{"id":55894,"date":"2024-03-20T10:14:14","date_gmt":"2024-03-20T10:14:14","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=55894"},"modified":"2024-04-03T05:24:41","modified_gmt":"2024-04-03T05:24:41","slug":"recent-advances-in-multiple-myeloma","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol17no1\/recent-advances-in-multiple-myeloma\/","title":{"rendered":"Recent Advances in Multiple Myeloma"},"content":{"rendered":"\n

Introduction<\/strong><\/p>\n\n\n\n

Multiple\nmyeloma (MM) represents a malignant proliferation of plasma cells originating\nfrom a single clone. The tumour results in neurologic symptoms, bone pain or\nfracture, renal failure, higher susceptibility to infections like pneumonia and\npyelonephritis, normocytic and normochromic anaemia, hypercalcemia, and possibly\nclotting abnormalities, as well as signs of hyperviscosity.1<\/sup>,<\/sup>2<\/sup>,<\/sup>3<\/sup> The median age at\ndiagnosis is 70 years.4<\/sup>,<\/sup>5<\/sup>,<\/sup>6<\/sup> Men are more\nimpacted than women,7<\/sup>,<\/sup>8<\/sup>,<\/sup>9<\/sup> and blacks have\nnearly twice the incidence than whites.10<\/sup><\/p>\n\n\n\n

The most recent numbers from the Global Cancer Observatory (GLOBOCAN) suggested that there were 1,76,404 instances of MM worldwide in 2020, making up 1.2% of all cancer diagnoses.11<\/sup><\/p>\n\n\n\n

Pathogenesis <\/strong><\/p>\n\n\n\n\n\n
\"\"<\/td>\n\n

Figure 1: Pathogenesis<\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Treatment modalities<\/strong><\/p>\n\n\n\n

Individuals who initially present with multiple myeloma are symptomatic and need cytotoxic chemotherapy. Melphalan (an alkylating agent) and prednisone (a glucocorticoid), together known as the “MP protocol,” was long accepted as the conventional first-line therapy.12,13<\/sup> Proteosome inhibitors and immunomodulatory analogues (IMiDS) have recently become important first-line treatments.14,15,16<\/sup> Currently, the most active treatment is a triplet regime consisting of a proteosome inhibitor, an IMiD and dexamethasone or a doublet regimen consisting of a proteasome inhibitor and dexamethasone.17,18<\/sup><\/p>\n\n\n\n

Currently prescribed drugs for multiple myeloma<\/strong><\/p>\n\n\n\n

Alkylating agents- melphalan and cyclophosphamide<\/p>\n\n\n\n

Anthracyclines- cyclophosphamide and doxorubicin<\/p>\n\n\n\n

Corticosteroid- dexamethasone<\/p>\n\n\n\n

Immunomodulatory drug (IMiD)- Thalidomide, lenalidomide and pomalidomide<\/p>\n\n\n\n

Proteasome inhibitor- Bortezomib, carfilzomib and ixazomib<\/p>\n\n\n\n

MonoclonalAntibodies- Daratumumab, Elotuzumab and Isatuximab<\/p>\n\n\n\n

Nuclear export inhibitor- Selinexor<\/p>\n\n\n\n

B-cell maturation antigen (BCMA)-directed antibody- Belantamab mafodotin<\/p>\n\n\n\n

CAR T-cell therapy-Idecabtagene vicleucel, Ciltracabtagene autoleucel<\/p>\n\n\n\n

Histone- deacetylase inhibitor – Panobinostat<\/p>\n\n\n\n

Bisphosphonate- Pamidronate and zoledronate<\/p>\n\n\n\n

Stem cell mobilizer-Prelixafor<\/p>\n\n\n\n

Thalidomide is a recognised treatment for refractory or relapsed forms of MM. The recommended dosage of thalidomide in combination with dexamethasone is 200 mg once daily (in a 28-day treatment cycle).  The dose-limiting adverse effects of thalidomide are sedation, fatigue, constipation and sensory neuropathy. Drug withdrawal alleviates the neuropathic symptoms, however, long-standing sensory loss might not reverse. The drug should be used cautiously in patients with diabetes19,20<\/sup>. Thalidomide enhances the sedative effects of barbiturates and alcohol and the catatonic effects of chlorpromazine21,22<\/sup>. Renal failure necessitates no dose modification.<\/p>\n\n\n\n

