Top

Published in:

01-12-2013 | Multiple Myeloma (R Niesvizky, Section Editor)

Management of Double-Refractory Multiple Myeloma

Authors: Jason P. Meadows, Tomer M. Mark

Published in: Current Hematologic Malignancy Reports | Issue 4/2013

Abstract

Widespread use of the novel agents bortezomib and lenalidomide has improved outcomes in multiple myeloma (MM). Despite remarkable progress, patients will eventually relapse after exhausting treatment with these drugs. Management of myeloma that is refractory to both bortezomib and lenalidomide (double-refractory MM, DRMM) is complicated due to disease, patient, and treatment-related factors and new therapies for these patients are required. A review of the unique challenges of treating DRMM, recently FDA-approved therapeutic agents, and selected novel drugs under active clinical investigation, is presented below.

SEER Cancer Statistics Review, 1975-2009 (Vintage 2009 Populations), National Cancer Institute. Available at http://seer.cancer.gov/csr/1975_2009_pops09/. Accessed May 2013.

Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999;341(21):1565–71.PubMedCrossRef

Rajkumar SV, Blood E, Vesole D, et al. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2006;24(3):431–6.PubMedCrossRef

Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277–300.PubMedCrossRef

FDA Approval for Lenalidomide. Available at http://www.cancer.gov/cancertopics/druginfo/fda-lenalidomide. Accessed May 2013.

Kane RC. Velcade(R): U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy. Oncologist. 2003;8(6):508–13.PubMedCrossRef

FDA Approval for Bortezomib. Available at http://www.cancer.gov/cancertopics/druginfo/fda-bortezomib. Accessed May 2013.

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.PubMedCrossRef

Rajkumar SV, Hayman SR, Lacy MQ, et al. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood. 2005;106(13):4050–3.PubMedCrossRef

10.

Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352(24):2487–98.PubMedCrossRef

11.

•• 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. Retrospective review showing the greatly increased mortality of patients with DRMM.PubMedCrossRef

12.

U.S. Food and Drug Administration: Carfilzomib. Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm312945.htm. Accessed May 2013.

13.

U.S. Food and Drug Administration: Pomalidomide. Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm339286.htm. Accessed May 2013.

14.

Rajkumar SV, Harousseau J-L, Durie B, et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011;117(18):4691–5.PubMedCrossRef

15.

Dimopoulos MA, Terpos E, Chanan-Khan A, et al. Renal impairment in patients with multiple myeloma: a consensus statement on behalf of the International Myeloma Working Group. J Clin Oncol. 2010;28(33):4976–84.PubMedCrossRef

16.

Dreisbach AW, Lertora JJ. The effect of chronic renal failure on drug metabolism and transport. Expert Opin Drug Metab Toxicol. 2008;4:1065–74.PubMedCrossRef

17.

Hoffmann M, Kasserra C, Reyes J, et al. Absorption, metabolism and excretion of [14C]pomalidomide in humans following oral administration. Cancer Chemother Pharmacol. 2013;71(2):489–501.PubMedCrossRef

18.

Richardson PG, Xie W, Mitsiades C, et al. Single-agent bortezomib in previously untreated multiple myeloma: efficacy, characterization of peripheral neuropathy, and molecular correlations with response and neuropathy. J Clin Oncol. 2009;27:3518–25.PubMedCrossRef

19.

Tosi P, Zamagni E, Cellini C, et al. Neurological toxicity of long-term (> 1 yr) thalidomide therapy in patients with multiple myeloma. Eur J Haematol. 2005;74:212–6.PubMedCrossRef

20.

Alsina M, Trudel S, Furman RR, et al. A phase I single-agent study of twice-weekly consecutive-day dosing of the proteasome inhibitor carfilzomib in patients with relapsed or refractory multiple myeloma or lymphoma. Clin Cancer Res. 2012;18(17):4830–40.PubMedCrossRef

21.

O'Connor OA, Stewart AK, Vallone M, et al. A phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients with hematologic malignancies. Clin Cancer Res. 2009;15(22):7085–91.PubMedCrossRef

22.

Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012;120(9):1801–9.PubMedCrossRef

23.

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.PubMedCrossRef

24.

Harousseau J-L, 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.PubMedCrossRef

25.

