Management Strategies for Relapsed/Refractory Multiple Myeloma: Current Clinical Perspectives

https://doi.org/10.1053/j.seminhematol.2012.05.003Get rights and content

In the last decade, the introduction of novel agents including the immunomodulatory drugs thalidomide and lenalidomide, and the first-in-class proteasome inhibitor bortezomib, has dramatically improved clinical outcome in patients with relapsed/refractory multiple myeloma (MM) compared to conventional chemotherapy alone. Although combination treatment approaches with traditional cytotoxic agents and novel agents have led to response rates as high as 85% in patients with relapsed/refractory disease, not all patients will respond to established novel agents, and even those who do respond will ultimately relapse or become refractory to currently available regimens. There is no generally accepted standard treatment for patients with relapsed/refractory disease; however, both disease-related (eg, quality and duration of response to previous therapies and the aggressiveness of the relapse) and patient-related (eg, preexisting toxicities, comorbid conditions, quality of life, age, and performance status) factors should be considered when selecting the best treatment option. This article will review up-to-date approaches for managing patients with relapsed/refractory MM, including the efficacy and safety of established novel agents, the use of adjunctive/supportive care, and strategies for tailored treatment.

Section snippets

Chemotherapy and Transplant

In the relapsed/refractory setting, conventional or high-dose chemotherapy has been a longstanding approach to salvage treatment. Regimens have included high-dose melphalan; high-dose methylprednisolone; high-dose dexamethasone; vincristine, doxorubicin, and pulsed high-dose dexamethasone (VAD); vincristine, melphalan, cyclophosphamide, and prednisone (VMPC) alternating with vincristine, carmustine, doxorubicin, and prednisone (VBAP); doxorubicin, vincristine, dexamethasone, etoposide, and

Incidence and Management of Treatment-Related Adverse Events

The established novel agents have different and specific toxicity profiles, which, along with patients' characteristics and comorbidities, should be considered when choosing a treatment regimen. In most cases, the adverse events (AEs) associated with these agents can be managed with patient monitoring, supportive care, and dose reduction and interruption where appropriate. Additional management strategies may also be appropriate for patients aged ≥75 years.

Adjunctive/Supportive Care

Important advances have occurred in adjunctive treatment and supportive care available for patients with MM. Approximately 85% of patients develop bone disease in the form of diffuse osteopenia and/or osteolytic lesions, and the related complications (eg, bone pain and pathologic fractures) are a major cause of deteriorating quality of life and performance status.11 Treatment of bone pain should start with non-opioid analgesics such as acetaminophen; however, nonsteroidal anti-inflammatory

Implications of Genetic Heterogeneity

MM is a disease with marked genetic heterogeneity, which has important implications for treatment because molecular subgroups respond differently to currently available regimens. Chromosomal abnormalities are detected with conventional cytogenetics or fluorescence in situ hybridization (FISH) in >90% of patients, and include deletions, trisomies, and translocations.141 Patients with hyperdiploid and t(11;14) mutations have standard-risk disease and typically respond well to conventional

Conclusions

In recent years, the introduction of thalidomide, lenalidomide, and bortezomib has changed the treatment paradigm for patients with relapsed/refractory MM and dramatically improved clinical outcome compared with conventional chemotherapy alone. However, not all patients will respond to established novel agents, and even those who do respond will eventually relapse or become refractory to treatment, owing in part to the changing biology of the tumor and development of drug-resistant phenotypes

Acknowledgment

The author wishes to acknowledge Marithea Goberville, PhD, Tristin Abair, PhD, and Trudy Grenon Stoddert, ELS, for their assistance in preparing the manuscript for publication.

References (154)

  • L. Mileshkin et al.

    Multicenter phase 2 trial of thalidomide in relapsed/refractory multiple myeloma: adverse prognostic impact of advanced age

    Blood

    (2003)
  • R. Alexanian et al.

    Thalidomide with or without dexamethasone for refractory or relapsing multiple myeloma

    Semin Hematol

    (2003)
  • M.A. Dimopoulos et al.

