Borrello Discusses Potential Triplet Combinations in Patients with Multiple Myeloma

Ivan Borrello, MD

Ivan Borrello, MD

Ivan Borrello, MD, recently shared the treatment considerations and decisions he makes when treating patients with multiple myeloma. Borrello, an associate professor of oncology, Johns Hopkins University School of Medicine, and director of cell therapy, Sydney Kimmel Comprehensive Cancer Center, in Baltimore, Maryland, explained his treatment decisions based on a case scenario during aTargeted Oncologylive case-based peer perspective presentation.

Case 1

December 2013

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 showed hyperdiploid disease.

He received treatment with 15 mg daily of lenalidomide (Revlimid) and low-dose dexamethasone. After 9 cycles of therapy, the M-spike plateaued at 0.6 g/dL and therapy was continued.

TARGETED ONCOLOGY: What is the rationale for the choice of lenalidomide and dexamethasone for this patient?

Borrello: Historically, lenalidomide and dexamethasone was approved in the relapsed setting for patients. There were also subsequent trials that showed that there was a benefit of this combination moving upfront. I would say that, in general, the standard accepted treatment for most patients would be a triplet combination therapy with an immunomodulatory drug (IMiD). However, with the level of frailty [this patient has], there still could be a rationale for doublet therapy with lenalidomide and dexamethasone.

TARGETED ONCOLOGY: Would you have considered a triplet combination for this patient?

Borrello: For the most part, I try to give most of the patients that I treat a 3-drug regimen. This certainly would not be unreasonable in a specific subset of patients. I am pretty much able to give triplet therapy to everyone. What I normally do, if I am giving bortezomib, would be to give it once a week in combination with a low dose of lenalidomide, I think somewhere between 10 and 15 mg is reasonable. In addition to that, 20 mg or less of dexamethasone for an elderly and frail patient.

Two things have emerged in the past couple of years. One is that the more drugs that you give, the better it is. The second is that continuation of therapy is actually of benefit to the patient. So, the one thing that should be done for this patient is, as long as he tolerates it, he should be considered for a maintenance-type regimen or to continue treatment until toxicity or disease progression for as long as they possibly can.

December 2015

Laboratory findings showed that his hemoglobin was 11.4 g/dL, his creatinine was 1.0 mg/dL, and his M-protein had risen 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?

Borrello: Once there is evidence of disease progression, there are a variety of options. Lenalidomide is an interesting drug because there is clearly an aspect of immunomodulation, but there is also an aspect of direct myeloma-targeted cytoplasmic therapy. I have clearly seen, in several patients, that just increasing the dose of the drug alone in some cases can salvage and induce or rescue a response that is failing. However, with this significant increase and the disease burden, I believe that potentially adding something new to the therapy would be of interest.

There is a lot of evidence to suggest that an IMiD in combination with a proteasome inhibitor has added benefit. The TOURMALINE-MM1 study is one example of that, where they are now using an oral proteasome inhibitor, specifically ixazomib (Ninlaro).¹In that trial, although the median age was around 66, there was an elderly patient population that was treated. Interestingly, in a subset analysis of these patients, the overall benefit of ixazomib plus lenalidomide and dexamethasone was less pronounced in the elderly population than it was in the younger population. Certainly, there is evidence to suggest that there is a benefit and would warrant trying such a treatment in this patient.

In this case, the lenalidomide dose was increased to 25 mg daily. The one caveat that I have with that is if it is an elderly patient, one needs to think about myelosuppression. As mentioned earlier, increasing the dose can rescue some responses, but in an elderly patient who needs to be balanced with potential comorbidities, a dose increase may be associated with that.

TARGETED ONCOLOGY: How do the nature and kinetics of progression impact your decision?

Borrello: The patient's M-spike was clearly increasing, but what we don't know is what the time frame is for these increases from 0.6 g/dL all the way to 1.5 g/dL. If it is rising very rapidly, I would completely switch regimens to use a proteasome inhibitor plus a different IMiD. Or, potentially think about integrating daratumumab in the regimen, possibly with pomalidomide (Pomalyst). However, with regards to a more gradual increase, one could consider using an oral proteasome inhibitor.

Lenalidomide was increased to 25 mg daily by the local physician.

May 2016

The patient was hospitalized 2 months previously for pneumonia, the patient complained of increasing back pain, fatigue, and weakness.

Laboratory findings showed that his M-protein level was 2.1 g/dL, his serum beta-2-microglobulin was 6.2 mg/L, his albumin level was 2.1 g/dL, and his creatinine clearance was 32 mL/min.