Barlogie B, Jagannath S, Dixon DO, et al. High-dose melphalan and granulocyte-macrophage colony-stimulating factor for refractory multiple myeloma. Blood. 1990;67(4):677–80.

26.

Egan JB, Shi C-X, Tembe W, et al. Whole-genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides. Blood. 2012;120(5):1060–6.PubMedCrossRef

27.

Stewart AK, Chang H, Trudel S, et al. Diagnostic evaluation of t(4;14) in multiple myeloma and evidence for clonal evolution. Leukemia. 2007;21(11):2358–9.PubMedCrossRef

28.

• Berenson JR, Yellin O, Kazamel T, et al. A phase 2 study of pegylated liposomal doxorubicin, bortezomib, dexamethasone and lenalidomide for patients with relapsed/refractory multiple myeloma. Leukemia. 2012;26(7):1675–80. Study demonstrating that retreatment of patients with bortezomib can be effective.PubMedCrossRef

29.

• Lentzsch S, O'Sullivan A, Kennedy RC, et al. Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective: results of phase 1/2 open-label, dose escalation study. Blood. 2012;119(20):4608–13. Study demonstrating that retreatment of patients with lenalidomide can be effective.PubMedCrossRef

30.

• Ludwig H, Kasparu H, Greil R, et al.: Treatment with Bendamustine-Bortezomib-Dexamethasone (BBD) in Relapsed/Refractory Multiple Myeloma Shows Significant Activity and Is Well Tolerated. Blood (ASH Annual Meeting Abstracts) 2012;120:Abstract 943. Study demonstrating that retreatment of patients with bortezomib can be effective.

31.

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;22:3269–76.PubMedCrossRef

32.

Streetly MJ, Gyertson K, Daniel Y, et al. Alternate day pomalidomide retains anti-myeloma effect with reduced adverse events and evidence of in vivo immunomodulation. Br J Haematol. 2008;141:41–51.PubMedCrossRef

33.

Vij R, Richardson PG, Jagannath S, et al: Pomalidomide (POM) with or without low-dose dexamethasone (LoDEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): Outcomes in pts refractory to lenalidomide (LEN) and/or bortezomib (BORT). J Clin Oncol. 2012;30(suppl; abstr 8016).

34.

•• Jagannath S, Hofmeister CC, Siegel DS, et al.: Pomalidomide (POM) with Low-Dose Dexamethasone (LoDex) in Patients (Pts) with Relapsed and Refractory Multiple Myeloma Who Have Received Prior Therapy with Lenalidomide (LEN) and Bortezomib (BORT): Updated Phase 2 Results and Age Subgroup Analysis. Blood (ASH Annual Meeting Abstracts) 2012;120:Abstract 450. Recent study demonstrating efficacy of pomalidomide.

35.

•• Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM). Leukemia. 2010;24:1934–9. Recent study demonstrating efficacy of pomalidomide.PubMedCrossRef

36.

•• 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 Myélome 2009-02. Blood. 2013;121(11):1968–75. Recent study demonstrating efficacy of pomalidomide.PubMedCrossRef

37.

•• Lacy MQ, Kumar SK, LaPlant BR et al. Pomalidomide Plus Low-Dose Dexamethasone (Pom/Dex) in Relapsed Myeloma: Long Term Follow up and Factors Predicting Outcome in 345 Patients. Blood (ASH Annual Meeting Abstracts) 2012;120:Abstract 201. Recent study demonstrating efficacy of pomalidomide.

38.

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;118:2970–5.PubMedCrossRef

39.

Quach H, Ritchie D, Stewart AK, et al. Mechanism of action of immunomodulatory drugs (IMiDs) in multiple myeloma. Leukemia. 2009;24(1):22–32.PubMedCrossRef

40.

•• San-Miguel JF, Weisel KC, Moreau P, et al.: MM-003: A phase III, multicenter, randomized, open-label study of pomalidomide (POM) plus low-dose dexamethasone (LoDEX) versus high-dose dexamethasone (HiDEX) in relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2013;31(suppl; abstr 8510). First phase 3 study demonstrating efficacy of pomalidomide.

41.

Mark TM, Boyer A, Rossi AC, et al. ClaPD (Clarithromycin, Pomalidomide, Dexamethasone) therapy in relapsed or refractory multiple myeloma. Blood. 2012;120:77.

