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Special Article

Clinical Pathways to Address the Challenges of Treatment Resistance and Relapse in Multiple Myeloma


J Clin Pathways. 2017;3(7):49-55.

Executive Summary

Multiple myeloma (MM) is caused by abnormal plasma cell growth in bone marrow, resulting in bone destruction, marrow failure, and adverse blood cell production. The course of MM is characterized by a repeating pattern of remission and relapse as patients cycle through available treatment options. Standardizing treatment options for relapsed/refractory MM poses a challenge to clinical pathway decision-makers, due to the need to individualize treatment decisions for the patient’s specific circumstances. Other challenges to treatment decision-making for relapsed/refractory MM include the disease’s heterogeneity and the proliferation of novel therapeutics and combinations. Economic consequences of the costs associated with maintenance therapy, the use of doublet and triplet regimens, and patients living longer as a result of effective treatments must also be considered. In this report, we review the complex nature of MM treatment, the current landscape of clinical practice guidelines and treatment pathways, and economic considerations for treatment.


Understanding the Different Phases of Treatment for Multiple Myeloma

Multiple myeloma (MM) is caused by clonal plasma cell growth, primarily in bone marrow, resulting in bone destruction, renal insufficiency, anemia, and hypercalcemia. MM accounts for 1% of all cancers and 10% of all hematological cancers in the United States.1 An estimated 30,000 new cases will be diagnosed in 20172 at a median patient age of 69 years, with most frequent diagnoses between ages 65 and 74.2

Between 2004 and 2013, new myeloma cases increased on average 0.8% per year; however, as a result of novel and more effective treatments, death rates have declined at the same average rate.2 An estimated 95,688 Americans in 2013 were living with MM, with a 5-year survival rate of 48.5%.1 Because MM is an incurable disease, treatment is an ongoing process.3

Initial treatment of MM differs for transplant-eligible and non-eligible patients. Transplant-eligible patients typically receive four to six cycles of induction therapy before stem cell collection and/or transplant (SCT), with response assessment after one to two cycles of therapy.2 The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology2 and other clinical practice guidelines recommend  choosing a regimen consisting of some combination of a proteosome inhibitor (bortezomib, carfilzomib, ixasomib); an immunomodulatory drug (IMiD; lenalidomide, thalidomide); an alkylating agent (cyclophosphamide); and/or chemotherapy (doxorubicin) along with dexamethasone for primary therapy.

Maintenance therapy follows, with consolidation therapy considered in some patients. The goal of maintenance therapy is achieving a longer progression-free survival (PFS) and overall survival (OS).4 Options for maintenance therapy include lenalidomide or bortezomib.2 Although lenalidomide maintenance improves survival, some studies show that lenalidomide can cause second malignancy during maintenance therapy, possibly when preceded closely by an alkylator-based therapy (eg, in a SCT patient).5 Bortezomib is well-tolerated and shows good response rates, and is not associated with a risk of secondary malignancies.2 Thus, it can be used instead of lenalidomide in cases with high-risk cytogenic markers or in some cases of advanced renal insufficiency.2

One of the controversies in MM therapy is the duration of maintenance treatment. The goal of extending remission must be balanced with the toxicity, tolerability, convenience, and cost associated with possibly treating a patient until progression.4 Capping lenalidomide maintenance therapy at 2 years for patients who achieve a sustained complete response can be considered; however, prospective data is lacking for this approach.5 Some clinical trials are currently underway to look at a longer maintenance period as well as other drug combinations.4 In addition to toxicity, there is concern over the economics of treating a patient indefinitely with costly maintenance therapy.

The biggest challenge of MM treatment comes when patients relapse after previous therapy. “Most people in the myeloma field are comfortable with what they’re recommending for upfront therapy. It’s when relapses happen that there’s a lot of choices, and it takes thought about what you’re trying to accomplish,” said Natalie S Callander, MD, a hematology/bone marrow transplant specialist at the University of Wisconsin School of Medicine and Public Health (Madison, WI).


