multiple myeloma

Pomalidomide in Combination with Low-Dose Dexamethasone as the Treatment of “Double Refractory” Multiple Myeloma

LYMPHOID TUMORS , , ,

AV Petrov2, DV Motorin2, OS Pokrovskaya1, ES Urnova1, MV Nareiko1, DV Babenetskaya2, YuA Alekseeva2, LL Girshova2, LP Mendeleeva1, AYu Zaritskii2

1 Hematology Research Center, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

2 Federal Almazov North-West Medical Research Centre, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341

For correspondence: Aleksei Vladilenovich Petrov, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; Tel.:+7(921)317-28-02; e-mail: avlpetrov@mail.ru

For citation: Petrov AV, Motorin DV, Pokrovskaya OS, et al. Pomalidomide in Combination with Low-Dose Dexamethasone as the Treatment of “Double Refractory” Multiple Myeloma. Clinical oncohematology. 2017;10(3):372–80 (In Russ).

DOI: 10.21320/2500-2139-2017-10-3-372-380

ABSTRACT

Background. The development of radical therapy for multiple myeloma (MM) is still a pressing problem. This progressive disease requires repeated courses of therapy using drugs without cross-resistance. The prognosis of “double refractory” MM which is resistant to key antitumor drugs, first generation protease inhibitors and immunomodulating agents, remains poor. The median progression-free survival (PFS) and overall survival (OS) in this cohort of patients are 5 and 9 months, respectively.

Aim. The aim was to assess the effectiveness and tolerability of pomalidomide in combination with low-dose of dexamethasone in “double refractory” relapsed/refractory multiple myeloma (RRMM).

Materials & Methods. According to study protocol, 10 patients from Hematology Research Center and Federal Almazov North-West Medical Research Centre with RRMM were included in the period from September 2015 to July 2016. The median age was 62.5 years (range 48–76 years), and the median number of therapy lines was 4 (range 3–5). All patients had a disease progression after the administration of bortezomib, lenalidomide, and alkylating agents. In addition, 6 (60 %) of 10 patients received high-dose melphalan chemotherapy followed by auto-HSCT. The median number of therapy lines was 6 (range 4–15).

Results. The overall response rate was 60 % and the minimum response (stabilization of the disease) was observed in 40 % of patients (IMWG criteria). The median PFS was 7.8 months; OS in 18 months was observed in 70 % of cases (the median not achieved). Treatment-associated grade III–IV hematologic toxicity was observed in 2 patients (5 episodes). Non-hematological adverse events of grade III–IV included acute coronary syndrome, deep vein thrombosis, neuropathic pain, and in 1 case acute delusional disorder, which required discontinuation of the therapy. The presence of initial cytopenia and renal failure before therapy with pomalidomide did not require the dosage reduction or discontinuation of treatment.

Conclusion. Pomalidomide with low-dose dexamethasone demonstrated a high overall response rate an acceptable toxicity profile in patients with RRMM.

Keywords: multiple myeloma, “double-refractoriness”, immunomodulating agents, pomalidomide.

Received: January 24, 2017

Accepted: May 6, 2017

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Myeloid-Derived Suppressor Cells in Some Oncohematological Diseases

REVIEWS ,

AV Ponomarev

NN Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Aleksandr Vasil’evich Ponomarev, graduate student, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; e-mail: kl8546@yandex.ru

For citation: Ponomarev AV. Myeloid-Derived Suppressor Cells in Some Oncohematological Diseases. Clinical oncohematology. 2017;10(1):29-38–хх (In Russ).

DOI: 10.21320/2500-2139-2017-10-1-29-38

ABSTRACT

Myeloid-derived suppressor cells are immature myeloid cells with immunosuppressive properties. The review presents characteristics of myeloid-derived suppressor cells. It includes phenotype variants, mechanisms of the suppressive effect on the immune system, and tumor recruitment mechanisms of myeloid suppressors. It provides a brief description of works which studied myeloid suppressor in oncohematological diseases including multiple myeloma, lymphomas, and leukemias.

