Dominik Dytfeld

Bortezomib in combination with thalidomide and dexamethasone—a successful treatment regimen in refractory extramedullary multiple myeloma

Dear editor, Extramedullary manifestation of multiple myeloma (MM) is an independent risk factor of worse prognosis. The main localization of extramedullary MM (up to 74% of cases) is upper aerodigestive tract [1]. Recently, new drugs have been discovered and new standard regimens applied. Thalidomide and bortezomib belong to new promising drugs. In 2006, Pantolidou et al. [2] presented in this journal a case of a patient with plasmocytoma of lymph node successfully treated with bortezomib. Herein, we present a case of a patient with diagnosed MM and tumor localization in the intravertebral space penetrating into the intrathecal space. A 58-year-old man was diagnosed with solitary plasmocytoma in 2002 according to immunohistopathological test performed on the biopsy taken from the tumor. The tumor shown in magnetic resonance imaging was infiltrating the thoracic part of the spinal column and inserting into spinal canal (Fig. 1). At the time of diagnosis, trace of monoclonal protein IgG kappa with suppression of normal immunoglobulins was stated. No other infiltrations were found. In repeated bone marrow aspiration biopsies, no more than 5% of plasmocytes were detected. On account of heavy pain complaint, patient received chemotherapy according to VAD (Vincristine + Adriamycin + Dexamethasone) regimen. Unfortunately, despite treatment, progression was stated. In the second line of treatment, EDAP (Etoposide + Cytarabine + Dexamethasone + Cisplatin) chemotherapy was introduced. Because of neurological progression (paraparesis and partial paralysis of sphincters), radiotherapy in the dose of 40 Gy/T on the thoracic part of spinal column was applied. Three next EDAP courses were supplemented with thalidomide (2× 200 mg). After 3 months, progression was stated (increase of the tumor size and M protein serum concentration). Combination therapy with bortezomib, dexamethasone, and thalidomide was chosen in an attempt to achieve rapid disease control. Bortezomib in the dose 1.3 mg/m was administered intravenously at days 1, 4, 8, and 11 of each 21-day cycle. Dexamethasone at dose of 20 mg/24 h and thalidomide at dose of 100 mg/24 h were given orally at days 1, 2, 4, 5, 8, 9, 11, 12 and everyday, respectively. At the time of introduction of this therapy, patient was complaining of slight polyneuropathy (grade 1 according to NCI v 3.0). Subsequently, subject received six courses of combined chemotherapy, and the 50% reduction of tumor mass in nuclear magnetic resonance (NMR) was confirmed. No deterioration in terms of polyneuropathy was stated. Patient was then qualified for high-dose chemotherapy supported by peripheral blood stem cell transplantation. Standard mobilization with filgrastim (10 mcg/kg) and endoxan 4 g/m iv allowed to collect 0.04×10/kg CD34+ cells only. However, patient refused re-mobilization procedure. Recently, he has been on sustaining treatment with thalidomide (400 mg daily) with no disease progression during 9 months of follow-up. Presented observations allow us to conclude that standard regimens—VAD and EDAP—were not effective in this case. Addition of thalidomide to the EDAP chemotherapy was effective only for a short period of time. Thalidomide is believed not to be effective in extramedullary tumors because one of its most important activities requires the Ann Hematol (2008) 87:253–254 DOI 10.1007/s00277-007-0401-8

Synergistic Myeloma Cell Death via Novel Intracellular Activation of Caspase-10–Dependent Apoptosis by Carfilzomib and Selinexor

Exportin1 (XPO1; also known as chromosome maintenance region 1, or CRM1) controls nucleo-cytoplasmic transport of most tumor suppressors and is overexpressed in many cancers, including multiple myeloma, functionally impairing tumor suppressive function via target mislocalization. Selective inhibitor of nuclear export (SINE) compounds block XPO1-mediated nuclear escape by disrupting cargo protein binding, leading to retention of tumor suppressors, induction of cancer cell death, and sensitization to other drugs. Combined treatment with the clinical stage SINE compound selinexor and the irreversible proteasome inhibitor (PI) carfilzomib induced synergistic cell death of myeloma cell lines and primary plasma cells derived from relapsing/refractory myeloma patients and completely impaired the growth of myeloma cell line–derived tumors in mice. Investigating the details of SINE/PI-induced cell death revealed (i) reduced Bcl-2 expression and cleavage and inactivation of Akt, two prosurvival regulators of apoptosis and autophagy; (ii) intracellular membrane-associated aggregation of active caspases, which depended on caspase-10 protease activity; and (iii) novel association of caspase-10 and autophagy-associated proteins p62 and LC3 II, which may prime activation of the caspase cascade. Overall, our findings provide novel mechanistic rationale behind the potent cell death induced by combining selinexor with carfilzomib and support their use in the treatment of relapsed/refractory myeloma and potentially other cancers. Mol Cancer Ther; 15(1); 60–71. ©2015 AACR.