Skeletal survey showed a new compression fracture in the L4/L5 vertebrae. Bone marrow biopsy showed 30% involvement by abnormal appearing plasma cells, which was confirmed by CD138+ immunohistochemistry stain. His ECOG performance status score was a 2.

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

Borrello: This patient is clearly progressing, even with his modifications. At that point, different and more aggressive therapy is likely needed. Possibilities would include daratumumab together with pomalidomide and dexamethasone or even bortezomib, or potentially with carfilzomib (Kyprolis), in combination with pomalidomide or dexamethasone.

In terms of choosing one of these regimens over the other, if the patient has preexisting neuropathy, I would be somewhat reluctant to go in the direction of bortezomib. In contrast, if the patient has a history of cardiac disease or pulmonary hypertension, I would be reluctant to choose carfilzomib. Daratumumab, for the most part, tends to be relatively well tolerated; however, the long infusion rates can be somewhat of an obstacle for a slightly frailer patient population. But, we have given daratumumab to elderly patients who have ultimately tolerated it well.

The patient was treated with daratumumab (Darzalex), weekly subcutaneous bortezomib (Velcade), and dexamethasone (collectively known as DVd).

TARGETED ONCOLOGY: What is the rationale for the treatment choice for this patient after disease progression?

Borrello: This is based on data from a randomized trial that compared bortezomib and dexamethasone to daratumumab in combination with bortezomib and dexamethasone in a refractory setting.²In that study, about 10% of the patients were over the age of 75. Regarding most of the patients who had prior lines of therapy, the vast majority of them had just 1 prior line of therapy. So, this patient population is not heavily pretreated. Interestingly, the use of prior proteasome inhibitors was present in more than 60% of these patients.

What was quite impressive from this trial was the significant benefit of the 3-drug combination compared to bortezomib and dexamethasone alone. This is both in terms of progression-free survival (PFS) as well as time until disease progression. With this study, as well as a companion study known as the POLLUX study, it has been clearly shown that there can be effective use of monoclonal antibody-targeted therapy, both in combination with a proteasome inhibitor as well as an IMiD.³

In the relapsed setting of [the CASTOR study], there was also a complete response (CR) rate of 15%, which is rather impressive. Similarly, significant responses were also seen in the POLLUX study, which was daratumumab plus lenalidomide and dexamethasone. The vast majority of the patients who were treated with lenalidomide were not previously treated or exposed to lenalidomide, although interestingly there was a slight increase of lenalidomide-naïve patients in the control group itself. Despite that, there were significant improvements in overall PFS at 12 months of 83% versus 63% in the patients that got the 3 drugs in that study.

What is also quite impressive is that I think this is one of the first times we are beginning to see this evidence of minimum residual disease (MRD) negativity. That was shown in up to 10% of the patients down to 10^-6negativity. This is an important point because there is evolving literature to suggest that there is a direct correlation between MRD negativity and overall long-term outcomes in patients treated with various regimens in multiple myeloma.

Case 2

December 2010

A 54-year-old Caucasian male presented with anemia. His bone marrow biopsy showed 40% plasma cells. FISH testing showed a 14;20 translocation, deletion 13, and deletion 17p (80% of the myeloma cells had a 17p deletion).

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

Borrello: This is a patient with high-risk disease as determined by the 17p deletion in 80% of the plasma cells. Deletion 13 used to be considered high-risk, but with the advent of more highly effective agents, this has become less relevant in the modern area. The patient is young, and induction therapy would clearly involve 3 drugs, which should include a proteasome inhibitor, an IMiD, and dexamethasone.

The IFM 2009 study was recently published and this showed that there was a substantial increase of PFS, as well as CR rate benefit, in patients that received transplant following RVD induction therapy compared with patients that were just induced and subsequently maintained with RVD.⁴This underscores the overall benefit of autologous transplantation, even in this era of modern therapies.

The role of consolidation is less clear. The IFM study had consolidation incorporated into it. However, there was a STaMINA trial that was reported from North America and it didn’t necessarily show a significant benefit to consolidation.⁵It did show a benefit to maintenance therapy. When one looks at the standard practices in the United States, for the most part, based on these studies, the standard treatment should be a triplet, involving an IMiD and proteasome inhibitor as induction therapy. This should be followed by autologous transplantation and maintenance therapy, for the most part, with an IMiD. This is now supported by the subsequent and most recent 700-patient trial from the IFM 2009.

