immunomodulating agents

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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REFERENCES

  1. Howlade N, Noone A, Krapcho M, et al. SEER Cancer Statistics Review, 1975–2009 (Vintage 2009 Populations). Bethesda, MD: National Cancer Institute; 2012.
  2. Kyle RA, Therneau TM, Rajkumar SV, et al. Incidence of multiple myeloma in Olmsted County, Minnesota: Trend over 6 decades. Cancer. 2004;101(11):2667–74. doi: 10.1002/cncr.20652.
  3. Менделеева Л.П., Вотякова О.М., Покровская О.М. и др. Национальные клинические рекомендации по диагностике и лечению множественной миеломы. Гематология и трансфузиология. 2014;1(приложение 3):2–24.
    [Mendeleeva LP, Votyakova OM, Pokrovskaya OM, et al. National clinical guidelines for diagnosis and treatment of multiple myeloma. Gematologiya i transfuziologiya. 2014;1(Suppl 3):2–24. (In Russ)]
  4. Каприн А.Д., Старинский В.В., Петрова Г.В. (ред.) Злокачественные новообразования в России в 2015 году (заболеваемость и смертность). М.: ФГБУ «МНИОИ им. П.А. Герцена» Минздрава России, 2017. 250 с.
    [Kaprin AD, Starinskii VV, Petrova GV, eds. Zlokachestvennye novoobrazovaniya v Rossii v 2015 godu (zabolevaemost’ i smertnost’). (Malignant tumors in Russia in 2015 (incidence and mortality).) Moscow: FGBU MNIOI im. PA Gertsena Minzdrava Rossii Publ.; 2017. 250 p. (In Russ)]
  5. Doo NW, Coory M, White V. Low Uptake of Upfront Autologous Transplantation for Myeloma in a Jurisdiction With Universal Health Care Coverage: A Population-Based Patterns of Care Study in Australia. Clin Lymph Myel Leuk. 2014;14(1):61–7. doi: 10.1016/j.clml.2013.09.011.
  6. Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia. 2012;26(1):149–57 doi: 10.1038/leu.2011.196.
  7. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111(5):2516–20. doi: 10.1182/blood-2007-10-116129.
  8. Harousseau JL, Attal M, Avet-Loiseau H, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol. 2010;28(30):4621–9. doi: 10.1200/JCO.2009.27.9158.
  9. Sonneveld P, Salwender HJ, Van Der Holt B, et al. Bortezomib Induction and Maintenance in Patients with Newly Diagnosed Multiple Myeloma: Long-Term Follow-up of the HOVON-65/GMMG-HD4 Trial. Blood. 2015;126(27):23.
  10. Cavo M, Tacchetti P, Patriarca F, et al. GIMEMA Italian Myeloma Network Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376(9758):2075–85. doi: 10.1016/S0140-6736(10)61424-9.
  11. Barlogie B, Anaissie E, van Rhee F, et al. Incorporating bortezomib into upfront treatment for multiple myeloma: early results of total therapy 3. Br J Haematol. 2007;138(2):176–85. doi: 10.1111/j.1365-2141.2007.06639.x.
  12. Вarlogie В, Mitchell А, van Rhee F, et al. Curing Multiple Myeloma (MM) with Total Therapy (TT). Blood. 2014;124(21):195.
  13. San Miguel JF, Schlag R, Khuageva NK, et al. Continued overall survival benefit after 5 years’ follow-up with bortezomib-melphalan-prednisone (VMP) versus melphalan-prednisone (MP) in patients with previously untreated multiple myeloma, and no increased risk of second primary malignancies: Final results of the phase 3 VISTA trial. 53rd Annual Meeting of the American Society of Hematology. Abstract 476. Presented December 12, 2011.
  14. Мещерякова Д.В., Моторин Д.В., Петров А.В. Аутологичная трансплантация стволовых гемопоэтических клеток у пациентов с множественной миеломой. Опыт трансплантации после терапии леналидомидом. Трансляционная медицина. 2012;6:82–90.
