Evolving Treatment Paradigms in the Management of Relapsed/Refractory Multiple Myeloma Cristina Gasparetto, MD
Summary In recent years, an improvement in the understanding of the underlying biology of multiple myeloma has led to improvements in treatment. Although relapsed/refractory disease is incurable, there are now multiple therapeutic options for those patients. Many more novel and innovative agents are under investigation and should become available in the next few years. • • •
Key Points Relapsed/refractory MM can be treated with multiple lines of treatment, but the response declines with each subsequent treatment. Oral agents are on the horizon. Monoclonal antibodies may be the next therapy innovation.
Multiple myeloma (MM) is a cancer of the plasma cell characterized by excessive numbers of abnormal plasma cells in the bone marrow. Many improvements in treatment have occurred over the past 14 years (Exhibit 1). With the introduction of novel agents and stem cell transplants, the outcome for patients with MM has improved in recent years, both in the relapsed setting as well as at diagnosis. Once considered relapsed or refractory, the disease is considered incurable, and the goal of therapy changes to disease stabilization and symptom minimization. Relapsed disease is the first progression in the absence of any therapy. It can be a biochemical or symptomatic relapse. Relapsed and refractory disease is progression on specific therapy or within 60 days of completion of a given therapy. Dual refractory disease is resistant to bortezomib and lenalidomide. Primary refractory disease is defined as no response following initial induction therapy.
Once someone relapses after initial induction therapy, they are committed to remaining on therapy for the remainder of their life; median survival in the relapsed/refractory setting is six to nine months. Relapsed/refractory MM can be treated with multiple lines of treatment, including retreatment with a previous agent, but the response declines with each subsequent treatment (Exhibit 2). Many factors have to be considered in choosing treatment at relapse (Exhibit 3). Novel agents for MM include immunomodulators [thalidomide (Thalomid®), lenalidomide (Revlimid®), and pomalidomide (Pomalyst®)] and proteasome inhibitors [bortezomib (Velcade®) and carfilzomib (Kyprolis®)]. Other treatment options include chemotherapy, novel agents in combination with chemotherapy combinations, salvage autologous stem cell transplant, allogeneic stem cell transplant, and clinical trials. Carfilzomib and pomalidomide are the most re-
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Exhibit 1: Treatments Approved Since 2000 Lenalidomide + Dexa Carfilzomib Thalidomide + Dexa Thalidomide
VDR CyBorD
Boretezomib
Pomalidomide
Boretezomib Doxorubicin 2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
Tandem Auto
MPT (Europe) Boretezomib > 1 therapy
MPV Auto-Allo
Maintenance Post-ASCT
Dexa = dexamethasone MPT = melphalan, prednisone, thalidomide MPV = melphalan, prednisone, bortezomib VDR = bortezomib, dexamethasone, lenalidomide CyBorD = cyclophosphamide, bortezomib, dexamethasone Auto-Allo = autologous/allogenic stem cell transplant ASCT = autologous stem cell transplant
cently approved agents. Carfilzomib, a selective irreversible proteasome inhibitor, has been studied in relapsed/refractory MM. Given intravenously, it resulted in a 23.7 percent overall response rate in a heavily pretreated population.1 The response lasts a median of 3.7 months, with overall survival of 15.6 months. The most commonly reported adverse effects with carfilzomib are thrombocytopenia and anemia. The major distinction from bortezomib, a reversible proteasome inhibitor, is a lower rate of peripheral neuropathy. Pomalidomide, an immunomodulatory lenalidomide analogue, was FDA approved for relapsed/ refractory MM in early 2013. When studied in a heavily pretreated population, 31 percent of patients achieved an overall response rate with pomalidomide in combination with dexamethasone.2 Progressionfree survival was four months compared with 1.9 months for dexamethasone alone. Overall survival was also longer with the combination (12.7 vs 8.1 months). Like lenalidomide, cytopenias are the most frequent adverse effects of this agent. Pomalidomide is indicated for patients with MM who have received at least two prior therapies including lenalidomide
and bortezomib and have demonstrated disease progression on therapy or within 60 days of completion of the last therapy. The combination of pomalidomide and carfilzomib has been studied in relapsed/refractory MM.3 The majority of subjects in this study were refractory to lenalidomide and bortezomib. Combination therapy resulted in a significantly higher response rate (70%) than seen with either agent alone. More than 300 agents are under study for MM with some of the most promising agents listed in Exhibit 4. Ixazomib is the agent closest to market and is the first oral proteasome inhibitor. Phase I/ II studies using ixazomib weekly or twice weekly in relapsed/refractory MM patients suggested antitumor activity of the single agent, but more promising results have been obtained with the combination of ixazomib, lenalidomide, and dexamethasone in newly diagnosed MM.4 Oprozomib (ONX-0912) is a structural analog of carfilzomib that is also an oral agent. This proteasome inhibitor binds selectively and irreversibly to its target. Different formulations of this agent are under investigation. A 20 percent overall response