The Challenges of Treatment Resistance and Relapse

The course of MM is characterized by a repeating pattern of remission and relapse as patients cycle through available treatment options. Therapy has improved to where the majority of patients can now experience a long remission, so myeloma is getting closer to being a chronic illness vs a lethal cancer, said Ehsan Malek, MD, a hematologist and oncologist at UH Cleveland Medical Center (Cleveland, OH). Despite the improvements in outcomes with new drug regimens, most patients still relapse or become refractory to the available treatments. “We all know that [in most cases] myeloma will eventually start to grow back despite the treatment,” said Cristina Gasparetto, MD, a multiple myeloma specialist at Duke University School of Medicine (Durham, NC).

One reason is that every drug has a lifespan for patients with MM. When a clinician starts a patient on a drug, the clock starts ticking, said Dr Gasparetto. “The drug isn’t going to last forever. Eventually the myeloma will acquire a resistance to that drug. That’s why it is such a difficult disease.” Triplet therapy can be used to avoid the patient developing a resistance relatively quickly. Eventually, though, nearly all MM patients will become refractory to all medications tried, Dr Gasparetto said.

There are many theories about why patients with MM relapse and become refractory, and this is a subject of ongoing research, said Dr Malek. Most traditional chemotherapy agents work through protein synthesis, said Dr Callander. Plasma cells grow relatively slowly, so with low cell turnover, some traditional agents will not work on them, making it impossible to fully eradicate them. There is also strong evidence that plasma cells are protected in bone marrow, where the macrophages and dendritic cells do not recognize that they are harmful.6 MM is dependent on its protective and permissive microenvironment, which prevents the agents from eradicating the disease. There is also the concept of clonal evolution, where MM cells evolve and acquire new, sometimes more aggressive genetic mutations, making them resistant to current therapy.6 Dr Callander said there are probably multiple mechanisms at work.

Each subsequent remission is typically shorter than the last. Researchers reviewed almost 5,000 MM patient charts for a study in the British Journal of Haematology.7 They found that 74% of patients achieved at least a very good partial response to first-line treatment, whereas only 11% of patients had the same type of response at the fifth line. As for complete response, they estimated that 32% experienced a complete response from the first line, down to 2% at the fifth line. The time from starting treatment to progression also decreased as the patient progressed through the treatment lines. For the first line, the time to progression was 18 months, whereas for the second line the median time to progression was 13 months. For third and fourth treatment lines, it decreased to 7 and 5 months respectively.


Evidence-Based Treatment Decision-Making and Clinical Pathways

Treatment options for MM have expanded substantially in the last 10 to 15 years, with the introduction of novel therapeutics. Prior to 2003, when bortezomib was approved, patients received VAD (vincristine, doxorubicin, and dexamethasone) or another regimen, and possibly a stem cell transplant, said Dr Callander. Once they relapsed, physicians tried thalidomide or melphalan and prednisone, but survival was poor, at 3 to 5 years. Lenalidomide was introduced in 2006. That and bortezomib changed the MM treatment landscape. “Not only did you have better choice up front, but better back-up options when people relapsed,” Dr Callander said. Around 2008 or 2009, the two were combined with other agents, with even better results. In the last few years, several more novel therapies were introduced for MM treatment, including a histone deacetylase inhibitor (panobinostat), monoclonal antibodies (daratumumab and elotuzumab), and an oral proteasome inhibitor (ixazomib), all approved for the treatment of relapsed MM.7

Choices for second and subsequent lines of therapy are selected based on the individual patient factors as well in addition to the efficacy and safety data of the particular regimen. For example, the treatment recommendation for a patient who is progressing slowly 5 or 6 years after transplant would differ from that for a young patient with aggressive disease. Clinicians consider comorbid issues, the patient’s age, fitness or frailty level, past treatment including maintenance therapy, toxicity experience, stage of relapse, and length of remission. 