    Thalidomide and dexamethasone combination for refractory multiple myeloma

    Ann Oncol

    (2001)
  • M.A. Hussein et al.

    Phase 2 study of pegylated liposomal doxorubicin, vincristine, decreased-frequency dexamethasone, and thalidomide in newly diagnosed and relapsed-refractory multiple myeloma

    Mayo Clin Proc

    (2006)
  • T.M. Moehler et al.

    Salvage therapy for multiple myeloma with thalidomide and CED chemotherapy

    Blood

    (2001)
  • G.W. Muller et al.

    Amino-substituted thalidomide analogs: potent inhibitors of TNF-alpha production

    Bioorg Med Chem Lett

    (1999)
  • P.G. Richardson et al.

    Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma

    Blood

    (2002)
  • P. Richardson et al.

    Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma

    Blood

    (2009)
  • R. Baz et al.

    Lenalidomide and pegylated liposomal doxorubicin-based chemotherapy for relapsed or refractory multiple myeloma: safety and efficacy

    Ann Oncol

    (2006)
  • S. Knop et al.

    Lenalidomide, adriamycin, and dexamethasone (RAD) in patients with relapsed and refractory multiple myeloma: a report from the German Myeloma Study Group DSMM (Deutsche Studiengruppe Multiples Myelom)

    Blood

    (2009)
  • S.V. Rajkumar et al.

    Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial

    Lancet Oncol

    (2010)
  • P.G. Richardson et al.

    Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial

    Blood

    (2007)
  • A. Palumbo et al.

    Bortezomib, doxorubicin and dexamethasone in advanced multiple myeloma

    Ann Oncol

    (2008)
  • M.H. Kropff et al.

    Bortezomib in combination with dexamethasone for relapsed multiple myeloma

    Leuk Res

    (2005)
  • R. Alexanian et al.

    VAD-based regimens as primary treatment for multiple myeloma

    Am J Hematol

    (1990)
  • R. Alexanian et al.

    Myeloablative therapy for primary resistant multiple myeloma

    Stem Cells

    (1995)
  • M. Attal et al.

    A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myelomaIntergroupe Français du Myélome

    N Engl J Med

    (1996)
  • M.A. Dimopoulos et al.

    Emerging therapies for the treatment of relapsed or refractory multiple myeloma

    Eur J Haematol

    (2011)
  • Y.K. Kim et al.

    Korean Multiple Myeloma Working Party (KMMWP)Clinical efficacy of a bortezomib, cyclophosphamide, thalidomide, and dexamethasone (Vel-CTD) regimen in patients with relapsed or refractory multiple myeloma: a phase II study

    Ann Hematol

    (2010)
  • J.F. San Miguel

    Relapse/refractory myeloma patient: potential treatment guidelines

    J Clin Oncol

    (2009)
  • B. Mohty et al.

    Treatment strategies in relapsed and refractory multiple myeloma: a focus on drug sequencing and ‘retreatment’ approaches in the era of novel agents

    Leukemia

    (2012)
  • National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology. Multiple myeloma. Version...
  • R. Alexanian et al.

    High-dose glucocorticoid treatment of resistant myeloma

    Ann Intern Med

    (1986)
  • M.A. Gertz et al.

    A phase II study of high-dose methylprednisolone in refractory or relapsed multiple myeloma

    Leukemia

    (1995)
  • B. Barlogie et al.

    Effective treatment of advanced multiple myeloma refractory to alkylating agents

    N Engl J Med

    (1984)
  • M.A. Gertz et al.

    Phase III study comparing vincristine, doxorubicin (Adriamycin), and dexamethasone (VAD) chemotherapy with VAD plus recombinant interferon alfa-2 in refractory or relapsed multiple myelomaAn Eastern Cooperative Oncology Group study

    Am J Clin Oncol

    (1995)
  • H.M. Lokhorst et al.

    VAD chemotherapy for refractory multiple myeloma

    Br J Haematol

    (1989)
  • J.K. Phillips et al.

