Orlowski on the Role of Maintenance Therapy in Multiple Myeloma

Robert Z. Orlowski, MD, PhD

Robert Z. Orlowski, MD, PhD

Robert Z. Orlowski, MD, PhD, recently discussed 2 cases of patients with multiple myeloma, and the treatment considerations and decisions he would make when treating these patients. Orlowski, chairman, ad interim, director of myeloma, and professor of medicine, The University of Texas MD Anderson Cancer Center, discussed these cases during aTargeted Oncologylive case-based peer perspectives dinner.

Case 1

July 2011

A 61-year-old Caucasian woman was diagnosed with stage III multiple myeloma. Genetic testing showed t(4:14). She was treated with lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVD) induction therapy, followed by autologous stem cell transplantation. 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:What is the rationale for the choice of upfront therapy in this patient?

Orlowski:She has been diagnosed with stage II multiple myeloma. We have to assume that she has symptomatic disease, which would be indicated with the presence of 1 or more of the following: hypercalcemia, renal insufficiency, anemia, bone lesions, or 60% or more involvement of the bone marrow, an involved to uninvolved free light chain ratio of 100 or more, or more than 1 focal MRI bone lesions. One or more of those would put the patient in a symptomatic category, and chemotherapy would be recommended for someone who has been diagnosed with symptomatic disease.

One of the most commonly accepted frontline regimens for younger patients such as this one, who would be eligible for stem cell transplant, would be RVD. The most recent data supporting that selection came from a randomized study that was led by SWOG, which is part of the National Clinical Trial Network (NCTN).¹In that study, it was a randomization between the previous standard of care, which was just lenalidomide and dexamethasone, whereas the experimental arm got RVD.

The 3-drug regimen had a higher response rate, progression-free survival (PFS), and overall survival (OS). That makes this the standard of care for all myeloma patients, and this patient in particular because she has t(4:14), which does put her at higher risk. There is a lot of literature supporting the use of proteasome inhibitors, particularly in high-risk patients. Although they don't completely negate the high-risk features, they do improve outcomes in high-risk patients.

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

Orlowski:The role of transplant has been used as a consolidation to achieve further cytoreduction after upfront induction chemotherapy. Multiple studies show that if you have transplant after induction chemotherapy, you have a better PFS and OS than if you do chemotherapy only. More recently, this was addressed by the IFM 2009 trial, where patients got RVD, and after 3 cycles they were randomized.²In 1 arm, patients got stem cell collection, then went on to stem cell transplantation, had some consolidation RVD afterwards, and then lenalidomide maintenance.

In the other arm, they also got stem cells collected, but they did not get the transplant early. Instead, they got more consolidation with RVD and then lenalidomide maintenance. The data were published earlier this year in theNew England Journal of Medicine,and what they showed was that the group that received the early stem cell transplant had a better PFS, which is not surprising, because they had more therapy.

At the 3- to 5-year follow-up point, there was no difference in OS. One thing in the analysis of that study that I found to be especially interesting was that of the minimal residual disease (MRD)-negative group. What was found is that if you were MRD-negative by flow cytometry after RVD without a transplant, you did just as well as patients who got into MRD-negativity only after RVD and a transplant. That suggests the possibility that if you have disease after induction, which is now MRD-negative, that [you could] collect stem cells and store them away for later use. Not doing a transplant with just maintenance would be reasonable, but we don't have a randomized study yet evaluating that possibility.

Also in this patient, because of the high-risk features, achieving MRD-negativity is very important. I think that a transplant, if the patient is not MRD-negative, would be very reasonable in this setting.

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

Orlowski:Most patients are considered candidates for maintenance after stem cell transplant, because even if you are MRD-negative after transplant, those patients can relapse. However, the risk of relapse is lower if you are MRD-negative than if you're MRD-positive. The standard of care for maintenance in the United States is lenalidomide, which has category 1 level recommendations, because of a study done by the CALGB, which is another branch of the NCTN. The study showed that lenalidomide provided a longer PFS compared to placebo, and also a longer OS as a maintenance after transplant.

As far as other options that can be considered, there are some data with bortezomib as a maintenance, which showed that it does provide a superior outcome. This was in a trial that compared bortezomib/doxorubicin (Adriamycin)/dexamethasone followed by transplant, followed by bortezomib maintenance in 1 arm versus thalidomide (Thalomid)/dexamethasone transplant and thalidomide maintenance in the other arm.

What was interesting, in reference to this patient, is that the high-risk patients on that trial benefitted particularly well from bortezomib maintenance. One could therefore argue that although this patient was placed on lenalidomide as a single-agent maintenance after transplant that perhaps a combination of lenalidomide and bortezomib would be more appropriate. In fact, there are data from Emory in a single-arm study where they did RVD as a consolidation and maintenance for high-risk patients and they were able to show that there were good outcomes. I would probably have suggested for this patient that lenalidomide with some kind of proteasome inhibitor would be appropriate. Bortezomib is the one for which we have the most data, but under some circumstances, one could also consider adding carfilzomib (Kyprolis) to lenalidomide, or even ixazomib (Ninlaro), which is more convenient because it is an oral agent.

