C. Ola Landgren, MD, PhD, recently shared the treatment considerations and decisions he makes when treating patients with multiple myeloma. Landgren, chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center, in New York, explained his treatment decisions based on 2 case scenarios during a <em>Targeted Oncology</em> live case-based peer perspectives dinner.
C. Ola Landgren, MD, PhD
C. Ola Landgren, MD, PhD, recently shared the treatment considerations and decisions he makes when treating patients with multiple myeloma. Landgren, chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center, in New York, explained his treatment decisions based on 2 case scenarios during aTargeted Oncologylive case-based peer perspectives dinner.
A 61-year-old Caucasian female was diagnosed with stage II multiple myeloma. Fluorescence in situ hybridization (FISH) testing showed a t(4;14) translocation. At the time, she was treated with lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVD) induction therapy, followed by autologous stem cell transplantation. She achieved a complete remission with RVD and transplant. The patient was placed on lenalidomide maintenance therapy.
TARGETED ONCOLOGY: Discuss the rationale for the choice of upfront therapy in this patient.
Landgren:This is a relatively young individual who is diagnosed with multiple myeloma. FISH testing [was] conducted [which showed] a translocation. Because it is a relatively young patient who has multiple myeloma, and she has this 4;14 translocation, I think most doctors would agree to use a proteasome inhibitor in combination with an immunomodulatory drug (IMiD) and a steroid. In many centers, this 4;14 translocation would be viewed as a high-risk feature. Because the patient is younger, the patient is offered combination therapy followed by transplant, because that has been one of the standard approaches for many years.
Then the patient is offered maintenance therapy with lenalidomide. There is data showing that that is associated with longer progression-free survival [PFS] and overall survival [OS] rates. I think all the literature would support the use of this treatment.
TARGETED ONCOLOGY: What is the role of transplant as part of frontline therapy for myeloma?
Landgren:The standard of care for many years has been to offer patients the use of melphalan [Alkeran], but also as the therapies have become better, a lot of patients have asked, and a lot of doctors have asked, whether every patient needs to do a transplantation or if they can collect the stem cells and keep them for later. That is an area of controversy.
A lot of patients in the United States are increasingly asking that question. There is a recent paper in theNew England Journal of Medicinethat was published in 2017 showing there is no survival benefit with the follow-up time that was presented in that paper to use transplant versus to just collect the cells and go right to maintenance. They have also updated information that will be presented at the ASH Annual Meeting this year showing that if you have molecular minimal residual disease [MRD], which is more sensitive, so it rules out one cell in a million instead of all the flow cytometry, that’s only one cell in a 100,000. If you reach that one cell in a million [that’s] negative, which happens not in every patient but if the patient does that, then the transplant seems to not even change and add any PFS time either. So, these are areas that are constantly under investigation by many studies.
TARGETED ONCOLOGY: Which patients are typically candidates for maintenance therapy? What are the options? What duration do you recommend?
Landgren:Most doctors in the United States would offer any patient who is treated with combination therapy with or without transplantation to go to maintenance, because there is data suggesting that continued therapy prevents progression and it adds survival.
One option [for maintenance therapy] would be lenalidomide. Lenalidomide is most commonly used, and that’s where the bulk of the current data is. That would be viewed as the standard of care. Other options would be to use other drugs such as a proteasome inhibitor like bortezomib, or potentially ixazomib [Ninlaro], but the data for that is less strong and it is not as mature yet. There are other things also in development, presumably, I would think that probably even monoclonal antibodies such as daratumumab [Darzalex] could become a maintenance drug. There are more studies needed.
For duration, there is no known fixed time window that is the right window to recommend. The studies show that the patients who stay on continuously demonstrate added PFS benefits. There are some studies, mostly outside of the United States, like European or Asian studies, where they are only funded for a year or 2. The literature has different kind of flavors of information. Typically, in the United States, the recommendation is to have continued treatment until progression or unacceptable toxicity.
TARGETED ONCOLOGY: What is the typical follow-up for this type of patient?
Landgren:The typical follow-up for the patient would be to do labs. In our practice, we would do labs every 3 months. Some centers do more often, they even do up to once a month. In our practice, that is usually not needed, in particular for patients who have a deep response.
TARGETED ONCOLOGY: Are you using MRD testing today? How do you use it?
Landgren:That is typically not implemented at most centers yet. We do have that at our center. We offer that for every patient and we have it as part of our standard of care, but most centers don’t have that yet.