Lenalidomide is a IMiD analog of thalidomide. The standard dosage of lenalidomide is 25 mg\/d for 21 days in a 28-day cycle. Lenalidomide results in bone marrow depression and leukopenia23,24<\/sup>. Hepatotoxicity and renal dysfunction are rare adverse effects. Lenalidomide can trigger a tumour flare-up and significant lymph node enlargement in some patients of chronic lymphocytic leukemia.<\/p>\n\n\n\n

Pomalidomide is the newest IMiD analogue of thalidomide. It is used in conjunction with dexamethasone, for patients with MM who have had at least two prior treatments with lenalidomide and a proteasome inhibitor and have shown signs of disease progression within or after 60 days of completion of the last treatment. It is taken orally at a dose of 4 mg per day on day 1 through 21 of repeated 28-day cycles. The most frequently reported side effects (\u226530%) were asthenia and fatigue, neutropenia, anaemia, constipation, nausea, diarrhoea, dyspnea, upper respiratory tract infections, back pain, and pyrexia. Pomalidomide has a black box warning for embryo-fetal toxicity and venous and arterial thromboembolism25<\/sup>. Pomalidomide is a substrate for several cytochrome P450 enzymes26<\/sup>. Studies revealed that co-administration of pomalidomide with fluvoxamine (CYP1A2 inhibitor) in the presence of ketoconazole (CYP3A4\/5 inhibitor) almost doubled pomalidomide exposure27<\/sup>. Pomalidomide’s ability to be used in thalidomide and lenalidomide resistant cases pose a potential benefit of this analogue28,29<\/sup>.<\/p>\n\n\n\n

Bortezomib is currently being used as initial therapy as well as for refractory and relapse cases of MM. It exerts its effects by inhibiting of the 26S proteosome. Bortezomib is administered at a dose of 1.3 mg\/m2<\/sup> as an intravenous bolus on days 1, 4, 8, and 11 of each 21-day cycle (with a 10-day rest period per cycle). Among the drug toxicities are thrombocytopenia (28%), fatigue (12%), peripheral neuropathy (12%), neutropenia, anemia, vomiting, diarrhea, limb pain, dehydration, nausea, and weakness30,31<\/sup>. Intravenous bortezomib may precipitate hypotension in patients with a history of syncope and hypertension. Congestive heart failure and prolonged QT interval has been reported.<\/p>\n\n\n\n

Carfilzomib and Ixazomib are second generation proteosome inhibitors. They have been licensed for patients with MM who have had at least two prior treatments, including bortezomib and an immunomodulatory agent. Ixazomib can be administered orally. They are associated with thrombocytopenia, cardiac, pulmonary and renal toxicity32,33<\/sup>. Furthermore, peripheral sensory neuropathy may be brought on by ixazomib. <\/p>\n\n\n\n

A dramatic evolution has taken place in treatment of MM with an explosion of new drugs that have clinical activity. Daratumumab is a CD38-directed cytolytic antibody indicated for the treatment of adult patients with multiple myeloma:<\/p>\n\n\n\n

As monotherapy, in patients who have failed at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory drug or who are double-refractory to both PI and an immunomodulatory agent.<\/p>\n\n\n\n

Along with lenalidomide and dexamethasone\/h bortezomib, melphalan and prednisone in newly diagnosed patients who are not eligible for autologous stem cell transplantation.<\/p>\n\n\n\n

The\nrecommended dose is 16 mg\/kg actual body weight given intravenously. The most\nfrequently reported adverse reactions (incidence \u226520%) are infusion reactions,\nneutropenia, thrombocytopenia, fatigue, asthenia, nausea, diarrhea,\nconstipation, decreased appetite, vomiting, muscle spasms, arthralgia, back\npain, pyrexia, chills, dizziness, insomnia, cough, dyspnea, peripheral edema,\nperipheral sensory neuropathy, bronchitis, pneumonia and upper respiratory\ntract infection34<\/sup>. Data on its\nusage in paediatric and pregnant patients are lacking.<\/p>\n\n\n\n