At MD Anderson, we have a pilot study that we have been running with the combination of lenalidomide and ixazomib, and we found it to be well tolerated and a good maintenance therapy. Duration is also something that is often debated in post-transplant maintenance. In the United States, the CALGB trial treated patients until progression, barring any toxicity, and so the recommendation in this patient would be the same—to continue until there is evidence of progression.

TARGETED ONCOLOGY:What is the follow-up for this type of patient?

Orlowski:Follow-up for patients that are on maintenance depends a little bit on how they are doing from a toxicity perspective. For example, sometimes patients on long-term lenalidomide will have cytopenias or diarrhea that may mean that more frequent evaluations are needed. But at a minimum, we tend to recommend monthly visits with at least a complete blood cell count and some myeloma parameters to be checked, because on occasion you do have to adjust the dose or schedule of lenalidomide maintenance.

TARGETED ONCOLOGY:What are your thoughts on using MRD testing?

Orlowski:In terms of looking at MRD in the post-transplant setting, MRD is a prognostic tool, meaning that people who are MRD-negative will do better, they will stay in remission longer, and the OS seems to be longer if you are MRD-negative than if you're MRD-positive. From that perspective, I think it's worth doing just so that you have additional information that you can give to the patient.

What we don't yet know is whether we can change maintenance based on MRD results. For example, it may prove in the future that if you're MRD-negative, especially 2 or 3 years into maintenance, maybe if you're MRD-negative, it would be reasonable to stop maintenance or give it on an intermittent basis. Whereas if you are MRD-positive, then the recommendation would be either to continue maintenance or maybe even add other drugs to the maintenance regimen to convert MRD-positive to MRD-negative. But we don't yet have that information and so I don't use MRD testing yet to make those kind of decisions.

The one thing to mention on this patient is because of her higher-risk disease, there are data showing that MRD-negativity is an important endpoint for the high-risk patient, and I would definitely try to push a little bit harder in this patient to achieve MRD-negativity.

August 2016

On routine follow-up, the patient reported having mild fatigue but continues to work full-time; she had grade 1 neuropathy. M-protein was 1.4 g/dL. Her light chain levels continued to rise. Hemoglobin was 10.3 g/dL. Creatinine was 1.3 mg/dL.

TARGETED ONCOLOGY:How do you define progression in myeloma?

Orlowski:There are 2 categories of progression. One category is biochemical progression, and this generally means patients in whom there is a slow increase in the M protein, the free light chains in the serum, or in the Bence-Jones protein level in the urine, but the patient is still feeling fairly well. They don't have any new bone symptoms, anemia, hypercalcemia, or kidney issues, and then there is a clinical relapse or symptomatic relapse. Usually, when you see symptoms, that typically is in a patient where the numbers are going up more rapidly than in the patient who does not have symptoms. The reason it can be helpful to differentiate between them is that if you have an asymptomatic relapse which is going slowly, it may be enough to just tweak the maintenance regimen that they are on. For example, if they are on a low dose of lenalidomide, you could maybe increase the dose a little bit, you could think about adding dexamethasone, or ixazomib if they are not already on it, or maybe a monoclonal antibody. But if you have a clinical or symptomatic relapse, that usually is a situation where you need to be more aggressive, because if you're not, then the symptoms or potential end organ damage will only worsen.

Usually, in that kind of setting, what I try to do is switch to a 3-drug regimen, preferably with a combination to which the patient has not been exposed. For example, if this patient were on lenalidomide maintenance as a single agent, good options would be to do pomalidomide (Pomalyst) with daratumumab (Darzalex) and dexamethasone or pomalidomide with carfilzomib and dexamethasone. If the patient were on a combination maintenance like lenalidomide and bortezomib, then I think pomalidomide with daratumumab would be very reasonable and you could still think about carfilzomib with pomalidomide in that setting.

Case 2

December 2013

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 were classified as intermediate-risk. He received treatment with lenalidomide (15 mg daily) and low-dose dexamethasone.

December 2015

The patient’s hemoglobin was 11.4 g/dL and creatinine was 1.0 mg/dL. His 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:What evidence supports increasing the dose of lenalidomide?

Orlowski:Typically, what we find in the clinical setting is that once we start on lenalidomide and we plan to continue it for a longer period of time, there can be some cumulative toxicities. The most common ones are myelosuppression or diarrhea. In those cases, it can be challenging to increase the dose of lenalidomide, because usually you've reduced it because of 1 of these problems. But if there are patients who are on a low dose and all of a sudden they have a slow increase in their biochemical disease parameters, then trying to increase the dose of lenalidomide would be very reasonable. We don't have a lot of information about exactly how to do that and exactly how effective that is because these approaches have not been the subject of randomized studies. 

