At the Fifth Annual Conference of the Association for Value-Based Cancer Care in Washington, DC, Grant Lawless, RPh, MD, FACP, of the University of Southern California, Los Angeles, moderated a multidisciplinary panel on value-based care for patients with multiple myeloma. The panel included Gary Palmer, MD, JD, MBA, MPH, medical director of NantHealth, who highlighted the growing role of genomics testing in multiple myeloma, and Carol Ann Huff, MD, of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, who discussed therapies in development for multiple myeloma, including novel monoclonal antibodies. The panelists outlined trends that are likely to affect costs and care patterns in multiple myeloma, including increasing use of triplet-drug regimens, maintenance therapy, and antibody-based therapies in development.
The Burden of Multiple Myeloma
Despite the clinical advances, multiple myeloma remains a serious hematologic malignancy in the United States and abroad. Worldwide, approximately 230,000 patients are living with multiple myeloma, and an estimated 114,000 new cases are diagnosed annually.1 In 2015 in the United States, an estimated 26,850 new cases of multiple myeloma will occur and an estimated 11,240 deaths will occur from this condition.2
Advances in medications, stem-cell transplantation, and better supportive care have led to improved survival in patients with multiple myeloma, particularly in the past 15 years. Gains in 5- and 10-year relative survival have been consistent from 1998 to 2009 (Figure 1).3
Since 2009, the positive survival trend has continued, and in 2015, an estimated 47% of patients are expected to survive at least 5 years after being diagnosed with multiple myeloma.4 Relative survival rates vary by disease acuity. Using the Durie-Salmon criteria, median survival rates vary from 62 months for patients with stage I disease to 29 months for patients with stage III disease.5 Variability in survival by disease stage may have important implications for researchers, particularly for patients at the highest risk for poor outcomes.
The treatment of multiple myeloma is complex and is dependent on disease stage and acuity. The main options for therapy include standard chemotherapy drugs, stem-cell (bone marrow) transplant, and, more recently, nonchemotherapy drugs that target cancer cells. In multiple myeloma, therapy is rarely curative, and nearly all patients fail 1 or more therapeutic regimens during the course of the disease. As a result, patients typically receive a series of treatments over time. Current treatment options for multiple myeloma are shown in the Table.6
Traditional chemotherapies are frequently coupled with steroids such as dexamethasone or prednisone.6 Newer targeted drugs have emerged as important options for the treatment of multiple myeloma in patients with newly diagnosed disease and in patients with advanced disease that has failed chemotherapy or transplantation. In most cases, these medications are used (1) in combination with dexamethasone, (2) in combination with each other, or (3) with standard chemotherapy agents.6
Stem-cell transplantation can be performed using the patient's stem cells (ie, autologous) or using cells from a close relative or a matched unrelated donor (ie, allogeneic). The majority of transplants performed in patients with multiple myeloma are autologous; allogeneic transplants are still considered investigative. Although stem-cell transplants are not curative, they have been shown to prolong life in selected patients. Stem-cell transplants can be done as initial therapy in patients with newly diagnosed disease or at the time of disease relapse. In selected patients, more than 1 transplant may sometimes be recommended to adequately control the disease.7
As increasing numbers of induction therapies with deeper responses have become available, many clinicians are choosing to delay stem-cell transplant for eligible patients.8 The current approach to the treatment of symptomatic multiple myeloma is shown in Figure 2. The initial choice of treatment depends on the patient's health, age, ability to undergo stem-cell transplantation in the future, and disease characteristics that denote high-, intermediate-, or standard-risk multiple myeloma.6,9
According to Dr Huff, in patients with good overall health status (independent of age), many oncologists prescribe a triplet-drug regimen for initial therapy. The backbones of these regimens typically include bortezomib, a proteasome inhibitor, and/or lenalidomide, an immunomodulatory drug.
Up to 90% of patients are now achieving a good response to therapy with 3-drug combinations. As a result, some clinicians are moving away from transplants for many of these patients. For patients who are not candidates for a transplant, triplet regimens may sometimes be used. However, for frail patients, because of age or comorbid illnesses, oncologists often consider 2-drug combinations. Patients receiving these doublet regimens frequently do not experience responses as deep as those seen with triplet therapy, but the therapy is better tolerated.
