Choosing treatment options for patients with relapsed/refractory multiple myeloma

Abstract

Multiple myeloma (MM) is a clonal plasma cell disorder that is still incurable using conventional treatments. Over the last decade, advances in front-line therapy have led to an increase in survival, but there are still some doubts in the case of relapsed/refractory disease. We searched the PubMed database for articles on treatment options for patients with relapsed/refractory MM published between 1996 and 2013. These treatments included hematopoietic cell transplantation (HCT), rechallenges using previous chemotherapy regimens, and trials of new regimens. The introduction of new agents such as the immunomodulatory drugs (IMIDs) thalidomide and lenalidomide, and the first-in-its-class proteasome inhibitor bortezomib, has greatly improved clinical outcomes in patients with relapsed/refractory MM, but not all patients respond and those that do may eventually relapse or become refractory to treatment. The challenge is therefore to select the optimal treatment for each patient by balancing efficacy and toxicity. To do this, it is necessary to consider disease-related factors, such as the quality and duration of responses to previous therapies, and the aggressiveness of the relapse, and patient-related factors such as age, comorbidities, performance status, pre-existing toxicities and cytogenetic patterns. The message from the trials reviewed in this article is that the new agents may be used to re-treat relapsed/refractory disease, and that the sequencing of their administration should be modulated on the basis of the various disease and patient-related factors. Moreover, our understanding of the pharmacology and molecular action of the new drugs will contribute to the possibility of developing tailored treatment.

Keywords::

• immunomodulatory drugs
• proteasome inhibitors
• relapsed/refractory multiple myeloma
• salvage therapies

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Multiple myeloma (MM) is a clonal disorder of plasma cells that still cannot be cured using conventional treatments because of frequent relapses.

• The introduction of thalidomide, lenalidomide and bortezomib has changed the treatment paradigm for patients with relapsed/refractory disease by improving clinical outcomes in comparison with conventional chemotherapy alone.

• Relapsing patients with multiple myeloma should be treated at the appearance of the typical clinical manifestations of MM which are summarized by the CRAB symptoms (elevated calcium, enal impairment, anemia and bone lesions), or when monoclonal protein in serum or urine has a significant growth.

• Treatments for patients with relapsed/refractory MM include hematopoietic cell transplantation, a rechallenge using a previous chemotherapy regimen, or a trial of a new regimen.

• At the time of a relapse, the challenge is to select the optimal treatment for each patient while balancing efficacy and toxicity. The decision will depend on disease- and patient-related factors, as well as the pharmacological characteristics of the anti-myeloma agents.

• Patients with indolent relapse can be treated first with two-drug or three-drug combinations. Patients with more aggressive relapse often require therapy with a combination of multiple active agents, consider ASCT as salvage therapy at first relapse for patients who have cryopreserved stem cells early in the disease course.

• Outcomes are significantly better when novel agents are used at first relapse, rather than as salvage treatment after two or more previous therapies

• Combined therapy can be used to prevent or overcome treatment resistance, and increase the efficacy of standard treatment regimens.