Keywords: myeloid suppressors, myeloid-derived suppressor cells, multiple myeloma, lymphomas, leukemias.

Received: September 8, 2016

Accepted: December 3, 2016

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Certain Aspects of Autologous Hematopoietic Stem Cell Transplantation in Patients with Multiple Myeloma

REVIEWS , , ,

SV Gritsaev, AA Kuzyaeva, SS Bessmel’tsev

Russian Scientific Research Institute of Hematology and Transfusiology under the Federal Medico-Biological Agency, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

For correspondence: Sergei Vasil’evich Gritsaev, DSci, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024; Tel: +7(812)717-58-57; e-mail: gritsaevsv@mail.ru

For citation: Gritsaev SV, Kuzyaeva AA, Bessmel’tsev SS. Certain Aspects of Autologous Hematopoietic Stem Cell Transplantation in Patients with Multiple Myeloma. Clinical oncohematology. 2017;10(1):7–12 (In Russ).

DOI: 10.21320/2500-2139-2017-10-1-7-12

ABSTRACT

The review dwells on certain problems of mobilization and conditioning regimens, as well as autologous hematopoietic stem cell transplantation (auto-HSCT) in patients with multiple myeloma. The aim of the review is to determine new approaches to improve the effectiveness of the auto-HSCT.

Keywords: multiple myeloma, autologous hematopoietic stem cell transplantation, mobilization regimen, conditioning regimen.

Received: July 13, 2016

Accepted: November 12, 2016

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Elotuzumab for Treatment of Multiple Myeloma (Literature Review)

LYMPHOID TUMORS , ,

OM Votyakova

NN Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Ol’ga Mikhailovna Votyakova, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel: +7(499)324-92-09; e-mail: omvtk@yandex.ru

For citation: Votyakova OM. Elotuzumab for Treatment of Multiple Myeloma (Literature Review). Clinical oncohematology. 2016;9(4):438–45 (In Russ).

DOI: 10.21320/2500-2139-2016-9-4-438-445

ABSTRACT

Chemotherapy has been the main treatment option for multiple myeloma for several decades. However, a considerable increase in the life expectancy was observed in multiple myeloma patients when thalidomide, bortezomib and lenalidomide had been introduced into clinical practice. Nevertheless, the disease remains incurable and there is an unmet need in fundamentally new treatment methods. Elotuzumab is a humanized IgG1 monoclonal antibody that specifically targets SLAMF7, an antigen belonging to the signaling lymphocytic activation molecule family, with its high expression detected on myeloma cells. This review presents the mechanism of action of elotuzumab, preclinical data and the main clinical studies of this monoclonal antibody.

Keywords: monoclonal antibodies, elotuzumab, clinical studies, multiple myeloma.

Received: May 25, 2016

Accepted: June 15, 2016

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Clinical Significance of Immunophenotyping of Bone Marrow Cells in Multiple Myeloma

LYMPHOID TUMORS , , , , ,

OYu Yakimovich, OM Votyakova, NV Lyubimova, NN Tupitsyn

N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Oksana Yur’evna Yakimovich, graduate student, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(499)324-28-54; e-mail: ronc_ramn@mail.ru

For citation: Yakimovich OYu, Votyakova OM, Lyubimova NV, Tupitsyn NN. Clinical Significance of Immunophenotyping of Bone Marrow Cells in Multiple Myeloma. Clinical oncohematology. 2016;9(3):296-301 (In Russ).

DOI: 10.21320/2500-2139-2016-9-3-296-301

ABSTRACT

Aim. To analyze the relationship between expression of aberrant CD45, CD19, CD56 markers on the plasma cells and clinical and laboratory findings and prognostically significant parameters in patients with multiple myeloma (MM).

Methods. This scientific research includes data on clinical investigation and immunophenotyping of bone marrow cells obtained from 64 MM patients treated in the N.N. Blokhin Russian Cancer Research Center over the period from 2004 to 2015. The three-color flow cytometry was performed using a direct immunofluorescence technique (CD38-PerCP, CD138-FITC monoclonal antibodies) and PE-conjugated monoclonal antibodies against CD45, CD19, and CD56.