    A randomized study of MOD versus VAD in the treatment of relapsed and resistant multiple myeloma

    Leuk Lymphoma

    (1995)
  • B.G. Durie et al.

    Improved survival duration with combination chemotherapy induction for multiple myeloma: a Southwest Oncology Group study

    J Clin Oncol

    (1986)
  • F.J. Giles et al.

    Cyclophosphamide, etoposide, vincristine, adriamycin, and dexamethasone (CEVAD) regimen in refractory multiple myeloma: an International Oncology Study Group (IOSG) phase II protocol

    Am J Hematol

    (2000)
  • H. Anderson et al.

    VAD chemotherapy as remission induction for multiple myeloma

    Br J Cancer

    (1995)
  • M. Dadacaridou et al.

    Dexamethasone, cyclophosphamide, etoposide and cisplatin (DCEP) for relapsed or refractory multiple myeloma patients

    J Buon

    (2007)
  • C.K. Lee et al.

    DTPACE: an effective, novel combination chemotherapy with thalidomide for previously treated patients with myeloma

    J Clin Oncol

    (2003)
  • N. Munshi et al.

    Dexamethasone, cyclophosphamide, etoposide and cisplatinum (DCEP), an effective regimen for relapse after high-dose chemotherapy and autologous transplantation (AT)

    Blood

    (1996)
  • G. Gahrton et al.

    Prognostic factors in allogeneic bone marrow transplantation for multiple myeloma

    J Clin Oncol

    (1995)
  • J.A. Burzynski et al.

    Toxicity of a second autologous peripheral blood stem cell transplant in patients with relapsed or recurrent multiple myeloma

    Leuk Lymphoma

    (2009)
  • F. Elice et al.

    Prolonged overall survival with second on-demand autologous transplant in multiple myeloma

    Am J Hematol

    (2006)
  • A. Krivanová et al.

    Second autologous transplantation for multiple myeloma patients relapsing after the first autograft—a pilot study for the evaluation of experimental maintenance therapies. Report of the prospective non-randomized pilot study of the

    Onkologie

    (2004)
  • R.L. Olin et al.

    Second auto-SCT is safe and effective salvage therapy for relapsed multiple myeloma

    Bone Marrow Transplant

    (2009)
  • M.H. Qazilbash et al.

    Second autologous or allogeneic transplantation after the failure of first autograft in patients with multiple myeloma

    Cancer

    (2006)
  • Cited by (33)

    • Meta-analysis of the efficacy and safety of bortezomib Re-treatment in patients with multiple myeloma

      2014, Clinical Lymphoma, Myeloma and Leukemia
      Citation Excerpt :

      Almost all patients with MM who survive initial treatment will eventually have progression of disease and require further therapy. The spectrum of treatment options available for relapsed and/or refractory MM has dramatically broadened over the past 10 years, largely because of the introduction of the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide and proteasome inhibitors including bortezomib and carfilzomib.3,4 The choice of treatment for patients with relapsed and/or refractory MM depends on a number of disease-related, regimen-related, and patient-related factors.1,2,4,5

    • Autologous Stem Cell Transplantation: An Effective Salvage Therapy in Multiple Myeloma

      2013, Biology of Blood and Marrow Transplantation
      Citation Excerpt :

      Age over 60 years and a short duration of response after the first ASCT were the two factors adversely affecting OS from the time of diagnosis and OS from the time of salvage ASCT (Table 4). Currently, there is no broadly accepted standard treatment for patients with relapsed/refractory MM [21]. For the selection of an appropriate treatment strategy at this stage, both disease-related and patient-related factors and, importantly, the type of previous therapy need to be considered [21-25].

    View all citing articles on Scopus

    Conflicts of interest: Dr Jakubowiak has received consulting fees from Bristol-Myers Squibb, Celgene, Millennium Pharmaceuticals, and Onyx Pharmacetuicals. He is also a member of the speakers' bureau for Celgene.

    Publication of this supplement was supported by Onyx Pharmaceuticals.

    View full text