The dramatic advances in the diagnosis and treatment of multiple myeloma over the past 20 years have resulted in significant improvements in overall survival, with 5-year relative survival rates now around 50% and more than 60% for patients younger than age 70.1 The proteasome inhibitors bortezomib, carfilzomib, and ixazomib; the immunomodulatory agents lenalidomide, pomalidomide, and thalidomide; the monoclonal antibodies daratumumab and elotuzumab; and now the histone deacetylase inhibitor panobinostat are credited with doubling survival rates in patients with multiple myeloma compared with the survival rates prior to 1995, when the mainstay of therapy was melphalan plus prednisone, and 5-year survival hovered around 29%.2
However, despite these more effective therapies, myeloma remains an incurable disease—this year, nearly 13,000 adults in the United States will die of the cancer3—and eventually, nearly all patients will relapse, or their cancer will become refractory to treatment and progress. As a result, most patients with myeloma will need to continue doublet or triplet combinations of therapies as maintenance treatment indefinitely, increasing their risk for both long-term treatment-related and financial toxicities due to the escalating costs of these therapies.
According to a presentation by S. Vincent Rajkumar, MD, Professor of Medicine at the Mayo Clinic, Rochester, Minnesota, on the cost-effective treatment of multiple myeloma, during the First International Summit on Interventional Pharmacoeconomics, each new drug for myeloma costs between $150,000 and $200,000 per year. For carfilzomib, a second-generation proteasome inhibitor and a mainstay in the treatment of patients with relapsed or refractory disease, the cost per year for doses at 56 mg/m2 can reach $260,000.
S. Vincent Rajkumar, MD
“Unlike [other hematologic cancers] such as large B-cell lymphoma or Hodgkin lymphoma, where you give 6 months of treatment and you’re done for most patients, in myeloma, treatment is pretty much lifelong, continuous therapy, for 7 or 8 years or more, which is the median survival of the disease,” said Dr. Rajkumar. “And we don’t use these drugs alone; we use them in combination, which then increases the cost even more…. Quadruplets are up-and-coming options now, very similar to R-CHOP [rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone] for the cure [of non-Hodgkin lymphoma]. You are talking about a four-drug combination of monoclonal antibodies costing between $350,000 and $600,000 for 1 year of treatment.”
In an extensive interview with The ASCO Post, Dr. Rajkumar talked about how treatment costs for multiple myeloma can be reduced; a clinical trial he is conducting investigating whether maintenance therapy given for a limited duration is as effective in disease management as continuous therapy; and whether myeloma can be converted into a curable cancer.
Strategies for Reducing the Cost of Treating Myeloma
During your presentation at the First International Summit on Interventional Pharmacoeconomics, you offered four suggestions as to what physicians, cancer institutions, and professional organizations can do to drive down treatment costs in multiple myeloma: choosing the best option, developing national guidelines, supporting the lowest cost options, and conducting strategic trials. Please explain these suggestions in more detail.
The challenges of ensuring access to affordable new treatments for cancer, both in the United States and around the world, are not unique to multiple myeloma. These four suggestions may apply to reducing the treatment costs of other cancers as well. To determine how to approach the treatment of myeloma in a cost-effective manner, we have to step back and see what to do if resources and access to good health insurance are limited.
In the front-line treatment setting, patients are classified into those who are eligible for transplant and those who are not. If patients are not transplant-eligible, typically we give them a triplet regimen of bortezomib, lenalidomide, and dexamethasone (VRd) for 9 months, followed by lenalidomide maintenance therapy.4 Using that strategy, you can achieve 4-year survival rates of 70% to 80% or higher. Or, you could use a different triplet combination of daratumumab, lenalidomide, and dexamethasone or carfilzomib, lenalidomide, and dexamethasone (KRd), which are more expensive regimens than VRd. Neither regimen has data showing it is better than VRd, and both are newer regimens than VRd, so we have shorter follow-up on long-term safety.
“We have to talk about treatment affordability with our patients, because even for patients with insurance in the United States, cost is a concern.”— S. Vincent Rajkumar, MD
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Clinicians should be aware of near-equivalent regimens that can provide pretty close to the same benefit at a lower cost. We have to pay attention to what is the best possible and affordable option for patients based on their circumstances, whether they live in the United States or Canada or India.