Toxicity. Clinicians tailor treatment to a patient’s tolerated toxicity. A large fraction of patients experience neuropathy, for example, so the clinician would choose an agent causing the least amount of neuropathy. Patients with a prolonged survival can live 10 to 15 years, said Dr Malek, so it is important not to leave the patient with irreversible side effects. Side effects cause permanent damage in stages, not overnight. With more than 10 drugs for MM approved by the US Food and Drug Administration (FDA), clinicians need to find ones that can give a good remission time without causing intolerable side effects.

Comorbidity. Patients’ comorbidities must be considered before determining appropriate treatment. For example, for patients with renal insufficiency, clinicians prefer to choose agents that do not interfere with kidney function.

Age/frailty. It is usually recommended that those who are elderly or frail receive a regimen that is less likely to cause side effects (eg, doublet rather than triplet therapy or reduced drug dosages), though this decision may be based on other factors as well.2

Past treatments. The most important factor to Dr Callander is how long the patient responded to their previous therapy. If a patient never responded to a therapy, or the amount of time was transient, she would recommend more aggressive therapy with different agents. If the patient relapsed a few years after stopping the previous therapy, however, it is reasonable to treat with the same regimen.

Type of relapse. Clinicians look at the type of relapse. Investigators may handle an asymptomatic relapse differently, depending on whether a patient has a clinical (symptomatic) or biochemical relapse. According to the European Society for Medical Oncology guidelines committee,8 treatment can be delayed for a biochemical relapse, although this is controversial because some patients will start with rising levels of monoclonal proteins or free light chains. According to Dr Callander, if the patient’s blood counts are normal and the patient feels fine but there is a small increase in the chosen protein marker, some clinicians recommend a full workup even if the patient does not meet the formal relapse definition. Those patients may start on a triplet combination to put them in remission. Others clinicians would recommend observation instead. A third approach is to intervene when the protein level increases to a certain amount. The latter situation is the most common one academics are seeing now, said Dr Callander. When there is a symptomatic relapse, like a new fracture or extreme anemia or low platelets, most agree to give a three-drug regimen. Some may recommend an autologous stem cell transplant if the patient had one a few years back. “Everyone would agree that they need aggressive treatment,” she said. The nature of the relapse is important too. If a patient is progressing within the first year of transplant, aggressive therapy is also warranted, though the utility of a second transplant in such cases remains controversial.

Clinical trials. Clinicians recommend that patients enroll in clinical trials whenever available and eligible.

Proximity to care. Another consideration is the proximity to medical care. With rural populations, clinicians must consider whether it is a burden for a patient to come to the clinic once or twice weekly for intravenous (IV) or infusion therapy. For some, it might be better to get an oral regimen instead of IV, especially if the IV drug requires long infusion times (eg, novel monoclonal antibodies).

Insurance. Realistically, determining treatments often means asking patients about their insurance coverage for oral drugs. Not all Medicare patients have coverage for some of the expensive oral agents, said Dr Callander. “Some [insurers] have 80% coverage for drugs, but if it’s $1600 a month, that won’t go far,” she said. Physicians are often unaware of treatment costs and are reluctant to ask patients what it is costing them.

Some of the trends in MM therapy include possibly adding monoclonal antibodies and combination therapies earlier in the treatment course, said Dr Malek. The phase 3 CASTOR and POLLUX trials published in 20169,10 showed that adding the monoclonal antibody daratumumab to lenalidomide and dexamethasone or bortezomib and dexamethasone for relapsed/refractory MM significantly lengthened PFS. Both of these trials introduced daratumumab to patients who had already completed at least one line of treatment. Though there are many therapy options, clinicians want to avoid exhausting an agent if a patient can still benefit from one they have not received before. “Sooner or later you might need that new agent,” Dr Malek said.