Although a small percentage of patients do not respond well to initial treatment, multiple myeloma eventually relapses in almost all patients. Dr Huff indicated that these patients are typically more difficult to treat than patients receiving first-line therapy. Bortezomib, lenalidomide, carfilzomib, pomalidomide, or thalidomide, given with steroids, and/or standard chemotherapy drugs such as melphalan or cyclophosphamide, form the major treatment options for relapsed or resistant disease. A newer drug, panobinostat, may also be used along with bortezomib and dexamethasone in certain cases.6
Scientific Advances in Treatment
There is a considerable amount of research taking place in multiple myeloma, with more than 500 active clinical trials under way to investigate novel agents and combinations of medications in multiple myeloma.10
At the cellular level, the proteasome remains a key target for new therapies. Proteasomes are multienzyme complexes that provide the main pathway for degradation of excess intracellular proteins, some of which are cytotoxic. Researchers have hypothesized that cancer cells are more dependent on the proteasome pathway for clearance of abnormal proteins than normal cells. By poisoning the proteasome, the cell cannot degrade proteins that accumulate in the cell, and the cell undergoes apoptosis and dies.11 In addition to the currently FDA-approved proteasome inhibitors bortezomib and carfilzomib, investigational medications, such as ixazomib, ONY8912, and NPI0052, directly target the proteasome. Additional agents target the HDAC6 pathway to repress DNA transcription, including the recently approved drug panobinostat and the investigational compounds romidepsin, vorinostat, and rocilinostat.12
Immunotherapeutic Strategies and Beyond
Immunotherapy is another fertile area of research in multiple myeloma. Elotuzumab, a humanized monoclonal antibody currently in clinical trials for refractory multiple myeloma, was granted breakthrough therapy status by the FDA in May 2014.13 Another agent, daratumumab, has shown positive clinical activity in heavily pretreated patients with refractory multiple myeloma in a phase 2 clinical trial.14 Several other compounds with diverse mechanisms of action, including monoclonal antibodies, cell-signaling inhibitors, and selective therapies targeting the bone marrow microenvironment, are showing promise in preclinical studies and in clinical trials.12
Dr Huff indicated that several investigational immunotherapeutic agents are believed to act synergistically with immunomodulatory drugs, such as lenalidomide and pomalidomide, conferring even greater clinical activity.
In addition to proteasome inhibitors and immunotherapies, a number of other compounds are being investigated for anticancer activity in patients with multiple myeloma, including nuclear transport (KPT) inhibitors, cyclin-dependent kinase (CDK) inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, bromodomain inhibitors, kinesin spindle protein inhibitors, and protein kinase B (AKT) inhibitors.
Advances in Precision Medicine
According to Dr Palmer, researchers are finding previously unsuspected genomic alterations in multiple myeloma, alterations thought to be associated more often with solid tumors. New investigative efforts seek to identify whether patients with similar genomic alterations respond differently to cancer agents, alone or in combinations, than patients with other alterations.
In one example of how treatment with a targeted therapy can be guided by prospective genomic profiling, researchers investigated the mitogen-activated protein kinase (MEK) pathway regulating protein expression in the cell. The researchers found that patients with the RAS or PAF gene mutations had diminished ability to regulate protein expression via the MEK pathway, leading to an overexpression of proteins typically found in tumor cells. In addition to alterations in MEK, researchers also found genetic alterations in NRAS, KRAS, and BRAF.
Patients were treated with trametinib to prevent downstream activity that resulted from the overexpression of the RAS and the RAF genes. The administration of trametinib resulted in clinical activity yielding 3 complete responses, 10 partial responses, and 30 stable disease patients.
As advances in genomic testing continue to discover new genetic alterations in multiple myeloma, further innovation is very likely. However, Dr Palmer stressed that data requirements will also increase with the explosion of data, and health systems may soon be facing considerable data informatics and storage pressures.
The Ongoing Quest for Value in Cancer Care
As the science continues to evolve, the combination of genomic research and drug development is likely to further advance the care of patients with cancer, including those with multiple myeloma.
However, novel diagnostic tests and new treatment regimens will also contribute to the rising cost of care. The cost of cancer care is expected to increase from $125 billion in 2010 to a projected $173 billion in 2020.15 Rising expenditures impact all key stakeholders in oncology care, and if the cost of delivering high-quality cancer care is allowed to continue unchecked, it will become less and less affordable for a growing segment of the US population.16
As additional agents with complementary mechanisms of action enter the treatment armamentarium and the number of management options expand, the cost of care will continue to increase. Clinicians will seek knowledge regarding the use of novel drugs alone and in combination, sequencing of therapy, and personalization of treatment based on patients' unique genetic signatures. Dr Huff indicated that genomic research is likely to play a major role in guiding decision processes needed to make rational, value-driven, evidence-based decisions about treatment rather than haphazardly adding new options without adequate regard to cost and toxicity.
