Hematopoietic cell transplantation for primary plasma cell leukemia: results from the Center for International Blood and Marrow Transplant Research.

There are limited data on hematopoietic cell transplantation (HCT) in primary plasma cell leukemia (pPCL), an aggressive plasma cell disorder. We report outcomes of 147 patients with pPCL receiving autologous (n=97) or allogeneic (n=50) HCT within 18 months after diagnosis between 1995 and 2006. Median age was 56 years and 48 years for autologous HCT and allogeneic HCT, respectively. Progression-free survival (PFS) at 3 years was 34% (95% confidence interval (CI), 23-46%) in the autologous group and 20% (95% CI, 10-34%) in the allogeneic group. Cumulative incidence of relapse at 3 years was 61% (95% CI, 48-72%) in the autologous group and 38% (95% CI, 25-53%) in the allogeneic group. Overall survival (OS) at 3 years was 64% (95% CI, 52-75%) in the autologous group and 39% (95% CI, 26-54%) in the allogeneic group. Non-relapse mortality (NRM) at 3 years was 5% (95% CI, 1-11%) in the autologous group and 41% (95% CI, 28-56%) in the allogeneic group. The encouraging OS after autologous HCT, establishes the safety and feasibility of this consolidative treatment option after initial induction therapy for pPCL. Allogeneic HCT, although associated with a significantly lower relapse rate, carries a much higher risk of NRM and no OS benefit.

Primary plasma cell leukemia in the era of new drugs: has something changed?

Primary plasma cell leukemia (PPCL) is a rare and aggressive variant of multiple myeloma. This disease is associated with a very poor prognosis, and unfortunately it has not significantly improved during the last three decades. Autologous stem cell transplantation is generally recommended in eligible patients, but survival in transplanted PPCL patients is significantly lower than that of multiple myeloma. Recent preliminary data indicate that new drugs, in particular lenalidomide and bortezomib, could significantly improve the clinical outcome of PPCL, increasing response rate and duration, as well as survival. In this review we report an updated literature analysis about the current therapeutic scenario of PPCL, with a particular focus on the use of novel agents.

Clinical outcomes of patients with plasma cell leukemia in the era of novel therapies and hematopoietic stem cell transplantation strategies: a single-institution experience.

BACKGROUND: PCL carries a poor prognosis and the optimal management remains unknown. PATIENTS AND METHODS: To evaluate the outcome of patients with PCL in the era of novel agents and innovative transplantation strategies, we conducted a review of patients with PCL who were treated at our institution from August 2003 to October 2009. Our primary endpoint was to determine overall survival, which was calculated from time of PCL diagnosis to death or last follow-up. Secondary endpoints included response rates and analyses regarding how the novel agents and presence of adverse cytogenetic analyses affected outcomes. RESULTS: We identified 25 patients with PCL (13 with primary PCL [pPCL], 12 with secondary PCL [sPCL]) from our institution. Eighteen patients received bortezomib-based regimens, 19 received high-dose melphalan followed by autologous hematopoietic stem cell transplantation (HCT), and 6 underwent allogeneic HCT. The median overall survival for all patients was 23.6 months. Bortezomib-treated patients had a median survival of 28.4 months vs. 4.0 months for the non-bortezomib-treated group (P < .001). CONCLUSIONS: Our analysis suggests that patients with PCL who were treated with bortezomib and/or allogeneic HCT had improved outcomes.

Primary plasma cell leukemia and autologous stem cell transplantation.

BACKGROUND: Primary plasma cell leukemia is a rare disorder accounting for less than 5% of malignant plasma cell diseases. It has a poor prognosis compared to multiple myeloma, with a median survival of 8-12 months. The results of conventional therapy are disappointing though autologous stem cell transplantation may improve survival. DESIGN AND METHODS: A retrospective analysis was undertaken of the European Group for Blood and Marrow Transplantation experience of 272 patients with plasma cell leukemia and 20844 with multiple myeloma undergoing first autologous transplantation between 1980 and 2006. All patients were reported to the European Group for Blood and Marrow Transplantation registry using MED-A (limited data) or MED-B (extensive data) forms. All patients were included regardless of availability of complete data. RESULTS: There was no difference in type of graft or use of total body irradiation between patients with plasma cell leukemia and multiple myeloma, but the group with plasma cell leukemia was transplanted earlier after diagnosis (6.0 versus 7.7 months, P=0.000). Patients with plasma cell leukemia were more likely to enter complete remission after transplantation but their overall survival (25.7 months, 95% confidence interval 19.5-31.9 months) was inferior to that of patients with multiple myeloma (62.3 months, 95% confidence interval 60.4-64.3 months) (P=0.000), due to the short duration of their post-transplant response and increased non-relapse-related mortality. CONCLUSIONS: This largest study ever reported on plasma cell leukemia suggests that autologous transplantation can improve outcome, although results are markedly inferior to those achieved in patients with multiple myeloma, highlighting the need for novel approaches to this aggressive disorder.