Elotuzumab, a SLAMF7-directed immunostimulatory antibody is recommended together with lenalidomide and dexamethasone for the treatment of patients with MM who have had one to three prior therapies Elotuzumab comes with the warning and precaution that it is more likely to cause infusion reactions, infections, second primary malignancies, and hepatotoxicity35<\/sup>. Data on its usage in paediatric and pregnant patients are lacking.<\/p>\n\n\n\n

Isatuximab2020<\/sup> is a CD38-directed cytolytic antibody indicated for the treatment of adults with multiple myeloma: <\/p>\n\n\n\n

In combination with pomalidomide and dexamethasone, who have failed at least 2 prior therapies including lenalidomide and a proteasome inhibitor.<\/p>\n\n\n\n

In combination with carfilzomib and dexamethasone, for cases of relapsed or refractory multiple myeloma who have received one to three prior lines of therapy. Warnings and precautions associated with this very drug are infusion-related reactions, neutropenia, second primary malignancies and embryo-fetal toxicity36<\/sup>. The drug should be permanently discontinued should a grade 4 infusion reaction occurs. The most common adverse reactions (\u226520%) were upper respiratory tract infection, infusion-related reactions, pneumonia, diarrhoea, decreased haemoglobin, decreased neutrophils, decreased lymphocytes, and decreased platelets.<\/p>\n\n\n\n

Selinexor is a nuclear export inhibitor recommended for use in combination with dexamethasone to treat adult patients with relapsed or refractory multiple myeloma (RRMM) who have received at least four prior therapies and whose disease has proven resistant to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti\u2010CD-38 Mab37,38<\/sup>.       <\/p>\n\n\n\n

Belantamab mafodotin is a B-cell maturation antigen (BCMA)-directed antibody and microtubule inhibitor conjugate indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have had at least four prior therapies, which included an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. The suggested dosage is 2.5 mg\/kg administered as an intravenous infusion over 30 minutes once every three weeks. It comes with a warning of serious ocular toxicity39<\/sup>, thrombocytopenia, infusion-related reaction and embryo-foetal toxicity.<\/p>\n\n\n\n

Idecabtagene vicleucel2021<\/sup> is a B-cell maturation antigen (BCMA)-directed genetically modified autologous chimeric antigen receptor (CAR) T-cell therapy. It is indicated in adults with relapsed or refractory multiple myeloma after four or more failed prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. Each dose is customized using patient\u2019s own T-cells, which are harvested, genetically modified, and then infused back into the patient. <\/p>\n\n\n\n

Adverse effect- \ncytokine release syndrome (CRS), neurologic toxicities, hemophagocytic    lymphistiocytosis\/ macrophage activation\nsyndrome, and prolonged cytopenia, infections, fatigue, musculoskeletal\npain, and hypogammaglobulinemia.<\/p>\n\n\n\n

Ciltracabtagene\nautoleucel feb 2022 <\/sup><\/strong><\/p>\n\n\n\n

This drug has adverse effects such as cytokine release syndrome (CRS), hemophagocytic lymphohistiocytosis\/macrophage activation syndrome (HLH\/MAS), Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), Parkinsonism and Guillain-Barr\u00e9 syndrome, pyrexia, cytokine  hypogammaglobulinemia, musculoskeletal pain, fatigue, infections, diarrhea, nausea, encephalopathy, headache, coagulopathy, constipation, and vomiting.<\/p>\n\n\n\n

Panobinostat is a pan-histone deacetylase inhibitor.  In individuals with relapsed\/refractory multiple myeloma, the combination of oral panobinostat to subcutaneous bortezomib and dexamethasone has showed favourable results40,41<\/sup>. It resulted in synergistic cell death, re-sensitization of tumour cells, progression free survival and lesser GIT toxicity. The most common adverse effect encountered was thrombocytopenia42<\/sup>.<\/p>\n\n\n\n

Prelixafor, a chemokine receptor 4 antagonist, is used to mobilise stem cells in patient previously treated with lenalidomide.<\/p>\n\n\n\n