Stem cell transplant gives an additional therapeutic option. Transplant has been the standard of care since the 1990s11 for patients typically younger than 70 years, and then the practice was questioned with the introduction of novel agents. Studies focusing on whether to delay transplant soon after diagnosis showed that performing stem cell transplants earlier results in longer PFS, but not necessarily longer OS.11 Some institutions recommend a second transplant after a remission period of 18 months if the patient was not on maintenance therapy and 36 months if the patient was on maintenance therapy.6 The NCCN2 guidelines cited a number of retrospective studies comparing patients who underwent a second autologous stem cell transplant vs those treated with conventional chemotherapy for relapsed MM. The studies showed a lower relapse-associated mortality of 68% vs 78% for conventional chemotherapy, and improved OS at 32% vs 22% at 4 years. They suggest that carefully selected patients may achieve durable complete or partial remission from a second transplant. Stem cell cryopreservation early in the course of disease is another option for a patient who is relapsing. Patients may elect to collect stem cells and delay transplant until later.

Clinicians treating relapsed/refractory MM have many options. With several FDA-approved drugs for MM, some approved in the last few years, plus dozens of combinations, it is difficult for oncologists to keep up with new evidence. The 2017 NCCN guidelines2 include 15 preferred regimens for previously treated MM patients, nine of the recommendations with uniform consensus for appropriateness (category 1). Most of them are to be used under specified conditions. The NCCN offers another 13 regimens to consider as well. The therapies are not differentiated for second-, third- or fourth-line treatment but depend on which treatments were previously used by the patient.

Some other organizations have also provided guidance for therapy decisions for relapsed patients. The Mayo Clinic’s mSMART (Stratification for Multiple and Risk-adapted Therapy) has its own 2017 relapse treatment recommendations (see mSMART Algorithm for First Relapse of Multiple Myeloma and mSMART Algorithm for Second and Subsequent Relapses of Multiple Myeloma).6


Dr Malek said his cancer center uses evidence-based software decision support tools for MM therapy, and his program developed a center-wide evidence-based treatment algorithm. However, he cautioned that clinical pathways are not standardized nationally and are a moving target as new treatment options continue to become available. For relapsed patients, the standard of care is individualized therapy, which is difficult to determine. Due to the rapidly changing myeloma landscape, especially in the last few years, gaps in knowledge include the role of drug combinations, which combinations to use, and how many drugs to include in a combination, as well as the role of retreatment with the newest agents including monoclonal antibodies and histone deacetylase inhibitors.

While the NCCN and mSMART guidelines are comprehensive and offer great options, it can be especially difficult for physicians in mixed oncology practices to determine the best MM treatments. Given that MM is only 1% of all diagnosed cancers, mixed oncology practices may only treat a handful of MM patients. It is difficult for physicians to stay on top of the treatment data, especially because it is complex and changing rapidly. It is recommended that patients with MM should be seen early at a center with clinicians experienced in the care of the disease who can share their knowledge for the care of the specific patient in collaboration with the community oncologist.

When getting referrals of pretreated patients from community oncologists, it is challenging for academic clinicians to determine the best course going forward. “We know we need to be strong out of the gate,” said Dr Gasparetto. Some patients may be disadvantaged in their early treatment, receiving two agents instead of three or they may not have gotten the optimal dose due to difficulty with administration or modified drug regimens. In addition, “there’s misunderstanding of toxicity and what a patient can tolerate. You don’t know if a patient isn’t responding because they’re not receiving the full dose or it’s refractory,” Dr Gasparetto said. It is important to modify regimens as outlined in the clinical trial designs that reported those regimens in order to get the optimal benefit from them.

Clinicians want to find the best combinations to allow patients to remain on the same therapy for the longest possible time, so as not to deplete treatment options too early. This includes careful dose modifications rather than outright discontinuation of a regimen at the onset of adverse events. Dr Gasparetto said she has seen some patients run out of options because the community oncologist used them all too quickly. “Choosing the second line is very important, not only because you need to choose the best option to control the myeloma, but also to think about the future, what you’ll do next to control progression,” she said. “How you choose this therapy is very important because every drug will have a lifetime. If you choose the drugs all at once, you won’t have anything left.”