[Cauda equina relapse after autologous stem cell transplantation in a patient with primary plasma cell leukemia].

We report a rare case showing involvement with the cauda equina after autologous peripheral blood stem cell transplantation for primary plasma cell leukemia (PCL). A 55-year-old man was diagnosed with PCL(IgA-k type, stage III)in November of 2006. He was treated with VAD chemotherapy consisting of vincristine, doxorubicin, and dexamethasone. After achieving hematological remission, he received tandem high-dose melphalan supported by autologous peripheral blood stem cell transplantation. Five months after his second transplant, he complained of lumbago and bilateral leg pain. M-protein and Bence-Jones protein were not detected in serum or urine. An axial magnetic resonance imaging study revealed enlargement of the cauda equina nerve roots on T-1 weighted image. A sagittal T-1 weighted gadolinium-enhanced imaging study showed hyperintensities along the cauda equina. Leptomeningeal enhancement was also seen below the level of Th6. A cytological examination of the cerebrospinal fluid (CSF) with May-Giemsa stain showed atypical plasma cells. Immunoelectrophoresis of the CSF revealed monoclonal IgA-k type protein. A diagnosis of central nervous system (CNS)relapse was made. The patient died of pneumonia two months after relapse. It should be kept in mind that CNS relapse can occur during hematological remission in patients with multiple myeloma including PCL.

Plasma cell leukemia maintaining complete remission by syngeneic stem cell transplantation combined with low-dose thalidomide maintenance therapy.

Plasma cell leukemia (PCL) is a rare variant of multiple myeloma, which is very aggressive and resistant to chemotherapy. We report a case of PCL successfully treated with syngeneic peripheral blood stem cell transplantation followed by low-dose thalidomide. As of March 2009, the patient has maintained CR for 39 months posttransplant. The clinical course of the present case suggests that autologous stem cell transplantation using a graft with reduced contamination of malignant cells followed by low-dose thalidomide maintenance therapy may improve the PCL treatment outcome.

[Long-term complete remission in primary plasma cell leukemia after treatment with VAD chemotherapy and tandem autologous peripheral blood stem cell transplantation].

A 54-year-old woman visited our hospital with the chief complaints of generalized pain and thirst. Through hematologic and bone marrow examination, we diagnosed her illness as primary plasma cell leukemia. Three courses of VAD (vincristine, adriamycin and dexamethasone)therapy induced complete remission. Afterward, the patient received high-dose cyclophosphamide (4 g/m(2))for hematopoietic stem cell mobilization, and peripheral blood hematopoietic stem cells were collected 14 days later from the start of chemotherapy. Thereafter, the patient received 2 courses of high-dose melphalan (200 mg/m(2)), followed by tandem autologous peripheral blood stem cell transplantation. The patient developed no adverse events other than fever and stomatitis during the 2 transplantation courses. Fifty-six months after the transplantations, she remains in complete remission with continuous oral administration of bisphosphonate alone. Taken together, although primary plasma cell leukemia is a rare hematologic malignancy with poor prognosis, the intensive chemotherapy followed by tandem autologous peripheral blood stem cell transplantation may well improve the clinical outcome.

[Plasma cell leukemia induced to complete remission with negative minimal residual disease by qualitative PCR analysis after hyper-CVAD and high-dose melphalan followed by autologous peripheral blood stem cell transplantation].

