Pereira Offers View on Maintenance Therapy for Patients with Multiple Myeloma

Denise. L. Pereira, MD

Denise. L. Pereira, MD

Denise. L. Pereira, MD, recently shared the treatment considerations and decisions she makes when treating patients with multiple myeloma. Pereira, assistant professor of clinical medicine, University of Miami, Sylvester Comprehensive Cancer Center, Miami, Florida, explained her treatment decisions based on 2 case scenarios during aTargeted Oncologylive case-based peer perspectives presentation.

Case 1

July 2011

• 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
• 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. What do you think of using lenalidomide, carfilzomib, and dexamethasone (KRd) instead?

Pereira:We know that triplets are better than doublets. The combination of a proteasome inhibitor and an immunomodulatory drug (IMiD) is linked to very good response rates with an acceptable toxicity profile. So, in general, within the United States, we are more likely to use RVD outside a clinical trial. This patient has no impaired kidney function or anything else that would make me lean toward using bortezomib, cyclophosphamide, and dexamethasone (CyBorD) instead.

I would use RVD, as was done in this case, to establish a very high response rate. There are other people who would suggest KRd as an even better option, and there is an ongoing ECOG trial to test this hypothesis with KRd as the experimental arm. I don’t think that it is close to the first-line yet because RVD is more established; however, KRd is far from a bad regimen.

TARGETED ONCOLOGY: What is the role of transplant as part of frontline therapy for myeloma?

Pereira:As a transplant physician, I must be a believer. I would transplant any patient who I think can safely go through the procedure. I don’t really have an age limit. I offer potential transplant-eligible candidates this option because I believe it has the potential to further deepen the response to therapy, and better responses are associated with better outcomes.

TARGETED ONCOLOGY: Which patients are typically candidates for maintenance therapy?

Pereira:I think all patients are candidates for maintenance therapy because maintenance therapy has been associated with an improvement in survival. There are multiple randomized trials that show progression-free survival (PFS) definitely improves with the use of maintenance therapy. Regarding overall survival (OS), there are some trials that are positive as well as a meta-analyses (when you collect all the trials together to pull the data and results into 1 study). In this case, PFS was better and OS was also better.

It is standard to use lenalidomide at a dose of 10 mg daily, with the option to switch to 21 out of 28 days. I use bortezomib in very specific circumstances. High-risk patients are the patient population in which I consider bortezomib and I use it every 2 weeks. Maintenance therapy should be given until progression or intolerable adverse effects.

TARGETED ONCOLOGY: What is the typical follow-up for this type of patient? Does minimal residual disease (MRD) testing play a role in this follow-up?

Pereira:This patient must be seen every 3 months and should have their blood checked every month.

I am not using MRD testing today, but I think more than anything else, MRD testing is a signal of improvement that can effectively gauge the effectiveness of a regimen. MRD is very important in research and clinical trials, but in the clinical setting I don’t believe that we are ready yet to move toward its use. I have not yet established it in my patients’ day-to-day care.

TARGETED ONCOLOGY: What is the potential impact of these data?

Pereira:The issue more than anything else with this trial is that bortezomib, melphalan, and prednisone (VMP) is not considered standard in the United States. The trial is important for proof of concept, but I don’t think that it will immediately change whether or not physicians will prescribe it in the United States. The proof of concept is that the addition of daratumumab would improve the results of the triplet.

TARGETED ONCOLOGY: Are these results strong enough to potentially replace transplant-eligible patients?

Pereira:No, the regimen has melphalan. Nobody will use melphalan on a transplant-eligible patient that early. Melphalan is toxic to the stem cells and is associated with increased risk of myelodysplasia. It is a drug that, aside from conditioning regimens for transplant on transplant-eligible patients, should not be used for transplant-eligible patients.

I would also add that being transplant-eligible is a moving target here in the United States. This means that what was not considered transplant-eligible 5 years ago is transplant-eligible nowadays. The melphalan makes it very hard to collect the stem cells for patients who could potentially be transplant-eligible at some point in their illness.

TARGETED ONCOLOGY: If daratumumab becomes available, how would you select a patient for this therapy versus other available frontline options?

Pereira:In the United States, I think you will be seeing people use this option in transplant-eligible and transplant-ineligible patients. However, the lack of familiarity with VMP is a significant barrier to the adoption of this regimen.

August 2016

• On routine follow-up, the patient reported having mild fatigue, but continued to work full-time; she had grade 1 neuropathy
  • M-protein, 1.4 g/dL
  • Light chain levels continued to rise
  • Hemoglobin (Hb), 10.3 g/dL
  • Creatinine, 1.3 mg/dL

TARGETED ONCOLOGY: How do you define progression in myeloma?