Economic Burden of Multiple Myeloma

With an aging population, from 2010 to 2030, there will be a 57% increase in the number of patients living with myeloma.12 A 2017 study published in Leukemia13 showed that the percentage of MM patients using novel therapeutics increased from 8.7% in 2000 to 61.3% in 2014. In a 2017 Journal of Clinical Oncology study,14 patients with MM were the highest percentage of patients taking targeted oral anticancer medications between 2010 and 2012 (26% of MM patients in 2012). That just includes lenalidomide and thalidomide, not ixazomib, which was approved in 2015.14

In addition to more diagnoses, patients are living longer due to more effective treatments. Patients diagnosed after 2010 had better survival outcomes and higher rates of novel therapy use than those diagnosed previously. The study found that the proportion of those diagnosed in 2012 with a 2-year survival rate was 1.25 times higher than those diagnosed in 2006. While the total costs for MM health care services increased, researchers found that drug costs remained fairly stable between 2009 and 2014.13 Cost increases are due to combinations of highly expensive agents, continuous treatment with maintenance, and improved survival leading to longer lifespans.15

Although treatments for MM can be costly, one study showed that direct cost to patients associated with oral drugs for MM can be significantly reduced through financial assistance.16 In a retrospective study, pharmacy claims were analyzed for patients with MM who received thalidomide, lenalidomide, or pomalidomide from a large specialty pharmacy in the United States between January 1, 2011, and December 31, 2013. Average direct cost to patients, per prescription, for any of these three agents was $227.23 prior to financial assistance and $80.11 after financial assistance, representing an average patient savings of $147.14 per prescription. With financial assistance, the percentage of all prescriptions with an average direct cost to patients of $50 or less increased from 57.6% to 86.2%.16

A different Journal of Clinical Oncology17 study showed that Medicare beneficiaries with MM who did not receive a low-income subsidy during 2007-2011 faced a substantial financial difficulty in accessing oral cancer medications. The median out-of-pocket cost for first IMiD prescriptions was $3178 for those without the subsidy, and the median out-of-pocket first year cost of IMiD therapy was $5623 for the same group. However, the patients treated with IMiDs had significantly fewer hospitalizations and emergency room visits compared with those who received only bortezomib. One-year survival rates and cumulative Medicare costs were the same with or without the IMiD.

The development of treatment guidelines and algorithms are a step in the right direction, said Dr Callander, but better data is needed to understand the relative value of different treatment options. “We’re operating to a certain extent without the best information we can have to say one treatment is more cost effective than another,” she said.

One study identified 2551 elderly Medicare patients with advanced MM from 2000 to 2009 who initiated novel agent-based therapy (bortezomib, lenalidomide, or thalidomide) or chemotherapy from the Surveillance, Epidemiology, and End Results-Medicare database.1 Twenty-month cost of care and OS related to MM were compared between patients treated with novel agent-based therapy and patients treated with chemotherapy. Overall, average 12-month MM total costs were 2.03 times higher for novel agent-based therapy ($144,665) than for chemotherapy ($47,750). Antimyeloma pharmacy costs represented about 31% ($45,095) of total MM costs for patients treated with novel agents but represented about 19% ($8921) of total MM costs for patients treated with chemotherapy. At the same time, 12-month survival rates increased significantly among patients receiving novel agents compared with patients receiving chemotherapy.1

A study in American Drug and Health Benefits18 estimated the annual costs—including administration, prophylaxis, adverse event monitoring, and adverse event treatment—for 7 common relapsed MM treatment regimens. The study found that total cost was highest for regimens that included lenalidomide (range: $126,000-$256,000), whereas treatments including bortezomib plus dexamethasone and the combination of panobinostat, bortezomib, and dexamethasone were less than $125,000 per patient (bortezomib plus dexamethasone was $90,616). While such analyses provide cost estimates, a balance between the cost and benefit from a regimen weighed with the adverse event profile and quality of life impact is very difficult discern for absolutely all regimens available.