A 69-year-old Japanese man was diagnosed as having primary plasma cell leukemia. His malignant plasma cells had a chromosomal translocation t(11;14)(q13;q32) that created overexpression of cyclin D1. Two courses of VAD (vincristine, doxorubicin, dexamethasone) therapy failed to achieve complete remission. Three subsequent courses of hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) therapy successfully induced remission with negative FISH test for t(11;14)(q13;q32). Thereafter, the patient received high-dose melphalan (125 mg/m(2)) followed by autologous peripheral blood stem cell transplantation. Cyclin D1 that was present prior to the high-dose chemotherapy, was no longer detected by qualitative PCR analysis. Despite complete cytogenetic remission, the disease relapsed 6 months later, and the patient eventually died 16 months following the diagnosis. Plasma cell leukemia is a rare hematological malignancy with a poor prognosis. The treatment has not been standardized yet. The present case suggested the effectiveness of the combination of hyper-CVAD and high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation. Nevertheless, because of the short remission duration, intensification using tandem high-dose chemotherapy or maintenance using new agents such as bortezomib and thalidomide should be considered for improving the prognosis.

Successful treatment of primary plasma cell leukaemia by allogeneic stem cell transplantation from haploidentical sibling.

Primary plasma cell leukaemia (PCL) is a rare, aggressive neoplasm of plasma cell dyscrasia. Conventional chemotherapy is usually ineffective, with an overall survival of only 8 months. Here, we describe a 42-year-old man with primary PCL, who was successfully treated with haploidentical (2-HLA loci mismatched) haematopoietic stem-cell transplantation (HSCT). To overcome the human leukocyte antigen (HLA) disparity, in vivo T-cell purging by the pre-transplant administration of antithymocyte globulin followed by a conventional prophylactic treatment against graft-versus-host disease (GVHD) resulted in an avoidance of severe GVHD as well as infectious complications. The patient has maintained complete remission for 13 months after haploidentical HSCT, indicating that a graft-versus-PCL effect might be preserved. Haploidentical HSCT can be a potentially curative treatment for patients with primary PCL who do not have an HLA-identical donor.

Development of solitary plasmacytoma in the internal auditory canal and inner ear after allogeneic hematopoietic stem cell transplantation for plasma cell leukemia.

Here we report the first case of the development of intracranial solitary plasmacytoma in the inner ear after allogeneic stem cell transplantation (allo-SCT) in a 39-year-old Japanese female with primary plasma cell leukemia (PCL). A point to note is that this is not a case on multiple myeloma but on PCL. She was successfully treated with local irradiation and survived more than 6 years from the time of diagnosis and transplantation. This case elucidates the biology of PCL and stresses the need for an individual approach to the clinical management of patients with plasma cell neoplasm undergoing allo-SCT.

AIDS, multicentric Castleman's disease, and plasmablastic leukemia: report of a long-term survival.

Plasmablastic leukemia (PL) as a complication of human herpes virus 8 (HHV8)-associated Castleman's disease is marked by a rapid and fatal outcome. In patients with AIDS, survival of 7 to 14 days after diagnosis has been reported. Prompt splenectomy and chemotherapy might lead to a significant survival benefit. Here we report a case of long-term survival in a patient with AIDS and multicentric Castleman's disease (MCD) complicated by PL.

Marrow transplantation for malignant plasma cell disorders: summary of the Seattle experience.

28 patients with plasma cell malignancies received marrow transplants from identical twins (N = 8), HLA-identical family members (N = 15), HLA partially-matched relatives (N = 3) or cryopreserved autologous marrow (N = 2). Treatment regimens included cyclophosphamide (CY) and total body irradiation (TBI) for 15 patients and busulphan (BU) and CY for 13 patients. 3 of 8 twins are alive, 2 without disease at 24 and 34 months, and 1 is alive and well at 116 months without evidence of disease except for at small residual monoclonal protein spike. 12 of the 18 allografted patients died of transplant-related causes and 2 died of progressive disease. 4 of 18 allograft recipients are alive; 2 are free of disease at 16 and 15 months, 1 is alive at 6 months without disease except for persistent monoclonal Kappa protein. 1 patient is alive with residual marrow involvement and a persistent IGA lambda monoclonal protein at 7 months. 1 of the 2 autograft recipients is alive 2 months after transplant and is not yet evaluable for tumor response and the other patient died early of transplant-related complications. Both CY + TBI and BU + CY resulted in remissions in patients with advanced plasma cell malignancies. However, the optimal treatment regimen and timing of transplantation remain to be determined.