Results. Comparison of average values of the total count of plasma cells, the number of plasmablasts, proplasmacyte and mature plasma cells (according to the myelogram) and comparison of these data with the level of expression of the CD19 marker demonstrated a significant relationship between the CD19 negative immunophenotype and both a higher level of the total count of plasma cells and immature plasma cells. There also was a significant correlation between the CD19 negative immunophenotype and a higher level of C-reactive protein, which is significant prognostic factor in MM. In addition, there was a significant relationship between the CD19 negative phenotype and a higher percentage of young neutrophils in blood, i.e. with a more frequent “left shift”. The CD56 negative phenotype is associated with plasmablastic morphology of plasma cells and with the presence of plasma cells in the peripheral blood. Plasma cell leukemia is more common in patients with СD56 negative phenotype of myeloma cells. The CD45 negative immunophenotype was associated with a higher level of k-type FLCs, Bence-Jones proteinuria and with a higher serum creatinine, than in the cases of CD45 positive phenotype.

Conclusion. The study of the immunophenotype of plasma cells in MM has important scientific and practical significance and requires further study.

Keywords: multiple myeloma, aberrant immunophenotype of malignant plasma cells, CD45, CD19, and CD56 markers, clinical and laboratory parameters.

Received: March 17, 2016

Accepted: April 1, 2016

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Pomalidomide for Treatment of Relapsed and Refractory Multiple Myeloma

LYMPHOID TUMORS , ,

S.V. Semochkin

N.I. Pirogov Russian National Research Medical University under the Ministry of Health of the Russian Federation, 1 Ostrovityanova str., Moscow, Russian Federation, 117997

For correspondence: Sergei Vyacheslavovich Semochkin, DSci, Professor, 1 Ostrovityanova str., Moscow, Russian Federation, 117997; Tel.: +7(495)653-14-78; e-mail: s.semochkin@gmail.com

For citation: Semochkin SV. Pomalidomide for Treatment of Relapsed and Refractory Multiple Myeloma. Clinical oncohematology. 2015;8(4):379–389 (In Russ).

DOI: 10.21320/2500-2139-2015-8-4-379-389

ABSTRACT

Pomalidomide is a third-generation immunomodulatory drug recommended for patients with multiple myeloma refractory to lenalidomide and bortezomib. The safety profile is optimized for application in patients with intensive and continuous anti-tumor treatment. Pomalidomide was approved by the Food and Drug Administration (FDA) and by the European Medicines Agency (EMA) in 2013 for use in patients with relapsed and refractory MM who have received at least two prior therapies, including lenalidomide and bortezomib, and have demonstrated disease progression on their last therapy or within 60 days after completion of the last therapy. Registration of pomalidomide for similar indications in Russia is pending in 2015. Pomalidomide has a similar mechanism of action with the other immunomodulators. The drug produces a direct cytostatic effect and causes an indirect effect by affecting the bone marrow microenvironment and T/NK-cells immunity. The recommended starting dose of pomalidomide is 4 mg daily (1–21/28) combined with low-dose dexamethasone 40 mg weekly for young patients or 20 mg for patients older than 75 years. The treatment should be performed till disease progression or unacceptable toxicity. This review summarizes current recommendations for dose adjustment depending on tolerance and prevention of thrombotic complications. The article presents author’s own clinical experience of successful application of pomalidomide for the management of a patient at high cytogenetic risk with «double» refractoriness to lenalidomide and bortezomib and preceding intensive anti-tumor treatment. The life expectancy was about 16 months after initiation of pomalidomide; this fact is consistent with literature data.

Keywords: pomalidomide, immunomodulatory drugs, multiple myeloma.