There are various drugs in pipeline for MM such as naked monoclonal antibodies and bispecific antibodies.<\/p>\n\n\n\n

Novel therapeutics called naked monoclonal antibodies target a specific protein on the surface of MM cells, allowing the patient\u2019s immune system to abolish the targeted myeloma cells43,44<\/sup>.<\/p>\n\n\n\n

Felzartamab is an investigational new drug (IND) currently in phase 3 of clinical trial. This novel anti-CD38 antibody has been shown to be safe and well tolerated in patients with relapsed\/refractory MM. Administered subcutaneously, it is indicated in patients with prior exposure to immunomodulatory drugs, proteasome inhibitors, alkylating agents, and corticosteroid therapy. <\/p>\n\n\n\n

Bispecific Antibodies<\/strong><\/p>\n\n\n\n

These are antibody-based immunotherapy, which contain two antibody fragments that have been fused together. One fragment targets the myeloma cells, in order to help the immune system locate them and the other helps immune cells by boosting their ability to find myeloma cells.3<\/sup> The majority of drugs in this class target B-cell maturation antigen (BCMA) on the myeloma cell and bind to a protein called CD3 found on the surface of T cells45<\/sup>.<\/p>\n\n\n\n

Elranatamab, currently under phase 2 trial is indicated in patients with relapsed\/refractory MM. It is given subcutaneously in patients who are refractory to at least one drug therapy in each of the 3 major classes of medications approved for MM treatment. It has been granted fast track designation by the FDA. No dose-limiting toxicities were observed.<\/p>\n\n\n\n

Conclusion<\/strong><\/p>\n\n\n\n

MM is an emerging disease. There are several drugs in pipeline like Cobemetinib, Enasidinib, Abemaciclib, Erdafitinib and Venetoclax  for potential role in the treatment of MM. Pharmacogenomics and precision medicine also play a crucial role in the treatment of multiple myeloma.<\/p>\n\n\n\n