Prognostic factors and long-term outcome of autologous haematopoietic stem cell transplantation following a uniform-modified BEAM-conditioning regimen for patients with refractory or relapsed Hodgkin lymphoma: a single-center experience

Despite the well-defined role of autologous haematopoietic stem cell transplantation (autoHCT) in the treatment of patients with relapsed or refractory Hodgkin lymphoma (HL), relapse remains the main cause of transplant failure. We retrospectively evaluated long-term outcome and prognostic factors affecting survival of 132 patients with refractory (nxa0=xa089) or relapsed HL (nxa0=xa043) treated with autoHCT following modified BEAM. With a median follow-up of 68xa0months, the 10-year overall survival (OS) and progression-free survival (PFS) were 76 and 66xa0%, respectively. The 10-year cumulative incidence of second malignancies was 7xa0%. In multivariate analysis, age ≥45xa0years, more than one salvage regimens and disease status at transplant worse than CR were factors predictive for poor OS. In relapsed HL, age at transplant, response duration (<12 vs. ≥12xa0months) and the number of salvage regimens were independent predictors for PFS. In the refractory setting, disease status at autoHCT and the number of salvage regimens impacted PFS. The number of risk factors was inversely correlated with PFS in both relapsed and refractory HL (pxa0=xa00.003 and <0.001, respectively). The median PFS for patients with >1 risk factor in the relapsed and refractory setting was 5 and 11xa0months, respectively, in comparison with the median PFS not reached for patients with 0–1 risk factor in both settings. We conclude that high proportion of patients with relapsed/refractory HL can be cured with autoHCT. However, the presence of two or more risk factors helps to identify poor prognosis patients who may benefit from novel treatment strategies.

Autologous stem cell transplantation as consolidation therapy for patients with peripheral T cell lymphoma in first remission: long-term outcome and risk factors analysis

This report is a retrospective analysis of 65 patients with peripheral T cell lymphoma (PTCL), who underwent high-dose therapy and autologous hematopoietic stem cell transplantation (autoHCT) as a consolidation of first response achieved with either induction or salvage chemotherapy. We intended to determine the prognostic factors that influenced outcome after autoHCT and to define the predictive value of the scoring systems most often applied for transplant outcomes. Nineteen patients in either complete or partial remission underwent autoHCT after induction chemotherapy. Forty-six patients received second-line chemotherapy as a consolidation of partial response after induction chemotherapy (nu2009=u200934) or as a salvage therapy after primary induction failure (nu2009=u200912), and thereafter proceeded to autoHCT. Finally, the 36 patients were in complete remission, and 29 in partial remission at autoHCT. The median follow-up of survivors was 53xa0months (range 7–157xa0months). The 5-year overall survival and progression-free survival for all patients were 61.5xa0% (95xa0% CI 47.0–74.2xa0%) and 59.4xa0% (95xa0% CI 46.1–71.5xa0%), respectively. In multivariate analysis, bone marrow involvement at diagnosis and less than partial remission after induction chemotherapy were factors independently predictive for overall survival and progression-free survival. The prognostic index for PTCL could reliably stratify the prognosis of PTCL in this analysis.