In that trial, it was also seen that the MRD negativity rate was higher in the patients that received transplant compared to those that didn't. As mentioned previously, this did appear to correlate with improvements in CR rate, as well as PFS rate. Overall outcomes for patients who were MRD negative prior to transplant appeared to be indistinguishable whether they got a transplant or not. Potentially, this begs the question whether a person going into transplant that is MRD negative can further improve his or her outcomes by getting transplanted, or if the ultimate goal of therapy should be MRD negativity itself. This trial is not powered or designed to answer that question, but I think it raises an interesting question as to the evolving role of interpreting MRD in the setting of this new data becoming available.

TARGETED ONCOLOGY: What factors do you consider when deciding treatment for this patient?

Borrello: For the most part, if the patient is of transplantable age—which in the United States is a biological 70—and does not have significant commodities, the data from the IFM 2009 study would strongly suggest moving in the direction of an autologous transplant. The subset analysis of this trial would argue that high-risk patients do not do as well as standard-risk patients, even when getting transplanted, because of an overlapping error bar in terms of the hazard ratio.⁴Still, there is a tendency towards improvement in overall survival (OS), even in this patient population.

One of the concerns that has been raised about that study is that, despite this improvement in PFS, there hasn't necessarily been a benefit in OS, as published in theNew England Journal of Medicine. However, one thing that needs to be considered is the maturity of the data. We have seen in a few other studies that curves are completely superposable until the patients are at least 5 years out from therapy. At that point, we start to begin to see the curves separating out. Obviously, we do not know if that is going to be the case or not in this trial. I do think that it is worthwhile to wait a few more years to look at OS before coming to conclusions as to what the ultimate impact of this initial upfront transplant is compared to no transplant in terms of the long-term outcomes of the patient.

TARGETED ONCOLOGY: What is the rational for treating this patient with RVD, followed by an autologous stem cell transplant and IRd maintenance therapy?

Borrello: The patient received a standard triplet induction therapy, followed by a standard transplant. The issue here in terms of the maintenance is the addition of a proteasome inhibitor. As shown from the IFM 2009 study, as well as other studies, there is no emerging evidence that the incorporation of an IMiD as part of the maintenance therapy would potentially be beneficial for patients with high-risk disease. A 17p deletion in the vast majority of the cells would classify this patient as high-risk disease. So, I think that such an approach is a reasonable one to offer patients in this setting.

In the TOURMALINE-MM1 study, there did appear that, even with patients of high risk, there was a benefit of IRd compared to Rd alone in the subset analysis. This, again, would justify giving this triplet as maintenance therapy for a patient with high-risk disease.

TARGETED ONCOLOGY: What would you expect in terms of toxicity with this regimen?

Borrello: Although this is an oral proteasome inhibitor, there is still evidence of peripheral neuropathy in patients, and it can also be seen in lenalidomide alone. The would be one thing that needs to be considered in the patient when administering this combination. In general, we are dealing with toxicity that can be effectively managed if properly recognized.

One must also consider the secondary malignancies, ranging between 2% and 4%, associated with IMiDs, but I think that a rather extensive analysis and investigation into this was done several years ago and still justifies the use of this considering the significant incremental benefit of IMiDs in the maintenance setting as compared with the potential toxicity.

The patient was treated with lenalidomide, bortezomib, and dexamethasone (collectively known as RVD) for 6 cycles, followed by autologous stem cell transplant (MEL200), and was then started on ixazomib, lenalidomide, and dexamethasone (collectively known as IRd) as maintenance.

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

Borrello: A patient who relapses on IRd would be a candidate for daratumumab, pomalidomide, and dexamethasone; or carfilzomib, pomalidomide, and dexamethasone as treatments that are considered the standard of care. Experimental therapies should also be discussed with this patient if there is access to clinical trials.

References:

1. Moreau P, Masszi T, Grzasko N, et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma.N Engl J Med. 2016;374:1621-1634. doi: 10.1056/NEJMoa1516282.
2. Palumbo A, Chanan-Khan A, Wesiel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma.N Engl J Med.2016;375:754-766. doi: 10.1056/NEJMoa1606038.
3. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma.N Engl J Med.2016;375:1319-1331. doi: 10.1056/NEJMoa1607751.
4. Attal M, Lauwer-Cances V, Hulin C, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma.N Engl J Med.2017;376:1311-1320. doi: 10.1056/NEJMoa1611750.
5. Stadtmauer EA, Pasquini MC, Blackwell B et al. Comparison of autologous hematopoietic cell transplant (autoHCT), bortezomib, lenalidomide and dexamethasone (RVD) consolidation with lenalidomide maintenance (ACM), tandem autoHCT with lenalidomide maintenance (TAM), and autoHCT with lenalidomide 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: the 58th ASH Annual Meeting and Exposition; December 3-6, 2016; San Diego, California. Abstract LBA-1.