Acknowledgement<\/p>\n\n\n\n

To almighty and my senior teachers<\/p>\n\n\n\n

Conflict of Interest<\/strong><\/p>\n\n\n\n

There is no conflict of interest.<\/p>\n\n\n\n

Funding Sources<\/strong><\/p>\n\n\n\n

There are no funding sources.<\/p>\n\n\n\n

References<\/strong><\/p>\n\n\n\n

  1. GAUSTAD V. Myelomatose. Tidsskr den Nor l\u00e6geforening  Tidsskr Prakt Med ny r\u00e6kke<\/em>. 1950;70(22):747-750.<\/li>
  2. Seesaghur A, Petruski-Ivleva N, Banks VL, et al. Clinical features and diagnosis of multiple myeloma: a population-based cohort study in primary care. BMJ Open<\/em>. 2021;11:52759. doi:10.1136\/bmjopen-2021-052759
    CrossRef <\/a><\/li>
  3. Kwaan HC. Hyperviscosity in plasma cell dyscrasias. Clin Hemorheol Microcirc<\/em>. 2013;55(1):75-83. doi:10.3233\/CH-131691
    CrossRef<\/a><\/li>
  4. Kazandjian D. Multiple myeloma epidemiology and survival, a unique malignancy. doi:10.1053\/j.seminoncol.2016.11.004
     CrossRef <\/a><\/li>
  5. Zhou L, Yu Q, Wei G, et al. Measuring the global, regional, and national burden of multiple myeloma from 1990 to 2019. BMC Cancer<\/em>. 2021;21(1):1-13. doi:10.1186\/s12885-021-08280-y
    CrossRef<\/a><\/li>
  6. Shatzel J, Silbermann R, Coriu D, et al. Approaches and Challenges in the Management of Multiple Myeloma in the Very Old: Future Treatment Prospects. Front Med | www.frontiersin.org<\/em>. 2021;8:612696. doi:10.3389\/fmed.2021.612696
    CrossRef <\/a><\/li>
  7. Boyd KD, Ross FM, Chiecchio L, et al. Gender Disparities in the Tumor Genetics and Clinical Outcome of Multiple Myeloma. doi:10.1158\/1055-9965.EPI-11-0157
     CrossRef <\/a><\/li>
  8. Cancer.Net. Multiple Myeloma: Risk Factors and Prevention. CancerNet<\/em>. Published online 2018:1-2. www.cancer.org\/cancer\/cancer-causes\/diet-physical-activity\/body-weight-and-%0Ahttps:\/\/www.cancer.net\/cancer-types\/multiple-myeloma\/risk-factors-and-prevention<\/li>
  9. Sarah Anne Bird, David Cairns, MSc, PhD, Faith E. Davies, MD, Kevin Boyd, MB BS, BSc, MRCP, FRCPath, PhD, Gordon Cook, Mark T Drayson, MB ChB, PhD FRCPath, Walter M Gregory, PhD, Matthew Jenner, MBBS, MRCP, FRCPath, John R Jones, MD, Martin F. Kaiser, Rog Frcp. Sex Differences in Multiple Myeloma Biology and Clinical Outcomes: Results from 3894 Patients in the Myeloma XI Trial. Blood<\/em>. 2019;134(1):4374. doi:10.1182\/blood-2019-128041
     CrossRef <\/a><\/li>
  10. Baker A, Braggio E, Jacobus S, Jung S, Larson D, Therneau T, Dispenzieri A, Van Wier SA, Ahmann G, Levy J, Perkins L, Kim S, Henderson K, Vesole D, Rajkumar SV, Jelinek DF, Carpten J FR. Uncovering the biology of multiple myeloma among African Americans: a comprehensive genomics approach. Blood<\/em>. 2013;121 10.118(16):3147-3152. doi:10.1182\/blood-2012-07-443606
     CrossRef <\/a><\/li>
  11. Zhao Y, Niu D, Ye E, Huang J, Wang J, Hou X. Secular Trends in the Burden of Multiple Myeloma From 1990 to 2019 and Its Projection Until 2044 in China. 2022;10(July):1-10. doi:10.3389\/fpubh.2022.938770
     CrossRef <\/a><\/li>
  12. Vernon MD, Roccaro AM, Gay J, et al. Front line treatment of elderly multiple myeloma in the era of novel agents. Biol Targets Ther<\/em>. 2009;3:99-109. doi:10.2147\/btt.s4275
     CrossRef <\/a><\/li>
  13. Hern\u00e1ndez JM, Garc\u00eda-Sanz R, Golvano E, et al. Randomized comparison of dexamethasone combined with melphalan versus melphalan with prednisone in the treatment of elderly patients with multiple myeloma. Br J Haematol<\/em>. 2004;127(2):159-164. doi:10.1111\/j.1365-2141.2004.05186.x
     CrossRef <\/a><\/li>
  14. Ito S. Proteasome inhibitors for the treatment of multiple myeloma. Cancers (Basel)<\/em>. 2020;12(2):1-19. doi:10.3390\/cancers12020265
     CrossRef <\/a><\/li>