Zalecenia Polskiej Grupy Szpiczakowej dotyczące rozpoznawania i leczenia szpiczaka plazmocytowego na rok 2012

STRESZCZENIE Nowe leki wprowadzane do leczenia szpiczaka w ostatnich latach pozwalają uzyskac odpowiedź terapeutyczną u przewazającej wiekszości chorych na szpiczaka plazmocytowego. Schematy oparte na talidomidzie i bortezomibie stosowane są obecnie w leczeniu nowo zdiagnozowanych chorych niezaleznie od tego, czy chorzy są kandydatami do chemioterapii duzymi dawkami melfalanu i przeszczepienia krwiotworczych komorek macierzystych, czy nie. W leczeniu chorych opornych na terapie indukującą stosuje sie schematy oparte na lenalidomidzie. Wazną cześcią leczenia chorych na szpiczaka jest leczenie wspomagające i podtrzymujące. W artykule tym przedstawiono rowniez zalecenia dotyczące rozpoznania i leczenia innych dyskrazji plazmocytowych.

Treatment strategy based on gemcitabine-containing salvage chemotherapy used with intent to proceed to second stem cell transplant for patients with Hodgkin lymphoma relapsing after a prior autologous transplant

Abstract This report is an analysis of patients with Hodgkin lymphoma who relapsed after autologous stem cell transplant (autoHCT) and who were treated with gemcitabine-based therapy as a bridge to either allogeneic or second autologous transplant. Sixteen patients were treated with gemcitabine, cisplatin and steroid and 21 with gemcitabine plus vinorelbine. The overall response rate was 68%. The grade 3–4 toxicity was myelosupression and infections. Fifteen patients proceeded to allogeneic and five to autologous transplant. Two-year overall survival (OS) and progression-free survival (PFS) for all patients were 36% and 25%, respectively. In multivariate analysis, relapse > 6 months after autoHCT and response to gemcitabine-based chemotherapy were associated with superior OS and response to gemcitabine-based chemotherapy with improved PFS. A treatment strategy based on gemcitabine-containing chemotherapy and second transplant appears to be an effective treatment option for patients relapsing > 6 months after autoHCT, providing a median survival time of 34 months.

Efficacy and safety of lenalidomide treatment in multiple myeloma (MM) patients—Report of the Polish Myeloma Group

UNLABELLEDnThe aim of the multi-centre retrospective study was to evaluate the efficacy and safety of lenalidomide (LEN) therapy in patients with resistant or relapsed multiple myeloma (MM) as well as in patients with stable disease (LEN used due to neurological complications). The primary endpoint of this study was an overall response rate (ORR). The secondary endpoints were as follows: time to progression (TTP), overall survival (OS) and the safety of drug use. Data were collected in 19 centres of the Polish Multiple Myeloma Study Group. The study group consisted of 306 subjects: 153 females and 153 males. In 115 patients (38.8%, group A), a resistant myeloma was diagnosed; in 135 (44.1%, group B) a relapse, and in 56 (18.3%, group C) a stable disease were stated. In 92.8% of patients, LEN+DEX combination was used; in remaining group, LEN monotherapy or a combination therapy LEN+bortezomib or LEN+bendamustine and other were used. In the entire study group, ORR was 75.5% (including 12.4% patients achieving complete remission [CR] or stringent CR [sCR]). Median time to progression (TTP) was 20 months. Median overall survival (OS) was 33.3 months. The regression model for treatment response was on the borderline of statistical significance (p=0.07), however the number of LEN treatment cycles ≥ 6 (R(2)=17.2%), baseline LDH level (R(2)=1.1%) and no ASCT use (R(2)=1.7%) where the factors most affecting treatment response achievement. The regression model for dependant variable--overall survival--was statistically significant (p=0.0000004). Factors with the most impact on OS were as follows: number of LEN cycles treatment ≥ 6 (R(2)=16.7%), treatment response achievement (R(2)=6.9%), β-2-microglobulin (β-2-M) level (R(2)=4.8%), renal function (R(2)=3.0%) and lack of 3/4 grade adverse events (R(2)=1.4%).nnnSUMMARYnLEN is an effective and safe therapeutic option, even in intensively treated resistant and relapsed MM patients, as well as in patients with stable disease and previous treatment-induced neurological complications. In particular, the number of LEN treatment cycles ≥ 6 was the factor which affected treatment response achievement the most, together with an important impact on OS.