These findings were contradicted by another retrospective study19 using 2006-2013 claims data from a large US database, which compared average patient monthly direct medical and pharmacy costs for patients who did not receive stem cell transplants. These patients received lenalidomide- or bortezomib-based treatment. The study tracked costs from treatment initiation to progression and initiation of second-line treatment, using time to next therapy (TTNT) to show progression. The study included 2843 newly diagnosed patients and found that total monthly cost for newly diagnosed patients was $15,734 initially, declining to $5082 at 18+ months after treatment. When second-line therapy was initiated, the total monthly costs were $13,876, declining to $6446 after 18 months. Patients on lenalidomide-based treatment had longer TTNT and longer periods of below-average costs compared with the bortezomib group. While treatment costs for both medications was similar, the lenalidomide group had mean monthly total costs at least $3200 lower than total costs for patients who received bortezomib as initial treatment. Cumulatively, that resulted in $120,000 in lower costs for lenalidomide patients.

The costs of adding the novel therapeutic panobinostat to the bortezomib and dexamethasone combination was published in a 2016 study.20 Panobinostat, the first histone deacetylase inhibitor, was approved for MM treatment by the FDA in 2015. The study estimated the economic impact of adding it to US health plan formulary as part of that treatment option for relapsed/refractory MM patients previously treated with a proteasome inhibitor and an IMiD. The study found that it was cost neutral and potentially cost saving compared with some newer treatments; commercial or Medicare plan costs increased by less than $0.01 per member per month, while PFS increased by 4 months compared with placebo.20 Such analyses are helpful but there are variations in how the cost-effectiveness analyses are conducted, making it difficult to obtain universal recommendation guidelines based on such analyses.


The Future of Relapsed/Refractory Multiple Myeloma Treatment

While the triplet therapy is standard of care for first line, Dr Malek said, quadruplet therapy will likely be used in the first-line setting as well, pending FDA approval. In addition, patients and clinicians are hopeful about the newest intervention, CAR-T therapy, which is currently in clinical trials for MM. “Most experts are thinking we’ll be moving that up in line,” Dr Callander said. But it’s not yet determined how it will fit into the treatment paradigm and whether it will be a substitute for autologous SCT.

In general, treatment of relapsed MM will continue pose a challenge to clinical pathway decision-makers, as it will continue to be important to individualize the treatment to the patient. In addition to treating patients based on disease aggressiveness, the patient’s years in remission, past experience with toxicity, and reaction to various agents, in the future clinicians may also base treatment on the cancer cell’s genetic mutation type, for which data is fast emerging. “It’s not so easy to narrow it down. It’s becoming more personalized medicine,” said Dr Gasparetto. 



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17. Olszewski A, Dusetzina S, Eaton C, Davidoff AJ, Trivedi AN. Subsidies for oral chemotherapy and use of immunomodulatory drugs among Medicare beneficiaries with myeloma [published online May 25, 2017]. J Clin Oncol. doi:10.1200/JCO.2017.72.2447.

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20. Bloudek L, Roy A, Kish JK, et al. Estimating the economic impact of adding panobinostat to the US formulary for relapsed and/or refractory multiple myeloma: a budget impact and cost-benefit model. J Manag Care Spec Pharm. 2016;22(8):991-1002.


Writing support for this report was provided by Deborah Abrams Kaplan. We thank Natalie S Callander, MD (University of Wisconsin School of Medicine and Public Health, Madison WI), Ehsan Malek, MD (UH Cleveland Medical Center, Cleveland, OH), and Cristina Gasparetto, MD (Duke University School of Medicine, Durham, NC) for contributing their insights and perspectives to this report. Dr Callander has no financial interests to disclose. Dr Malek has received speaker honoraria, research grants, and/or travel grants from Takeda, Celgene, Amgen, and Sanofi. Dr Gasparetto has received research grants, travel grants, and/or payment for advisory board membership from Celgene, Takeda, and Janssen. We also thank David Dingli, MD, PhD (Mayo Clinic, Rochester, MN) and Shaji Kumar, MD (Mayo Clinic, Rochester, MN) for reviewing this report.

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