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Exhibit 2: Best Response to Regimen, by Regimen Number 50 45 40 35 30
CR%
25
VGPR%
20
PR%
15
CR = complete response
10
VGPR = very good partial response
5
PR = partial response
0 1st N = 213
2nd N =9 0
3rd N = 49
4th N = 27
5th N = 18
Exhibit 3: Factors in Selecting Treatment for Relapsed/Refractory Myeloma
1. Disease-related factors -Duration of response to initial therapy -FISH or cytogenetic profile (e.g. t(4;14) or p53 deletion) 2. Regimen-related -Prior drug exposure (relapsed vs refractory) -Toxicity of regimen (combination vs single agent) -Mode of administration (oral, sq, vs IV) -Previous transplant (durability of response after transplant) 3. Patient-related factors -Pre-existing toxicities (e.g., cumulative myelosuppression, peripheral neuropathy) -Co-morbid conditions (e.g., renal failure, diabetes mellitus) -Age -Performance status -Distance from Center -Insurance
rate was seen in a Phase Ib/II dose escalation study in heavily pretreated MM.5 Panobinostat, another oral agent, is a nonselective histone deacetylase inhibitor (HDAC inhibitor) being investigated in many different cancers. It increases acetylation of proteins involved in multiple oncogenic pathways. Combination with a proteasome inhibitor results in a buildup of intracellular
misfolded cytotoxic proteins, leading to MM cell apoptosis through synergistic inhibition of the aggresome and proteasome pathways. 6 The combination of bortezomib and panobinostat appears to be effective in those with bortezomib resistance (31% overall response rate). Monoclonal antibodies against myeloma-specific antigens are also under investigation and appear to
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Exhibit 4: Promising Novel Agents
Agent
Class
Ixazomib (MLN9708) Oprozomib (ONX-0912) Marizomib (NPI-0052)
Proteasome inhibitors
Rocilinostat (ACY-1215) Panobinostat
HDAC inhibitors
Filanesib (ARRY-520)
Kinesin Spindle Protein inhibitor
Afuresertib (GSK2110183)
AKT inhibitor
HDAC = histone deacetylase AKT = protein kinase B
have significant activity.8 Daratumumab, a fully human IgG1k monoclonal antibody that targets CD38, has demonstrated promising activity as monotherapy and in combination with other novel agents in patients with relapsed/refractory multiple myeloma, resulting in the initiation of several Phase III clinical trials. Elotuzumab is a humanized monoclonal IgG1 antibody targeting human CS1, a cell surface glycoprotein. CS1 is highly and uniformly expressed on MM cells while there is restricted expression on NK cells and little to no expression on normal tissues. Preliminary results from a trial in combination with lenalidomide-dexamethasone showed an overall response rate of 82 percent in a relapsed/refractory population.
trial. Lancet Oncol. 2013;14(11):1055-66. 3. 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. 4. Offidani M, Corvatta L, Caraffa P, et al. An evidence-based review of ixazomib citrate and its potential in the treatment of newly diagnosed multiple myeloma. Onco Targets Ther. 2014;7:1793-1800. 5. Allegra A, Alonci A, Gerace D, et al. New orally active proteasome inhibitors in multiple myeloma. Leuk Res. 2014;38(1):1-9. 6. Hideshima T, Richardson PG, Anderson KC. Mechanism of action of proteasome inhibitors and deacetylase inhibitors and the biological basis of synergy in multiple myeloma. Mol Cancer Ther. 2011;10:2034-2042. 7. Anderson KC, Kyle RA, Rajkumar SV, et al. Clinically relevant end points and new drug approvals for myeloma. Leukemia. 2008;22(2):231-9. 8. Kuroda J, Nagoshi H, Shimura Y, Taniwaki M. Elotuzumab and daratu-
Conclusion
mumab: emerging new monoclonal antibodies for multiple myeloma. Expert
Many treatment options are available for patients with MM that has relapsed. When selecting salvage therapy, numerous factors including disease-related, patient-related, regimen-related, and prior therapy have to be considered. Although strides have been made in improving survival, better agents are still needed. Numerous agents, which will hopefully make it to market, are under study.
Rev Anticancer Ther. 2013;13(9):1081-8.
Christina Gasparetto, MD is an Associate Professor of Medicine at Duke University Medical Center.
References 1. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120(14):2817-25. 2. San Miguel J, 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
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