    [Meshcheryakova DV, Motorin DV, Petrov AV. Autologous stem cell transplantation in patients with multiple myeloma: experience of successful transplantation after lenalidomide treatment. Translyatsionnaya meditsina. 2012;6:82–90. (In Russ)]
  15. Kumar S, Therneau T, Gertz M, et al. Clinical Course of Patients With Relapsed Multiple Myeloma. Mayo Clin Proceed. 2004;79(7):867–74. doi: 10.4065/79.7.867.
  16. Абрамова Т.В., Обухова Т.Н., Покровская О.С. и др. Анализ общей выживаемости больных множественной миеломой в отдельных цитогенетических группах. Гематология и трансфузиология. 2016;61(1 Suppl 1):30.
    [Abramova TV, Obukhova TN, Pokrovskaya OS, et al. Analysis of overall survival in patients with multiple myeloma in different cytogenetic groups. Gematologiya i transfuziologiya. 2016;61(1 Suppl 1):30. (In Russ)]
  17. Marriott JB, Muller GW, Stirling D. Immunotherapeutic and anti-tumour potential of thalidomide analogues. Exp Opin Biol Ther. 2001;1:675–82. doi: 10.1517/14712598.1.4.675.
  18. Muller GW, Chen R, Huang S-Y, et al. Amino-substituted thalidomide analogs: potent inhibitors of TNF-α production. Bioorg Med Chem Lett. 1999;9(11):1625–30. doi: 10.1016/s0960-894x(99)00250-4.
  19. Rychak E, Mendy D, Shi T, et al. Pomalidomide in combination with dexamethasone results in synergistic anti-tumour responses in pre-clinical models of lenalidomide-resistant multiple myeloma. Br J Haematol. 2016;172(6):889–901. doi: 10.1111/bjh.13905.
  20. Семочкин С.В. Помалидомид в лечении рецидивов и рефрактерных форм множественной миеломы. Клиническая онкогематология. 2015;8(4):379–89. doi: 10.21320/2500-2139-2015-8-4-379-389.
    [Semochkin SV. Pomalidomide for Treatment of Relapsed and Refractory Multiple Myeloma. Clinical oncohematology. 2015;8(4):379–89. doi: 10.21320/2500-2139-2015-8-4-379-389. (In Russ)]
  21. Quach H, Ritchie D, Stewart AK, et al. Mechanism of action of immunomodulatory drugs (IMiDS) in multiple myeloma. Leukemia. 2010;24(1):22–32. doi: 10.1038/leu.2009.236.
  22. Dredge K, Marriott JB, Macdonald CD, et al. Novel thalidomide analogues display anti-angiogenic activity independently of immunomodulatory effects. Br J Cancer. 2002;87(10):1166–72. doi: 10.1038/sj.bjc.6600607.
  23. Pal R, Monaghan S, Hassett A Immunomodulatory derivatives induce PU.1 down-regulation, myeloid maturation arrest, and neutropenia. Blood. 2010;115(3):605–14. doi: 10.1182/blood-2009-05-221077.
  24. Davies FE, Raje N, Hideshima T, et al. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood. 2001;98(1):210–6. doi: 10.1182/blood.v98.1.210.
  25. Ito T, Ando H, Suzuki T, et al. Identification of a primary target of thalidomide teratogenicity. Science. 2010;327(5971):1345–50. doi: 10.1126/science.1177319.
  26. Lindner S, Jan Krоnke. The Molecular Mechanism of Thalidomide Analogs in Hematologic Malignancies. J Mol Med (Berl). 2016;94(12):1327–34. doi: 10.1007/s00109-016-1450-z.
  27. Bjorund CC, Lu L, Kang J, et al. Rate of CRL4CRBN substrate Ikaros and Aiolos degradation underlies differential activity of lenalidomide and pomalidomide in multiple myeloma cells regulation of c-Myc and IFR4. Blood Cancer J. 2015;5(10):e354. doi: 10.1038/bcj.2015.66.