One construct that seeks to define a process for value-driven care–the integrated care flow–was discussed by Dr Lawless (Figure 3). In this process, targeted evidence-based care is delivered via broadly accepted pathways or protocols to patient populations that are stratified according to their demographics, medical history, and genomic profile. By setting clear expectations and defining goals regarding cost to benefit of treatment, healthcare stakeholders can define and apply best practices in the context of value (rather than clinical benefit alone), thereby providing optimal care while reducing waste and containing cost.
Multiple myeloma can therefore be viewed as a microcosm of the larger cancer care landscape, with newer, more effective therapies used in combinations that have improved outcomes to a considerable degree, but have also added substantially to the cost of treatment. As a result, it is important to shift the discussion from cost to value from a health economics perspective; that is, which therapeutic regimens offer the optimal clinical benefit relative to cost for specific populations of patients.
- International Agency for Research on Cancer. GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. http://globocan.iarc.fr/. Accessed June 25, 2015.
- American Cancer Society. Multiple myeloma: what are the key statistics about multiple myeloma? Revised March 9, 2015. www.cancer.org/cancer/multiplemyeloma/detailedguide/multiple-myeloma-key-statistics. Accessed June 17, 2015.
- Pulte D, Redaniel MT, Brenner H, et al. Recent improvement in survival of patients with multiple myeloma: variation by ethnicity. Leuk Lymphoma. 2014;55:1083-1089.
- Cancer.Net. Multiple myeloma: statistics. www.cancer.net/cancer-types/multiple-myeloma/statistics. Accessed June 18, 2015
- American Cancer Society. Multiple myeloma: survival rates by stage for multiple myeloma. Revised March 9, 2015. www.cancer.org/cancer/multiplemyeloma/detailedguide/multiple-myeloma-survival-rates. Accessed June 18, 2015.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): multiple myeloma. Version 4.2015. March 10, 2015. www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed June 29, 2015.
- Rajkumar SV. Multiple myeloma: 2013 update on diagnosis, risk-stratification, and management. Am J Hematol. 2013;88:226-235. Erratum in: Am J Hematol. 2014;89:669.
- Mikhael JR, Dingli D, Roy V, et al; for the Mayo Clinic. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines 2013. Mayo Clin Proc. 2013;88:360-376. Erratum in: Mayo Clin Proc. 2013;88:777.
- Zimmerman TM. Evolving management of multiple myeloma: 2015. www.wmcc.org/wp-content/upLoads/Novel-Therapeutic-Treatment-Strategies-Multiple-Myeloma.pdf. Accessed June 30, 2015.
- ClinicalTrials.gov. Multiple myeloma open studies. Search results. https://clinicaltrials.gov/ct2/results?term=multiple+myeloma&recr=Open. Accessed July 1, 2015.
- 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.
- Varga C, Laubach J, Hideshima T, et al. Novel targeted agents in the treatment of multiple myeloma. Hematol Oncol Clin North Am. 2014;28:903-925.
- Bristol-Myers Squibb. Bristol-Myers Squibb and AbbVie receive U.S. FDA Breakthrough Therapy Designation for elotuzumab, an investigational humanized monoclonal antibody for multiple myeloma. Press release. May 19, 2014. http://news.bms.com/press-release/rd-news/bristol-myers-squibb-and-abbvie-receive-us-fda-breakthrough-therapy-designatio. Accessed June 30, 2015.
- Inman S. Daratumumab data impresses in myeloma, FDA submission expected. OncLive. May 30, 2015. www.onclive.com/conference-coverage/asco-2015/Daratumumab-Data-Impresses-in-Myeloma-FDA-Submission-Expected. Accessed June 30, 2015.
- Mariotto AB, Yabroff KR, Shao Y, et al. Projections of the cost of cancer care in the United States: 2010-2020. J Natl Cancer Inst. 2011;103:117-128. Erratum in: J Natl Cancer Inst. 2011;103:699.
- American Society of Clinical Oncology. ASCO in Action Brief: value in cancer care. January 21, 2014. www.asco.org/advocacy/asco-action-brief-value-cancer-care. Accessed July 6, 2015.