Received: April 8, 2015

Accepted: October 20, 2015

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Correlation between Expression of RARa Transcription Factor and Genes of VEGFR3-Dependent Signaling System in Multiple Myeloma

EXPERIMENTAL STUDIES , ,

NN Kalitin, IV Buravtsova

N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Nikolai Nikolaevich Kalitin, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(499)324-17-69; e-mail: f.oskolov@mail.ru

For citation: Kalitin NN, Buravtsova IV. Correlation between Expression of RARa Transcription Factor and Genes of VEGFR3-Dependent Signaling System in Multiple Myeloma. Clinical oncohematology. 2015;8(1):31–5 (In Russ).

ABSTRACT

Background. All-trans retinoic acid (ATRA) is a natural metabolite of vitamin A, which can regulate the gene expression by means of interaction between different types of nuclear retinoic acid receptors (RARs). It has been demonstrated that it may lead to suppression of in vivo and in vitro tumor cell growth and can contribute to its survival. For example, in a number of studies, it has been demonstrated that one of RAR subtypes, RARa, modulates expression of a number of vascular endothelial growth factors (VEGFs), mainly VEGF-A. At the same time, the exact mechanisms regulating the RARa-mediated regulation of VEGF (especially VEGF-C and VEGF-D and their receptor VEGFR3) expression are still unclear.

Methods. Changes in expression of mRNAs of VEGF-C, VEGF-D genes and their receptor VEGFR3 in a group of 17 multiple myeloma patients before and after treatment were analyzed in the article. The obtained data were then compared with changes in gene expression of the RARa receptor.

Results. It has been found that overall levels of VEGF-C, VEGF-D and VEGFR3 gene expression were reduced in response to the therapy. Changes in expression of these genes correlated with the RARa expression.

Conclusions. The correlation between VEGF-C, VEGF-D and VEGFR3 expression and RARa expression could indicate a possible involvement of RARa- protein in regulation of VEGFR3-associated signaling system gene expression.

Scientific value. These results may describe a possible mechanism of VEGF-C, VEGF-D and VEGFR3 expression by the RARa transcription factor.

Keywords: multiple myeloma, gene expression, VEGFR3-dependent system, RARa.

Received: August 27, 2014

Accepted: October 20, 2014

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Role of TGF-b1 Gene Polymorphism in Development of Multiple Myeloma

LYMPHOID TUMORS , ,

AA Pavlova1, LN Bubnova1, YuV Sokolova1, EV Karyagina2, SS Bessmel’tsev1, IE Pavlova1

1 Russian Scientific Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

2 Municipal Hospital No. 15, 4 Avangardnaya str., Saint Petersburg, Russian Federation, 198205

For citation: Pavlova AA, Bubnova LN, Sokolova YuV, et al. Role of TGF-b1 Gene Polymorphism in Development of Multiple Myeloma. Clinical oncohematology. 2015;8(3):274–80 (In Russ).

ABSTRACT

Background & Aims. Multiple myeloma (MM) is a hematological malignancy characterized by uncontrolled proliferation of the clonal plasma cells. Studies showed that the TGF-b1 cytokine induces growth of the tumor clone in MM. The aim of this study was to detect single nucleotide polymorphisms (SNP) of the TGF-b gene (codon 10, codon 25) associated with the development of MM and to determine risks of the bone disease development in residents of the Northwest Russia.

Methods. 43 patients with MM were examined (mean age: 69.2 ± 9.0 years). Patients were divided into two groups: the 1st group with severe osteolytic bone lesions and the 2nd one with signs of osteoporosis and solitary foci of lysis. The control group consisted of 40 healthy donors (mean age: 49.8 ± 10.1 years).

Results. The study demonstrated that MM was associated with TGF-b1 codon 25 CC genotype and TGF-b1 codon 10/codon 25 T/C haplotype. However, the TGF-b1 codon 25 GG genotype can be considered a marker of resistance to development of MM. Osteoporosis was associated with the TGF-b1 codon 25 GG genotype, whereas the TGF-b1 codon 25 GC was detected more frequently in patients with severe osteolytic bone lesions.

Conclusion. The obtained results indicate that individual genotypes and haplotypes of TGF-b1 are involved in the formation of predisposition to development of multiple myeloma.

Keywords: multiple myeloma, cytokines, TGF-b1, single nucleotide polymorphisms.