The literature shows that the patients who are MRD-negative have the longest PFS and OS. We have implemented molecular sequencing-based MRD in our clinical practice. We also have old technology with flow cytometry that we have improved as much as possible. We do both the flow cytometry and more modern molecular sequencing. But most centers don’t have that, and usually it is not yet available in private practices, but that will probably change in the coming year or 2.
On routine follow-up, the patient reported having mild fatigue, but continued to work full time; she had grade 1 neuropathy. M-protein was 1.4 g/dL. Light chain levels continued to rise. Hb, 10.3 g/dL. Creatinine, 1.3 mg/dL.
TARGETED ONCOLOGY: How do you define progression in myeloma?
Landgren:There are criteria for progression based on the proteins. If the M-spike goes up 0.5 g/dL or more and the increment is 25%, that would be viewed as a progression event by clinical trial criteria. Also, a patient with light chain myeloma, only if the light chains were to go up 25% from the lowest point, that would also be viewed as such.
There could also be clinical criteria. If your patient has a new plasmacytoma, if your patient develops symptoms, these are other clinical features that could also be viewed. In the non-clinical trial setting, it is more of a clinical assessment, but of course clinicians would look at these things.
What we see here is that the patient initially had an M-spike and then it says that she achieved a complete remission. When we see that the M-spike is 1.4 g/dL, the progression criteria are clearly met.
TARGETED ONCOLOGY: When do you start therapy for relapsed disease?
Landgren:If the patient were to start developing symptoms, or if the labs start to drift off, that would be an indicator. There is no 1 number that’s defined as where you have to start treatment. However, the M-spike is going up this high and the patient is having symptoms. If the patient is having fatigue, I think that probably would not prompt the initiation of treatment.
TARGETED ONCOLOGY: What are the options for the treatment of a patient who is largely asymptomatic with a good performance status but who is developing biochemical relapse on lenalidomide?
Landgren:The patient initially was diagnosed in July 2011 and this [progression occurs] in August 2016. That is 5 years out. You probably could redo the same therapy that was done in the beginning, because it’s so long ago. That could be 1 option. You could also think of using carfilzomib [Kyprolis]-based therapy, and you could also think of using a monoclonal antibody, such as daratumumab. You can also switch from lenalidomide to pomalidomide [Pomalyst] instead of increasing the dose of lenalidomide to 25 mg.
A 77-year-old African American man was diagnosed 24 months ago with stage III multiple myeloma and was not eligible for transplant, based on his level of frailty. His cytogenetics showed hyperdiploid disease. He received treatment with lenalidomide (15 mg daily) and low-dose dexamethasone. After 9 cycles of therapy, the M-spike plateaued at 0.6 g/dL; therapy was continued.
Laboratory findings showed: hemoglobin, 11.4 g/dL; creatinine, 1.0 mg/dL, M-protein rose from 0.6/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?
Landgren:If you keep the same drug, you clearly cannot just do the same low dose. But, on the other hand, if you increase the dose, maybe the patient cannot tolerate it or is on the older side of the spectrum. So the question is then, would it be proper to do some other therapy? The people in the group felt it was the right thing to do. People said would it be evident to increase the dose. There are some old European studies that have done that in different settings, but in clinical practice it’s usually not very successful.
Lenalidomide was increased to 25 mg daily by the local physician.
The patient was hospitalized for 2 months previously for pneumonia. The patient complained of increasing back pain, fatigue, and weakness. Laboratory findings showed: M-protein, 2.1 g/dL; serum beta-2-microglubin, 6.2 mg/L; albumin, 2.1 g/dL; creatinine clearance, 32 mL/min. Skeletal survey showed new compression fracture in the vertebrae. Bone marrow biopsy showed 30% involvement by abnormal appearing plasma cells, confirmed by CD138+ immunohistochemistry stain. His ECOG performance status was 2.
TARGETED ONCOLOGY: What are the options for this patient when symptomatic disease progression occurs?
Landgren:A proteasome inhibitor could be 1 option. Some people thought to use a monoclonal antibody, such as daratumumab. Those are the key options.
TARGETED ONCOLOGY: What factors do you consider when choosing the next therapy for this patient?
Landgren:If the patient had neuropathy, you would not do a proteasome inhibitor. It could be done, but the patient is older and it may be a little bit cumbersome to do that for an older patient. Daratumumab, on the other hand, is a good option. It is easier on a relative scale.
The patient was treated with daratumumab, weekly subcutaneous bortezomib, and dexamethasone.