Proteomic profiling of naïve multiple myeloma patient plasma cells identifies pathways associated with favourable response to bortezomib-based treatment regimens

Toward our goal of personalized medicine, we comprehensively profiled pre‐treatment malignant plasma cells from multiple myeloma patients and prospectively identified pathways predictive of favourable response to bortezomib‐based treatment regimens. We utilized two complementary quantitative proteomics platforms to identify differentially‐regulated proteins indicative of at least a very good partial response (VGPR) or complete response/near complete response (CR/nCR) to two treatment regimens containing either bortezomib, liposomal doxorubicin and dexamethasone (VDD), or lenalidomide, bortezomib and dexamethasone (RVD). Our results suggest enrichment of ‘universal response’ pathways that are common to both treatment regimens and are probable predictors of favourable response to bortezomib, including a subset of endoplasmic reticulum stress pathways. The data also implicate pathways unique to each regimen that may predict sensitivity to DNA‐damaging agents, such as mitochondrial dysfunction, and immunomodulatory drugs, which was associated with acute phase response signalling. Overall, we identified patterns of tumour characteristics that may predict response to bortezomib‐based regimens and their components. These results provide a rationale for further evaluation of the protein profiles identified herein for targeted selection of anti‐myeloma therapy to increase the likelihood of improved treatment outcome of patients with newly‐diagnosed myeloma.

Inhibitory effects of bortezomib on platelet aggregation in patients with multiple myeloma

INTRODUCTIONnMultiple myeloma (MM) therapy affects prothrombotic and anticoagulant processes. Patients receiving thalidomide, especially in combination with steroids, are at increased risk of venous thromboembolism (VTE), while the incidence of VTE on bortezomib is low. In vitro studies indicate that bortezomib causes a reduction in ADP-induced platelet aggregation.nnnOBJECTIVESnTo analyse the influence of bortezomib on platelet aggregation induced by various agonists in patients with MM.nnnPATIENTS AND METHODSnA total of 30 patients (median age 57.5years) with relapsed/refractory MM receiving bortezomib-based regimens were analysed. Optical platelet aggregometry was performed with the agonists collagen, ADP and ristocetin and measured over two 21-day cycles. The results from two groups: those treated with bortezomib and thalidomide (BT group, n=11) and those without thalidomide (B group, n=19) were analysed.nnnRESULTSnDuring the second cycle, significantly decreased platelet aggregation was observed in the B group: 5μM ADP (p=0.0285, day 1 versus 8); 3.5μM ADP (p=0.0005, day 1 versus 8 and day 1 versus 11), collagen (p=0.0014, day 4 versus 8, day 4 versus 11), 1.25mg/ml ristocetin (p=0.0017, day 1 versus 8 and day 1 versus 11). Agonist-induced platelet aggregation tended to be reduced over time during the 1st cycle in group B. In the thalidomide group, significant platelet aggregation inhibition by collagen only was found. Transient reduction in platelet count was observed in all patients, but more prominently in group B.nnnCONCLUSIONnThe inhibitory effects of prolonged exposure of bortezomib on platelet aggregation were demonstrated in relapsed/refractory MM patients, but antithrombotic activity of bortezomib should be clarified in further prospective studies.

Chromosome 1 amplification has similar prognostic value to del(17p13) and t(4;14)(p16;q32) in multiple myeloma patients: analysis of real-life data from the Polish Myeloma Study Group

Abstract The study aimed to assess prognostic significance of del(13q14), del(17p13), t(4;14)(p16;q32), and amp(1q21) in newly diagnosed myeloma patients treated mostly with thalidomide-based therapies. All genetic abnormalities except del(13q14) were independent prognostic factors associated with shortened progression-free survival (PFS) and overall survival (OS). Patients with no abnormalities, one abnormality, and ≥2 abnormalities had a median PFS of 41.8, 17.0, and 10.0 months, respectively; a median OS was not reached, 48.0 and 23.3 months, respectively. According to the presence of amp(1q21), t(4;14)(p16;q32), and del(17p13) and the International Staging System (ISS), we stratified patients into low-risk, intermediate-risk and high-risk groups. A median PFS was 52.9, 25.6, and 10.0 months, respectively; a median OS was not reached, 64.0 and 25.0 months, respectively. In conclusion, our study confirmed the prognostic value of cytogenetic changes and showed that prognostic models based on ISS and cytogenetic studies should include not only del(17p13) and t(4;14)(p16;q32), but also amp(1q21).