In the relapsed setting, since most patients are relapsing on lenalidomide, our strategy would be to begin treatment with daratumumab in combination with either bortezomib or pomalidomide. If patients are not refractory to lenalidomide, we can use daratumumab with lenalidomide.
As you can see, there are multiple different regimens we can use as alternatives. Unfortunately, none of them have been compared head-to-head, so we have to use our best judgment to choose a regimen we think will be effective.
Providing Value in Myeloma Care
The first suggestion is always to choose the best available option; if the best treatment option is not available, because in many situations the best option is unaffordable for patients, you could get near-equivalent treatment at a lower cost. A few years ago, Dr. Jean Luc Harousseau and I wrote a paper in which we provided alternative strategies for treating myeloma that could be much less expensive and still produce almost similar results, particularly in resource-poor situations.5
My second suggestion is to develop powerful national guidelines. These guidelines should specifically state that cost be taken into account when prescribing equivalent treatments that clearly recommend the lower-cost option over an equivalent, more expensive alternative, rather than simply listing the various options as being reasonable alternatives and that hold experts and cancer societies to higher standards when publicizing the benefits of new drugs.
My third suggestion is always to support the lower-cost treatment option in clinical practice and to prefer generic and biosimilar drugs over branded ones when such a choice is available. Then pharmaceutical companies will know that, given a choice between two equal drugs, you will always prescribe the lowest-priced drug.
For example, the bisphosphonate zoledronic acid and the monoclonal antibody denosumab have been shown to be equally effective in the prevention and treatment of bone lesions in patients with myeloma, but zoledronic acid costs $60 a month and denosumab costs $2,150 a month. Similarly, studies have shown that VRd and KRd yield similar response rates, progression-free survival, and overall survival, but VRd costs $220,000 per year and KRd costs $300,000 per year. Since both regimens are equal, we should have guidelines stating the more expensive option is not recommended, rather than list them as equivalent and reasonable alternatives.
And, finally, we should conduct strategic clinical trials investigating ways to reduce the cost of myeloma treatment without compromising patient outcomes, for example by using modified dosing to reduce side effects and cost. There is a trial underway now testing the tolerability and efficacy of taking pomalidomide every 2 days instead of daily, as is the protocol now, in patients with refractory multiple myeloma (ClinicalTrials.gov identifier NCT03520985).
We also need to conduct trials investigating limited-duration therapy. If we always conduct trials that compare two drugs given indefinitely, we will never know whether indefinite treatment is actually necessary. We need some clever trials to determine whether it really is necessary to give a drug for 5 years, or can we get the same benefit if we give the drug for 1 year and restart therapy when the disease comes back? We have to have trials in which we take response into account and show whether a patient who is minimal residual disease–negative can stop treatment while achieving the same benefit. Can we cure the disease? How will we know whether we are curing cancer if the treatment is always indefinite? You only know if you are curing a disease if you stop therapy and the disease doesn’t come back.
These are ideas I’ve been promoting in terms of what physicians can do to provide value in myeloma care and reduce cost without governmental intervention in drug pricing.
The last message I have, although I didn’t include it in my presentation, is we have to talk about treatment affordability with our patients, because even for patients with insurance in the United States, cost is a concern. We need to be willing to raise this issue, because then we will know whether patients can afford the treatment being prescribed. If not, we have to see how we can help these patients by getting them discounted or free drugs; giving alternative drugs that are less expensive; or trying a different, less-expensive dosing strategy.
We also have to advocate for lower drug prices and use our own personal clout within our institutions and societies, including ASCO and the American Society of Hematology, to accomplish that goal.
Shortening Treatment Duration to Reduce Toxicities and Costs
During your presentation, you also talked about investigating whether maintenance therapy following primary treatment of multiple myeloma could be given in limited durations of up to 2 years, rather than as continuous treatment to reduce drug toxicity and the cost of treatment. What maintenance therapy is your trial investigating?