I think there are 2 definitions. One is biochemical relapse, when you have some changes in the bloodwork when you can see that the protein studies are getting worse and the patient remains symptomatic. The other is clinical relapse, where the patient has anemia, new lesions, change in calcium levels, or a rise or fall of creatinine. That to me would be a clinical relapse.

TARGETED ONCOLOGY: When do you start therapy for relapsed disease?

Pereira:I start therapy when they have clinical relapse, and only in some cases when they have biochemical relapse.

TARGETED ONCOLOGY: What are the options for treatment of a patient who is largely asymptomatic with good performance status but who is developing biochemical relapse on lenalidomide?

Pereira:I would tend to make minor changes. If they were on a low dose of lenalidomide, I would add steroids to the regimen. The other option is to add elotuzumab to a patient who is on low-dose lenalidomide and is starting to have biochemical relapse. There are data with the combination and it is a well-tolerated regimen with lenalidomide and dexamethasone.

This case, however, is not a case of a biochemical relapse. This patient has a drop of hemoglobin levels and a worsening of her creatinine, which does not qualify as biochemical relapse. It would be a biochemical relapse only if there were changes in the protein studies, without any organ damage. [Therefore, this would be considered a clinical relapse.]

TARGETED ONCOLOGY: How does tolerance to previous therapy affect your choice?

Pereira:If I have a patient who is older and has poor tolerance to adverse effects, I tend to keep a lower profile. I tend not to give a very aggressive regimen. But with a younger and fit patient, I tend to treat with a triplet again.

Case 2

December 2010

• A 54-year-old Caucasian male presented with anemia
• Bone marrow biopsy showed 40% plasma cells
• Florescence in situ hybridization t(14:20), del 13, del 17p (80% of the myeloma cells had a 17p deletion)

TARGETED ONCOLOGY: What is the prognosis of this patient?

Pereira:This patient has a worse prognosis than the majority of patients with myeloma because he has a combination of high-risk cytogenetics. Specifically, the deletion of 17p is associated with mostly poor prognoses.

TARGETED ONCOLOGY: What are the treatment choices for this patient?

Pereira:I would usually use [as induction therapy] something that has, in the backbone, a proteasome inhibitor. Most of us would agree that you should also use an IMiD. I would say that most of us at this point will be using RVD.

I would consolidate this patient with an autologous stem cell transplant. I don’t tend to use consolidation post transplant because the most recent trial—the [Blood and Marrow Transplant Clinical Trials Network’s] StaMINA trial, which has not yet been published but has been presented—shows that patients in general, not specifically high-risk patients, seem to have no benefit with consolidation. I would have to wait for the subset analysis to come back to see if there are any specific benefits in the high-risk patient population. So far, I have not seen very convincing data on whether or not they should get chemotherapy consolidation after transplant, and I would not give it.

As for maintenance therapy, everyone should get it. This patient specifically should be treated with a proteasome inhibitor regimen, reusing bortezomib every 2 weeks plus or minus lenalidomide. The proteasome inhibitor seems to be a better class of drugs when treating high-risk patients. Lenalidomide is the 1 drug that has the majority of data in the maintenance therapy setting.

TARGETED ONCOLOGY: What factors do you consider when deciding on treatment?

Pereira:Age, performance status, and the ability to comply with such a demanding maintenance schedule. Even though it is every 2 weeks, it still requires the patient to come to the medical center. They have to have a willingness to do this kind of thing for a long period of time.

The patient was treated with KRd for 6 cycles, followed by autologous stem cell transplant (MEL 200), then 6 cycles of consolidation with KRd, and then transitioned to maintenance with KRd for another 6 months. This was followed by lenalidomide maintenance

TARGETED ONCOLOGY: Do you think daratumumab could be added to this regimen in the frontline setting?

Pereira:Absolutely; it is a very appealing concept. Although the data are not fully there yet with KRd, it is very appealing. I have seen some of the data of the small study that was done in the first line, which was not isolated for high-risk patients, but I think the results are very interesting.

TARGETED ONCOLOGY: What would you give the patient if he again develops symptomatic relapse?

Pereira:In this case, I would say for sure a regimen that would have daratumumab, assuming that the patient did not get it in the first line. I would certainly give the patient a daratumumab-containing regimen, probably daratumumab, carfilzomib (Kyprolis), and pomalidomide (Pomalyst), plus dexamethasone.

Reference:

Stadtmauer EA, Pasquini MC, Blackwell B, et al. Comparison of autologous hematopoietic cell transplant (autoHCT), bortezomib, lenalidomide (len) and dexamethasone (RVD) consolidation with len maintenance (ACM), tandem autoHCT with len maintenance (TAM), and autoHCT with len maintenance (AM) for upfront treatment of patients with multiple myeloma (MM): primary results from the randomized phase III trial of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0702 — StaMINA Trial). Presented at: 58th American Society of Hematology Annual Meeting & Exposition; December 3-6, 2016; San Diego, CA. Abstract LBA-1.