  15. Merin NM, Kelly KR. Clinical use of proteasome inhibitors in the treatment of multiple myeloma. Pharmaceuticals<\/em>. 2014;8(1):1-20. doi:10.3390\/ph8010001
     CrossRef <\/a><\/li>
  16. Chang X, Zhu Y, Shi C, Stewart AK. Mechanism of immunomodulatory drugs\u2019 action in the treatment of multiple myeloma. Acta Biochim Biophys Sin (Shanghai)<\/em>. 2014;46(3):240-253. doi:10.1093\/abbs\/gmt142
     CrossRef <\/a><\/li>
  17. Rajkumar SV, Kumar S. Multiple myeloma current treatment algorithms. Blood Cancer J<\/em>. 2020;10(9). doi:10.1038\/s41408-020-00359-2
     CrossRef <\/a><\/li>
  18. M A, V L-C, C H, et al. Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma. N Engl J Med<\/em>. 2017;376(14):1311-1320. doi:10.1056\/NEJMoa1611750.Lenalidomide<\/li>
  19. Iqbal N, Zayed M, Boden G. Thalidomide impairs insulin action on glucose uptake and glycogen synthesis in patients with type 2 diabetes. Diabetes Care<\/em>. 2000;23(8):1172-1176. doi:10.2337\/diacare.23.8.1172
     CrossRef <\/a><\/li>
  20. Pathak R, Jayaraj K, Blonde L. Thalidomide-Associated Hyperglycemia and Diabetes: Case Report and Review of Literature<\/em>. Diabetes Care 26, 1322-1323 (2003). doi:https:\/\/doi.org\/10.2337\/diacare.26.4.1322-a
     CrossRef <\/a><\/li>
  21. Gordon JN, Goggin PM. Thalidomide and its derivatives: Emerging from the wilderness. Postgrad Med J<\/em>. 2003;79(929):127-132. doi:10.1136\/pmj.79.929.127
     CrossRef <\/a><\/li>
  22. SOMERS GF. Pharmacological Properties of Thalidomide (\u0391\u2010Phthalimido Glutarimide), a New Sedative Hypnotic Drug. Br J Pharmacol Chemother<\/em>. 1960;15(1):111-116. doi:10.1111\/j.1476-5381.1960.tb01217.x
    CrossRef<\/a><\/li>
  23. Miller IJ, Hsu WT, Weisberger J, Venugopal P. A case of lenalidomide-dependent myelodysplastic syndrome. Blood Adv<\/em>. 2017;1(16):1238-1242. doi:10.1182\/bloodadvances.2017006114
     CrossRef <\/a><\/li>
  24. Kotla V, Goel S, Nischal S, et al. Mechanism of action of lenalidomide in hematological malignancies. J Hematol Oncol<\/em>. 2009;2(36):1-10. doi:10.1186\/1756-8722-2-36
     CrossRef <\/a><\/li>
  25. FDA. POMALYST \u00ae (pomalidomide) capsules, for oral use Initial US Approval: 2013. Published online 2013. https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2013\/204026lbl.pdf<\/li>
  26. Li Y, Liu L, Wang X, et al. In Vivo Assessment of the Effect of CYP1A2 Inhibition and Induction on Pomalidomide Pharmacokinetics in Healthy Subjects. J Clin Pharmacol<\/em>. 2018;58(10):1295-1304. doi:10.1002\/jcph.1145
    CrossRef <\/a><\/li>
  27. Kasserra C, Assaf M, Hoffmann M, et al. Pomalidomide: Evaluation of cytochrome P450 and transporter-mediated drug-drug interaction potential in vitro and in healthy subjects. J Clin Pharmacol<\/em>. 2015;55(2):168-178. doi:10.1002\/jcph.384
     CrossRef <\/a><\/li>
  28. Clark SM, Steinbach A, Clemmons AB. Pomalidomide for the Treatment of Multiple Myeloma. J Adv Pr Oncol<\/em>. 5(1):51-56. doi:10.6004\/jadpro.2014.5.1.7
     CrossRef <\/a><\/li>
  29. Berenson JR. Pomalidomide for Lenalidomide for Relapsed or Refractory Multiple Myeloma Patients. ClinicalTrials.gov<\/em>. Published online 2020. https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02188368#moreinfo<\/li>
  30. Pancheri E, Guglielmi V, Wilczynski GM, et al. Non-hematologic toxicity of bortezomib in multiple myeloma: The neuromuscular and cardiovascular adverse effects. Cancers (Basel)<\/em>. 2020;12(9):1-21. doi:10.3390\/cancers12092540
     CrossRef <\/a><\/li>
  31. Blad\u00e9 J, Cibeira MT, Rosi\u00f1ol L. Bortezomib: A valuable new antineoplastic strategy in multiple myeloma. Acta Oncol (Madr)<\/em>. 2005;44(5):440-448. doi:10.1080\/02841860510030002
     CrossRef <\/a><\/li>