42.

Rossi, A., Mark, T., Rodriguez, M, et al.: Clarithromycin, pomalidomide, and dexamethasone (ClaPD) in relapsed or refractory multiple myeloma. J Clin Oncol. 2012;30(suppl; abstr 8036).

43.

Palumbo A, Larocca A, Montefusco V, et al.: Pomalidomide Cyclophosphamide and Prednisone (PCP) Treatment for Relapsed/Refractory Multiple Myeloma. Blood (ASH Annual Meeting Abstracts) 2012;120:Abstract 446.

44.

•• Vij R, Siegel DS, Jagannath S, et al. An open-label, single-arm, phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been previously treated with bortezomib. Br J Haematol. 2012;158:739–48. FDA registration study for carfilzomib.PubMedCrossRef

45.

•• Lendvai N, Landau H, Lesokhin A, et al.: Phase II Study of Infusional Carfilzomib in Patients with Relapsed or Refractory Multiple Myeloma. Blood (ASH Annual Meeting Abstracts) 2012;120:Abstract 947. Recent study demonstrating efficacy of high-dose carfilzomib.

46.

U.S. National Institutes of Health: Phase 3 Study Comparing Carfilzomib, Lenalidomide, and Dexamethasone (CRd) vs Lenalidomide and Dexamethasone (Rd) in Subjects With Relapsed Multiple Myeloma. Available at http://clinicaltrials.gov/ct2/show/NCT01080391?term=carfilzomib+AND+myeloma&phase=2&rank=4. Accessed May 2013.

47.

Hájek R, Bryce R, Ro S, et al. Design and rationale of FOCUS (PX-171-011): a randomized, open-label, phase 3 study of carfilzomib versus best supportive care regimen in patients with relapsed and refractory multiple myeloma (R/R MM). BMC Cancer. 2012;12:415.PubMedCrossRef

48.

U.S. National Institutes of Health: A Study of Carfilzomib vs Best Supportive Care in Subjects With Relapsed and Refractory Multiple Myeloma (FOCUS). Available at http://clinicaltrials.gov/ct2/show/NCT01302392?term=carfilzomib+AND+myeloma&phase=2&rank=5. Accessed May 2013.

49.

U.S. National Institutes of Health: Phase 3 Study With Carfilzomib and Dexamethasone Versus Velcade and Dexamethasone for Relapsed Multiple Myeloma Patients (ENDEAVOR). Available at http://clinicaltrials.gov/ct2/show/NCT01568866?term=carfilzomib+AND+myeloma&phase=2&rank=1. Accessed May 2013.

50.

• Shah JJ, Stadtmauer EA, Abonour R, et al.: A Multi-Center Phase I/II Trial of Carfilzomib and Pomalidomide with Dexamethasone (Car-Pom-d) in Patients with Relapsed/Refractory Multiple Myeloma. Blood (ASH Annual Meeting Abstracts) 2012;120:Abstract 74. First trial using combination pomalidomide and carfilzomib regimen.

51.

Kumar S, Bensinger W, Zimmerman TM, et al.: Weekly MLN9708, an investigational oral proteasome inhibitor (PI), in relapsed/refractory multiple myeloma (MM): Results from a phase I study after full enrollment. J Clin Oncol. 2013;31(suppl; abstr 8514).

52.

Kumar SK, Berdeja JG, Niesvizky R et al.: A Phase 1/2 Study of Weekly MLN9708, an Investigational Oral Proteasome Inhibitor, in Combination with Lenalidomide and Dexamethasone in Patients with Previously Untreated Multiple Myeloma (MM). ASH Annual Meeting Abstracts. 2012;120:332.

53.

Offidani M, Polloni C, Cavallo F, et al. Phase II study of melphalan, thalidomide and prednisone combined with oral panobinostat in patients with relapsed/refractory multiple myeloma. Leuk Lymphoma. 2012;53(9):1722–7.PubMedCrossRef

54.

Bottomley MJ, Surdo Lo P, Di Giovine P, et al. Structural and functional analysis of the human HDAC4 catalytic domain reveals a regulatory structural zinc-binding domain. J Biol Chem. 2008;283(39):26694–704.PubMedCrossRef

55.