Received: February 9, 2015

Accepted: May 30, 2015

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Multiple Myeloma: 7-Year Experience of Applying Targeted Therapy in Novosibirsk and Its Results

LYMPHOID TUMORS , ,

T.I. Pospelova1, N.V. Skvortsova1, I.N. Nechunaeva2

1 Novosibirsk State Medical University, 52 Krasnyi pr-t, Novosibirsk, Russian Federation, 630091

2 Municipal Hospital No. 2, 21 Polzunova str., Novosibirsk, Russian Federation, 630051

For correspondence: Nataliya Valer’evna Skvortsova, PhD, associate professor, 52 Krasnyi pr-t, Novosibirsk, Russian Federation, 630091; Tel.: +8(383)279-94-06; e-mail: nata_sk78@mail.ru

For citation: Pospelova T.I., Skvortsova N.V., Nechunaeva I.N. Multiple Myeloma: 7-Year Experience of Applying Targeted Therapy in Novosibirsk and Its Results. Klin. Onkogematol. 2015;8(3):267–73. (In Russ.)

ABSTRACT

Objective. To evaluate results of the 7-year experience in treatment of multiple myeloma (MM) with proteasome inhibitor (bortezomib) in the Novosibirsk Municipal Hematological Center.

Methods. 199 MM patients treated in the Novosibirsk Municipal Hematological Center over the period from July, 2006, till December, 2014, were enrolled in the study. The median age of patients was 68 years (varied from 36 to 81). 98 patients received bortezomib as the first line therapy and 101 patients as the second line.

Results. The overall response rate of the first line therapy was 78.5 %; at that, 25 % of patients achieved a complete and almost complete remission. The median time to achieve response was 72 days. With the progression or refractory MM, the efficacy of bortezomib as a part of a combined antitumor therapy was 68.3 %. Bortezomib proved to be effective when its administration was resumed by patients who had received bortezomib and other components of the combined regimen previously (overall response: 68.4 %). The median overall survival rate has not been achieved, and 7-year survival rate was 70 %. Adverse events of bortezomib were predictable and manageable; the most relevant of them included gastrointestinal and hematologic disorders, fatigue, and peripheral neuropathy.

Conclusion. Bortezomib is a highly effective drug, which plays an important role in the treatment of MM as the first and subsequent line therapies; its administration results in significant increase in patients’ overall survival.

Keywords: multiple myeloma, effectiveness of treatment, bortezomib, overall survival.

Received: February 16, 2015

Accepted: May 28, 2015

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Role of Bendamustine in Treatment of Multiple Myeloma

CLINICAL PRESENTATION, DIAGNOSIS, AND MANAGEMENT OF LYMPHOID MALIGNANCIES ,

O.M. Votyakova

N.N. Blokhin Russian Cancer Research Center of RAMS, Moscow, Russian Federation

For citation: Votyakova O.M. Role of Bendamustine in Treatment of Multiple Myeloma. Klin. onkogematol. 2014; 7(3): 301–10 (In Russ.).

ABSTRACT

Bendamustine is an antineoplastic drug with a double mechanism of action combining the properties of alkylating compound and purine analog; it has a promising activity in multiple myeloma (MM). In 2013, Bendamustine (Ribomustin) was registered in Russia for treatment of patients older than 65 years of age with newly diagnosed ММ who are not eligible for high dose chemotherapy (HDC) with autologous transplantation of hemopoetic stem cells and who have clinical signs of neuropathy which impede the use of thalidomide and/or bortezomib. The review presents data on the product efficacy and safety both as monotherapy and in combination with glucocorticoids and target therapy (bortezomib, thalidomide, lenalidomide), in newly diagnosed and relapsed MM patients. The presented data permit to recommend bendamustine combined with glucocorticoids and novel drugs for MM patients with relapses and as the first line therapy in some patients with polyneuropathy who are not eligible for HDC with autologous transplantation of hemopoetic stem cells.

Keywords: multiple myeloma, bendamustine, ribomustin.

Address correspondence to: omvtk@yandex.ru

Accepted: May 23, 2014

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