  32. Fotiou D, Roussou M, Gakiopoulou C, et al. Carfilzomib-associated renal toxicity is common and unpredictable: a comprehensive analysis of 114 multiple myeloma patients. Blood Cancer J<\/em>. 2020;10(11). doi:10.1038\/s41408-020-00381-4
     CrossRef <\/a><\/li>
  33. Ludwig H, Delforge M, Facon T, et al. Prevention and management of adverse events of novel agents in multiple myeloma: A consensus of the European Myeloma Network. Leukemia<\/em>. 2018;32(7):1542-1560. doi:10.1038\/s41375-018-0040-1
     CrossRef <\/a><\/li>
  34. FDA. 1 INDICATIONS AND USAGE DARZALEX is indicated for the treatment of adult patients with multiple myeloma\u202f: \u2022 in combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patien. Published online 2019:1-41. https:\/\/www.accessdata.fda.gov\/drugsatfda _docs\/label\/2019\/761036s024lbl.pdf<\/li>
  35. (National Institute of Diabetes and Digestive and Kidney Disease) B. Elotuzumab<\/em>.; 2017. https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK548728\/<\/li>
  36. FDA. INDICATIONS AND USAGE SARCLISA is indicated\u202f: \uf0b7 in combination with pomalidomide and dexamethasone , for the treatment of adult patients with multiple myeloma who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor . Published online 2021. https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2021\/761113s003lbl.pdf<\/li>
  37. Chen C, Siegel D, Gutierrez M, et al. Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and Waldenstrom macroglobulinemia. Blood<\/em>. 2018;131(8):855-863. doi:10.1182\/blood-2017-08-797886
    CrossRef <\/a><\/li>
  38. Tao Y, Zhou H, Niu T. Safety and Efficacy Analysis of Selinexor-Based Treatment in Multiple Myeloma, a Meta-Analysis Based on Prospective Clinical Trials. Front Pharmacol<\/em>. 2021;12(December):1-13. doi:10.3389\/fphar.2021.758992
     CrossRef <\/a><\/li>
  39. Wahab A, Rafae A, Mushtaq K, et al. Ocular Toxicity of Belantamab Mafodotin, an Oncological Perspective of Management in Relapsed and Refractory Multiple Myeloma. Front Oncol<\/em>. 2021;11(May):1-6. doi:10.3389\/fonc.2021.678634
     CrossRef <\/a><\/li>
  40. San-Miguel JF, Einsele H, Moreau P. The Role of Panobinostat Plus Bortezomib and Dexamethasone in Treating Relapsed or Relapsed and Refractory Multiple Myeloma: A European Perspective. Adv Ther<\/em>. 2016;33(11):1896-1920. doi:10.1007\/s12325-016-0413-7
     CrossRef <\/a><\/li>
  41. San-Miguel JF, Hungria VTM, Yoon SS, et al. Panobinostat plus bortezomib and dexamethasone: impact of dose intensity and administration frequency on safety in the PANORAMA 1 trial. Br J Haematol<\/em>. 2017;179(1):66-74. doi:10.1111\/bjh.14821
     CrossRef <\/a><\/li>
  42. Lin R, Hu J, Paul S, et al. Characteristics of Thrombocytopenia in Patients Treated with Oral Panobinostat (LBH589). Blood<\/em>. 2009;114(22):2740-2740. doi:10.1182\/blood.v114.22.2740.2740
     CrossRef <\/a><\/li>
  43. D\u2019agostino M, Innorcia S, Boccadoro M, Bringhen S. Monoclonal antibodies to treat multiple myeloma: A dream come true. Int J Mol Sci<\/em>. 2020;21(21):1-20. doi:10.3390\/ijms21218192
     CrossRef <\/a><\/li>
  44. Romano A, Storti P, Marchica V, et al. Mechanisms of Action of the New Antibodies in Use in Multiple Myeloma. Front Oncol<\/em>. 2021;11(July):1-24. doi:10.3389\/fonc.2021.684561
    CrossRef<\/a><\/li>
  45. Caraccio C, Krishna S, Phillips DJ, Sch\u00fcrch CM. Bispecific Antibodies for Multiple Myeloma: A Review of Targets, Drugs, Clinical Trials, and Future Directions. Front Immunol<\/em>. 2020;11(April):1-25. doi:10.3389\/fimmu.2020.00501
     CrossRef <\/a><\/li><\/ol>\n","protected":false},"excerpt":{"rendered":"

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