Usually only one drug, lenalidomide, is used in the maintenance setting, and that is the drug we are investigating in our ongoing ECOG study. Unlike in other hematologic cancers such as large cell lymphoma, where patients are given a 6-month course of therapy and then they are done, in myeloma, treatment is usually lifelong. Patients receive continuous therapy year after year for 7 or 8 years, which is the median survival of the disease, or longer.
During the maintenance phase, treatment is given until disease progression. One of the strategies I mentioned in my presentation is to start looking at whether we need to give indefinite maintenance therapy to maintain a remission or prevent disease progression. Or, can we do clinical studies to figure out whether shorter-term maintenance therapy can provide the same benefit with less cost and less toxicity?
We have a clinical trial underway investigating lenalidomide maintenance for 2 years vs indefinitely to see whether there is an overall survival benefit with indefinite maintenance therapy. We should have results from the study in 1 to 2 years.
The Escalating Costs of Treating Myeloma
One of the most startling slides in your presentation showed the total lifetime costs to treat patients with multiple myeloma diagnosed in 2017, which came to $22.4 billion, excluding costs for physician visits, hospital stays, laboratory testing, and imaging. How might the costs of treating multiple myeloma increase even higher with the advent of newer approaches to treatment, such as chimeric antigen receptor (CAR) T-cell therapy?
The good news for patients with myeloma is that the number of effective therapies keeps growing, and we can prolong life longer. However, each new drug inevitably brings higher costs. I would say, if CAR T-cell therapy is approved for myeloma, the price will be upward of $500,00 for a single treatment, and that is on top of the costs for supportive care, hospital stays, and physician visits.
In addition, there are also new monoclonal antibodies in the pipeline, which will cost between $150,000 and $200,000 per year. Maintenance lenalidomide costs about $168,000 per year, and patients stay on the therapy for years until they experience disease progression and have to go on another expensive regimen. As newer drugs become approved by the U.S. Food and Drug Administration, which is good, hundreds of thousands of dollars per patient per year are added to the overall cost of managing myeloma.
Looking for a Cure
Will multiple myeloma ever become a curable cancer?
Yes, I think so. What we are doing now is trying to see whether we can cure this cancer. Our hypothesis for why we have not been able to cure it so far is that we are treating myeloma too late. We think if we can treat the cancer aggressively early in the course of disease, even in the smoldering stage, before people experience symptoms and before the disease has spread to multiple bones, it may be curable.
The GEM-CESAR trial is investigating the potential of curing multiple myeloma in the smoldering, asymptomatic phase of the disease, and initial results are encouraging.6 In the United States, my colleague at the Mayo Clinic, Shaji Kumar, MD, is investigating a curative strategy in the ongoing ASCENT trial (NCT03289299). We have made numerous advances to enable a small proportion of people to live a normal life span, but we are achieving this with continuous expensive therapy, with the added inconvenience of cost and toxicity.
Our goal is to truly cure a large proportion of patients with myeloma with limited-duration therapy.
DISCLOSURE: Dr. Rajkumar has received authorship royalties from UpToDate.
REFERENCES
1. Turesson I, Bjorkholm M, Blimark CH, et al: Rapidly changing myeloma epidemiology in the general population: Increased incidence, older patients, and longer survival. Eur J Haematol. April 20, 2018 (early release online).
2. Brenner H, Gondos A, Pulte D: Recent major improvement in long-term survival of younger patients with multiple myeloma. Blood 111:2521-2526, 2008.
3. Cancer.Net: Multiple myeloma: Statistics. Available at www.cancer.net/cancer-types/multiple-myeloma/statistics. Accessed August 7, 2020.
4. Rajkumar SV: Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol 95:548-567, 2020.
5. Rajkumar SV, Harousseau JL: Next-generation multiple myeloma treatment: A pharmacoeconomic perspective. Blood 128:2757-2764, 2016.
6. Mateos MV, Martinez-López J, Otero PR, et al: Curative strategy (GEM-CESAR) for high-risk smoldering myeloma: Carfilzomib, lenalidomide and dexamethasone (KRd) as induction followed by HDT-ASCT, consolidation with KRd and maintenance with Rd. 2019 EHA Annual Congress. Abstract S871. Presented June 15, 2019.