  28. Lopez-Girona A, Mendy D, Ito T, et al. Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia. 2012;26(11):2326–35. doi: 10.1038/leu.2012.119.
  29. Hideshima T, Cottini F, Nozawa Y. p-53-related protein kinase confers poor prognosis and represents a novel therapeutic target in multiple myeloma. Blood. 2017;129(10):1308–19. doi: 10.1182/blood-2016-09-738500.
  30. Schey SA, Fields P, Bartlett JB, et al. Phase I study of an immunomodulatory thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. J Clin Oncol. 2004;22(16):3269–76. doi: 10.1200/JCO.2004.10.052.
  31. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol. 2009;27(30):5008–14. doi: 10.1200/JCO.2009.23.6802.
  32. Richardson PG, Siegel D, Baz R, et al. Phase 1 study of pomalidomide MTD, safety, and efficacy in patients with refractory multiple myeloma who have received lenalidomide and bortezomib. Blood. 2013;121(11):1961–7. doi: 10.1182/blood-2012-08-450742.
  33. Lacy MQ, Allred JB, Gertz MA, et al. Pomalidomide plus low-dose dexamethasone in myeloma refractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies in dual-refractory disease. Blood. 2011;118(11):2970–5. doi: 10.1182/blood-2011-04-348896.
  34. Leleu X, Attal M, Arnulf B, et al. Pomalidomide plus low-dose dexamethasone is active and well tolerated in bortezomib and lenalidomide-refractory multiple myeloma: Intergroupe Francophone du Myelome 2009-02. Blood. 2013;121(11):1968–75. doi: 10.1182/blood-2012-09-452375.
  35. Miguel JS, Weisel K, Moreau P, et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14(11):1055–66. doi: 10.1016/S1470-2045(13)70380-2.
  36. Baz RC, Martin TG, Lin H-Y, et al. Randomized multicenter Phase II study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood. 2016;127(21):2561–8. doi: 10.1182/blood-2015-11-682518.
  37. Lacy MQ, La Plant BR, Laumann KM, et al. Pomalidomide, bortezomib and dexamethasone (PVD) for patients with relapsed lenalidomide refractory multiple myeloma (MM). Blood. 2014;124(21):304.
  38. Richardson PG, Hofmeister C, Raje NS, et al. A Phase 1, multicenter study of pomalidomide, bortezomib, and low-dose dexamethasone in patients with proteasome inhibitor exposed and lenalidomide-refractory myeloma (Trial MM-005). Blood. 2015;126(23):3036.
  39. Chari A, Lonial S, Suvannasankha A, et al. Open-label, multicenter, Phase 1b study of daratumumab in combination with pomalidomide and dexamethasone in patients with at least 2 lines of prior therapy and relapsed or relapsed and refractory multiple myeloma. Blood. 2015;126(23):508.
  40. Ramasamy K, Dimopoulos M, van de Donk NWCJ, et al. Safety of treatment (Tx) with pomalidomide (POM) and low-dose dexamethasone (LoDEX) in patients (Pts) with relapsed or refractory multiple myeloma (RRMM) and renal impairment (RI), including those on dialysis. Blood. 2015;126(23):374.
  41. Leleu X, Karlin L, Macro M, et al. Pomalidomide plus low-dose dexamethasone in multiple myeloma with deletion 17p and/or translocation (4;14): IFM 2010-02 trial results. Blood. 2015;125(9):1411–7. doi: 10.1182/blood-2014-11-612069.
  42. Richardson PG, Siegel DS, Vij R, et al. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized Phase II study. Blood. 2014;123(12):1826–32. doi: 10.1182/blood-2013-11-538835.
  43. Palumbo A, Bringhen S, Mateos MV, et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: In International Myeloma Group report. Blood. 2015;125(13):2068–74. doi: 10.1182/blood-2014-12-615187.
  44. Kumar S, Paiva B, Anderson K. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328–46. doi: 10.1016/S1470-2045(16)30206-6.