Clinical Pathways to Address the Challenges of Treatment Resistance and Relapse in Multiple Myeloma: Evidence-Based Treatment Decision-Making and Clinical Pathways


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.”



Read the Full Special Report: Clinical Pathways to Address the Challenges of Treatment Resistance and Relapse in Multiple Myeloma