Wolf JL, Siegel D, Goldschmidt H, et al. Phase II trial of the pan-deacetylase inhibitor panobinostat as a single agent in advanced relapsed/refractory multiple myeloma. Leuk Lymphoma. 2012;53(9):1820–3.PubMedCrossRef

56.

Catley L, Weisberg E, Kiziltepe T, et al. Aggresome induction by proteasome inhibitor bortezomib and alpha-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells. Blood. 2006;108:3441–9.PubMedCrossRef

57.

Hideshima T, Bradner JE, Wong J, et al. Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc Natl Acad Sci U S A. 2005;102:8567–72.PubMedCrossRef

58.

Palumbo A, Avonto I, Bruno B, et al. Intravenous melphalan, thalidomide and prednisone in refractory and relapsed multiple myeloma. Eur J Haematol. 2006;76:273–7.PubMedCrossRef

59.

Jakubowiak AJ, Benson DM, Bensinger W, et al. Phase I trial of anti-CS1 monoclonal antibody elotuzumab in combination with bortezomib in the treatment of relapsed/refractory multiple myeloma. J Clin Oncol. 2012;30(16):1960–5.PubMedCrossRef

60.

Lonial S, Jagannath S, Moreau P, et al.: Phase (Ph) I/II study of elotuzumab (Elo) plus lenalidomide/dexamethasone (Len/dex) in relapsed/refractory multiple myeloma (RR MM): Updated Ph II results and Ph I/II long-term safety. J Clin Oncol. 2013;31:(suppl; abstr 8542).

61.

Lonial S, Vij R, Harousseau J-L, et al. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. J Clin Oncol. 2012;30(16):1953–9.PubMedCrossRef

62.

Richardson PG, Jagannath S, Moreau P, et al.: A Phase 2 Study of Elotuzumab (Elo) in Combination with Lenalidomide and Low-Dose Dexamethasone (Ld) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (R/R MM): Updated Results. Blood (ASH Annual Meeting Abstracts) 2012;120:Abstract 202.

63.

U.S. National Institutes of Health: Phase 3, randomized, open label trial of lenalidomide/dexamethasone with or without elotuzumab in relapsed or refractory multiple myeloma (mm). Available at http://clinicaltrials.gov/ct2/show/NCT01239797?term=elotuzumab&phase=2&rank=1. Accessed May 2013.

64.

ClinicalTrials.gov: Study of bortezomib and dexamethasone with or without elotuzumab to treat relapsed or refractory multiple myeloma. Available at http://clinicaltrials.gov/ct2/show/NCT01478048?term=elotuzumab bortezomib&rank=2. Accessed May 2013.

65.

Noort WA, Groen RWJ, Raymakers R, et al.: Daratumumab, a Novel Therapeutic Human CD38 Monoclonal Antibody, Induces Killing of Refractory Patient-Derived Multiple Myeloma Cells, Growing in a Novel Humanized Mouse MM Model. Blood (ASH Annual Meeting Abstracts) 2012; 120:Abstract 940.

66.

de Weers M, Tai Y-T, van der Veer MS, et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol. 2011;186(3):1840–8.PubMedCrossRef

67.

Lokhorst HM, Plesner T, Gimsing P, et al.: Phase I/II dose-escalation study of daratumumab in patients with relapsed or refractory multiple myeloma. J Clin Oncol. 2013; 31(suppl; abstr 8512).

Title: Management of Double-Refractory Multiple Myeloma
Authors: Jason P. Meadows
Tomer M. Mark
Publication date: 01-12-2013
Publisher: Springer US
Published in: Current Hematologic Malignancy Reports / Issue 4/2013
Print ISSN: 1558-8211
Electronic ISSN: 1558-822X
DOI: https://doi.org/10.1007/s11899-013-0173-2

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

Illustration of figure on mountain summit/© Orapun / Stock.adobe.com, STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2013

There’s Risk, and Then There’s RISK: The Latest Clinical Prognostic Risk Stratification Models in Myelodysplastic Syndromes

When to Transplant MDS, and What to Do When Transplant Fails

Incorporating Novel Agents in the Management of Elderly Myeloma Patients

New Insights and Modern Treatment of AL Amyloidosis

Preclinical Models for Drug Selection in Myeloproliferative Neoplasms

Genetic Basis of MPN: Beyond JAK2-V617F

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage