Keith Stewart, MB, ChB, discusses treatment decisions centered around the care of patients with multiple myeloma, including the roles of autologous stem cell transplant and MRD testing.
Keith Stewart, MB, ChB
Keith Stewart, MB, ChB, recently discussed treatment decisions centered around the care of patients with multiple myeloma, including the roles of autologous stem cell transplant and MRD testing. Stewart, Vasek and Anna Maria Polak Professorship in Cancer Research, Dean for Research, Mayo Clinic, explained his treatment decisions in 2 case scenarios during aTargeted Oncologylive case-based peer perspectives dinner.
A 61-year-old Caucasian female was diagnosed with stage II multiple myeloma. Genetic testing showed t(4:16). At the time, she was treated with lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVD) induction therapy followed by autologous stem cell transplantation (ASCT). She achieved a near complete remission with RVD and transplant. Based on her high-risk cytogenetics, the patient was placed on lenalidomide maintenance therapy.
Targeted Oncology: Discuss the rationale for the choice of upfront therapy in this patient.
Stewart:This is a relatively young patient with high-risk cytogenetics. Recent trials have supported the use of triplet therapies. In particular, a clinical trial from SWOG, which demonstrated an overall survival (OS) advantage to patients receiving the combination of lenalidomide, bortezomib, and dexamethasone when compared to lenalidomide/dexamethasone alone. The trial supported using the 3-drug combination in newly diagnosed patients. Also, recent studies from the IFM (Intergroupe Francophone du Myélome) in France have supported the ongoing use of ASCT to prolong progression-free survival (PFS).
Targeted Oncology: What is the role of transplant as part of frontline therapy for myeloma?
Stewart:ASCT is still recommended as the frontline therapy for patients who are physically well enough to undergo this procedure. Generally, that means healthy patients up to the age of 17 to 75 in the United States. Recent studies from Italy and France have confirmed that ASCT, even in the new drug era, continues to confer more frequent response, deeper response, and longer PFS, although, at this time, most studies have not been ongoing for long enough to demonstrate OS advantages.
Targeted Oncology: Which patients are typically candidates for maintenance therapy?
Stewart:A recent meta-analysis of a number of phase III trials, [which was] confirmed by a very large study from the Medical Research Council (MRC) in the United Kingdom, has reinforced the role of lenalidomide maintenance therapy in patients with multiple myeloma post-ASCT. Thus, essentially, all patients are candidates for maintenance therapy. For patients who are intolerant of lenalidomide or those who have high-risk disease, such as the patient here, bortezomib can be added, typically subcutaneously every 2 weeks as part of the maintenance therapy regimen.
Targeted Oncology: What duration do you recommend?
Stewart:Most studies have used lenalidomide until progression, however, there is not a real consensus on the duration of maintenance therapy post-transplant. In my own practice, I continue maintenance until the patient becomes MRD-negative, and at that point, if that is confirmed at a second follow-up visit, lenalidomide maintenance can be discontinued. In practice, many patients are unable to tolerate lenalidomide for more than a couple of years, and there is some concern about long-term use contributing to second malignancies, so generally speaking, by 2 to 3 years post-transplant, I am inclined to try and stop the treatment, although many of my colleagues would continue until progression.
Targeted Oncology: What is the typical follow-up for this type of patient?
Stewart:Generally, post-transplant, patients are seen at least every 3 months while they are on active therapy. In the early months of therapy before side effect management, seeing them more frequently may be recommended.
Targeted Oncology: What are your thoughts on MRD testing?
Stewart:MRD testing can be performed using full cytometry or molecular next-generation sequencing. My preference is to use next-generation sequencing, which seems to be more reproducible across centers and more sensitive. Many studies have now demonstrated that obtaining MRD negativity is optimal in the care of myeloma patients and correlates with longer PFS in numerous studies already published.
Targeted Oncology: Is your institution equipped for MRD testing?
Stewart:Yes, we are already performing MRD testing, although we are still learning much about the test, where it is best applied, and whether it should be used for escalation or de-escalation of therapy. I think the era of performing MRD testing is already upon us.
On routine follow-up, the patient reports having mild fatigue, but continues to work full-time. She has grade 1 neuropathy. Her M protein was 1.4 g/dL. Her light-chain levels continued to rise. Her hemoglobin was 10.3 g/dL and her creatinine was 1.3 mg/dL.
Targeted Oncology: How do you define progression in myeloma?
Stewart:Progression is generally biochemical in this situation. A rise in the M protein of .5 grams per deciliter or the free light chain by over 10, or progressive anemia, or bone lesions would all qualify as progression.
Targeted Oncology: When do you start therapy for relapsed disease?
Stewart:Although in the recent past we would generally wait for patients to become symptomatic, I think that era has passed. Today, we are much more inclined to start treatment at the first signs of relapse even when it's only the biochemical stage to avoid risk of organ damage, and because many of the agents we have available now are so effective.
Targeted Oncology: What are the options for treatment of a patient who is largely asymptomatic, with good performance status, and developing biochemical relapse on lenalidomide?
Stewart:There are many options for a patient like this. We have had 5 new drugs approved in the last few years and therapy needs to be tailored specifically to each patient. In a young patient like this with high-risk disease, however, it appears that triple therapies continue to be preferred. Since this patient is progressing on lenalidomide, we would probably stop that drug and switch to a different immune modulator, so it's pomalidomide (Pomalyst) with dexamethasone, but we would definitely add a third drug, either carfilzomib (Kyprolis) or daratumumab (Darzalex). Another alternative would be to use bortezomib in combination with pomalidomide and dexamethasone.
Targeted Oncology: How did his tolerance to previous therapy affect your choice?
Stewart:This is a critical point that speaks to the need to personalize therapy for each patient. Clearly, this patient had some mild neuropathy, which would lead us away from bortezomib. He did seem to tolerate immune-modulating drugs quite well, so escalating lenalidomide to pomalidomide and adding either the proteasome inhibitor carfilzomib or the monoclonal antibody daratumumab would be very appropriate. If convenience is an issue, then drugs such as ixazomib or obinutuzumab (Gazyva) could also be considered.
A 77-year-old African American male was diagnosed 24 months ago with stage III multiple myeloma and was not eligible for transplant, based on his level of frailty. His cytogenetics were classified as intermediate risk. He received treatment with lenalidomide (15 mg daily) and low-dose dexamethasone.
The patient’s Hb was 11.4 g/dL. M protein rose from 0.6 g/dL to 1.2 g/dL to 1.5 g/dL. He reported feeling tired but continued to do well functionally.
Targeted Oncology: Do you continue the patient on lenalidomide or switch to another therapy?
Stewart:This gentleman received lenalidomide/dexamethasone at diagnosis and is now progressing on this regimen. Generally speaking, we have not had great success in escalating the doses and would be likely to switch therapy in this case. We could use pomalidomide, which is more potent than lenalidomide, as part of our treatment options.
Lenalidomide was increased to 25 mg daily.
The patient was hospitalized 2 months ago for pneumonia. He now complained of increasing back pain, fatigue, and weakness. Laboratory findings showed his M protein was 2.1 g/dL, his serum beta-2-microglobulin was 6.2 mg/L, and his albumin was 2.1 g/dL. He had a creatinine clearance of 32 ml/min. A skeletal survey showed a new compression fracture in the L4/L5 vertebrae. Bone marrow biopsy showed 30% involvement by abnormal appearing plasma cells, confirmed by a CD138+ IHC stain. His ECOG performance status was 2.
Targeted Oncology: What are the options for this patient when symptomatic disease progression occurs?
Stewart:Again, there are many options for this patient. He has not received a proteasome inhibitor. The use of bortezomib in combination with dexamethasone and likely a third drug like cyclophosphamide (Cytoxan), or pomalidomide would be 1 option. Ixazomib (Ninlaro) in combination with cyclophosphamide or pomalidomide would also be attractive since this patient prefers oral-based treatments and less visits to the hospital. At this stage, and with the comorbidity he's had, a final option would be the use of daratumumab in combination with bortezomib. I think carfilzomib would likely be saved for later, given the comorbidities he has.
Targeted Oncology: What factors do you consider when choosing the next therapy for this patient?
Stewart:His tolerance of prior therapy, the duration of remission of prior therapy, distance from the hospital, comorbidities, and frailty are all things to consider when choosing therapy for this patient, which needs to be highly personalized in today's environment.
Targeted Oncology: What supportive care measures are necessary for this patient?