Lenalidomide was increased to 25 mg daily.

May 2016

The patient was hospitalized 2 months prior for pneumonia. Then he presented with increasing back pain, fatigue, and weakness. Laboratory findings showed M-protein was 2.1 g/dL. Serum beta-2-microglobulin was 6.2 mg/L, albumin was 2.1 g/dL, and he had 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 CD138-positive IHC stain. His ECOG performance status was 2.

TARGETED ONCOLOGY:What are the options for this patient when symptomatic disease progression occurs?

Orlowski:Part of this depends on whether the progression has been on or off lenalidomide, although it sounds like the progression occurs while the patient is on lenalidomide. In cases where patients are progressing both biochemically and symptomatically, and in this case that would be the new compression fracture, my preference is usually to try to switch drugs and introduce up to 3 novel drugs, if possible. Since this patient would be considered refractory to lenalidomide, I would prefer to go with a pomalidomide-based combination. Probably the best would be pomalidomide with daratumumab and dexamethasone. One could also consider pomalidomide with carfilzomib, although there is a little bit of concern in 75-year-olds and up about cardiac effects being a little bit more likely with carfilzomib. If this patient had a cardiac history, you might want to avoid carfilzomib. Another option would be to consider ixazomib, the oral proteasome inhibitor, with pomalidomide and dexamethasone. For right now, only daratumumab with pomalidomide/dexamethasone has FDA approval. The other combinations are very active, but don't yet have phase III data. In terms of trying to practice based on the highest level of evidence, I think pomalidomide with daratumumab would be the best way to go.

TARGETED ONCOLOGY:What factors do you consider when choosing the next therapy for this patient?

Orlowski:The factors to consider when deciding on the next therapy would include how the patient tolerated therapy before, what their goals for therapy are now, and other considerations. For example, how far away they live. The patient may decide that infusional daratumumab—which has to be done weekly for the first 8 weeks, and then every 2 weeks for the next 4 months, and then once a month, starting with month 7—that they are not able to travel back and forth or do not want to travel back and forth that often. Then you may want to think about even going back to bortezomib with pomalidomide/dexamethasone as an option. I would still prefer to go with a daratumumab-based therapy.

TARGETED ONCOLOGY:What supportive care measures are necessary for this patient?

Orlowski:Given that he has a new compression fracture, one question would be whether or not he is having significant pain in this area. If the pain is quite significant, then he could be a candidate for kyphoplasty or vertebroplasty. If that is not the case, but he is still having pain that is not being well controlled with an oral regimen, consideration could be given to radiation therapy, to palliative levels, 20 gray or so, just to the area of involvement. Also, because the patient does have a new fracture, we would need to review whether the patient had zoledronic acid before. If he did not, it should definitely be started after a dental examination has hopefully cleared him and showed no evidence of active infection. If the patient did have zoledronic acid before, then we would have to look at how long that was done and finished, and if that was finished quite a while ago, restarting zoledronic acid would be very reasonable. The main things to remember, other than the dental exam, is that it may have to be adjusted for creatinine clearance—that should be preferably measured with a 24-hour urine test, and there can be risks of renal insufficiency, in addition to the jaw osteonecrosis.

Every few months or so, one should get a 24-hour urine test to monitor for proteinuria and albuminuria, because an increase in those parameters sometimes can indicate that there may be emerging diphosphonate renal toxicity. Finally, on the diphosphonate front, there was a paper published earlier this year comparing administration of zoledronic acid given once a month to administration once every 3 months in all cancer patients with bone metastases, and they found that the skeletal-related event endpoint was essentially equivalent, suggesting that every-3-month dosing would be very appropriate.³This could be something that could hopefully reduce the risk of jaw osteonecrosis, as well as renal insufficiency, because of a decreased frequency of care. 

References:

1. Durie B, Hoering A, Rajkumar SV, et al. Bortezomib, lenalidomide and dexamethasone vs. lenalidomide and dexamethasone in patients (pts) with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant (ASCT): results of the randomized phase III trial SWOG S0777. Presented at: 2015 ASH Annual Meeting; December 5-8, 2015; Orlando, FL. Abstract 25.
2. Attal M, Lauwers-Cances V, Hulin C, et al; IFM 2009 investigators. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma.N Engl J Med. 2017;376:1311-1320. doi: 10.1056/NEJMoa1611750.
3. Himelstein AL, Foster JC, Khatcheressian JL, et al. Effect of longer-interval vs standard dosing of zoledronic acid on skeletal events in patients with bone metastases: a randomized clinical trial.JAMA.2017;317(1):48-58. doi: 10.1001/jama.2016.19425.