Landgren Touches Upon Promising New Studies in the Field of Multiple Myeloma

C. Ola Landgren, MD, PhD

C. Ola Landgren, MD, PhD

C. Ola Landgren, MD, PhD, recently shared the treatment considerations and decisions he makes when treating patients with newly diagnosed multiple myeloma. Landgren, chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center in New York, explained how he would treat these patients based on the review of a case scenario during aTargeted Oncologylive case-based peer perspectives dinner discussion.

Case 1

December 2010

A 54-year-old Caucasian man presented with anemia. A bone marrow biopsy showed 40% plasma cells. Fluorescence in situ hybridization [FISH] showed a [4:20] translocation and a 13 and 17p deletion. Eighty percent of the myeloma cells had a 17p deletion.

TARGETED ONCOLOGY: What are your initial impressions of this patient?

Landgren:This is a relatively young patient who has typical plasma cell infiltration, which many patients with myeloma would present with. He presented with anemia, which is probably an indicator that the disease has biological activity. The workup shows that a very high proportion of these cells have a deletion of the 17th chromosome. There is a high GH translocation, the 14:20, that is when theMAFgene is translocated with IGH.  

TARGETED ONCOLOGY: Is this a typical case that you might see?

Landgren:This is a typical case that comes through our clinic. I would say that this could represent maybe 10% to 15% of the newly diagnosed patients, but there are certainly many different variables.

TARGETED ONCOLOGY: What is the prognosis for this patient?

Landgren:Because a high proportion of the patient’s bone marrow cells are being impacted by the deletion of the 17th chromosome, the prognosis presumably is quite negative and a poorer OS [can be expected].

It should be emphasized that these are statistical probabilities, so not every patient who has a chromosome 17p [deletion] will have a poor outcome. At the very least, the outcome could vary a lot within this group of patients. For the percentage of cells that have this deletion but is lower, it is debatable, but many studies would suggest that the prognosis would not be very different compared to the patients who don't have the 17p deletion. In this case it says he's 80%, so obviously that's a high percentage.

The other aspect is that every gene has 2 alleles, 1 comes from the mother and 1 from the father. We don't know in this case if the deletion from the 17th chromosome is present in both of the alleles. There are studies showing that if a person has deletion in 17p in both alleles that it is conferring to an even worse prognosis.

A 17p deletion is known to have worse prognosis for OS, which is typically thought to be due to down regulation of the p53 tumor suppression gene that signals downstream of this deletion in 17p. But, 2 major variables seem to be important [to consider]. One is the percentage of the cells being affected, here we have a lot. The second is whether it is 1 or 2 alleles being impacted. If both alleles are impacted it is worse, but we don't know that here. My overall thinking is that the patient shows up, has anemia, 40% plasma cells, and carries this deletion in 80% of the cells, therefore the prognosis is inferior. But, again, it may not be as bad as we think.

Lastly, all of the literature that talks about bad prognosis or less bad prognosis are of course done in the setting of given treatments. Many of these studies that people refer to when they talk about bad prognosis and they look at the projected survival are quite a few years old. So, the therapies that were given at that time may not be accurate to look at. It is possible that this 17p may have less of a worse prognosis in the setting of more modern therapy.

TARGETED ONCOLOGY: What are the treatment choices for induction therapy?

Landgren:Most doctors would agree to do a combination therapy, typically based on 3 drugs, at least in the current era. Typically, people will use a chromosome inhibitor, an immunomodulatory drug [IMiD], and a low dose of steroid. Maybe in the future we will [add] additional drugs, for example adding a monoclonal antibody to that combination—now we are talking about a 4-drug combination, but the field is not there yet.

Consolidation after induction is reflective of the use of melphalan chemotherapy together with collective stem cells, which would be given back after the chemotherapy. Going forward, it's reasonable to think that the newer combination therapies, maybe with 4 drugs, could obtain very deep responses. You could merge what historically has been called induction and consolidation therapy into a more advanced combination therapy. For now, people would think of 3 drugs followed by transplantation.

The next step would be to do maintenance. The standard of care across the world for maintenance would be to use 10 mg of lenalidomide. That would typically be given every day for 3 weeks on and 1 week off. For patients who have a standard risk biology myeloma, it would typically last for 4 to 6 years, sometimes longer, but these are the averages. There are patients who, fortunately, need it for a much shorter period of time, but there could also be patients who need it for much longer. For the high-risk features that this patient has, historically that median time is significantly shorter. It would probably range from 12 to 18 months for progression-free survival [PFS].

I think with these new drugs, it is probably going to be longer. There is new emerging data indicating that, but it is too early to say exactly how long that is because the literature is very immature at this point when it comes to these groups of patients. If you could use other types of maintenance, could you continue with combination drugs also in the maintenance setting? There is more work to be done for sure [to answer these types of questions].

TARGETED ONCOLOGY:Could daratumumab [Darzalex] be included in the treatment regimen for this patient?

Landgren:At this time, daratumumab has an indication [currently pending with the FDA] for the combination with bortezomib [Velcade], melphalan, and prednisone, which comes from a pretty old regimen that was developed in Europe. It is typically not used here in the United States, at least not for the past 10 years. Adding daratumumab to that old regimen is not something that many doctors would use here. However, it proves that you can use the drug upfront and you can also combine it with other drugs.

There are several ongoing studies that are using bortezomib, lenalidomide, and dexamethasone [RVD] in combination with daratumumab and also KRd. It is going to happen, and there are also studies using daratumumab with lenalidomide and dexamethasone. It is just a matter of time until daratumumab will be used upfront. There is no reason why that couldn't happen from a scientific and clinical standpoint. What is really holding [us] back is the regulatory of the reimbursement steps that now need to come into place.

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

Landgren:These days most patients presented with multiple myeloma should be offered a 3-drug combination, which would be the chromosome inhibitor, IMiD, and steroid. Going forward, I could envision that 4 drugs with an antibody could probably become the new standard of care here in the United States.

TARGETED ONCOLOGY:What are the reasons to use 1 drug over the other in each of these categories?

Landgren:I think patients that have certain comorbidities, such as neuropathy, frailty, cardiac issues with congestive heart failure, arrhythmia, renal failure, and other similar things, would impact the choice of different chromosome inhibitors, and also the use of IMiDs. There might be deviations using cyclophosphamide [Cytoxan] instead of an iMiD the patient has kidney failure. There are lot of things to consider, but the bottom line is to use the most modern and efficacious drugs early on and offer patients the best we have upfront.

I think that is where the field is going, to use drugs based on what’s possible to give from the standpoint of tolerability. If the patient has cardiac, renal, or other deficiencies, then certain drugs may or may not be preferable. Of course, it has to be done in agreement with the patient. A preference, a convenience, or other limiting factors could also impact [the choice of treatment]. Lastly, for a patient who is frail, or has other comorbidities or limitations, then of course you would step down and would have to consider doing less active therapy.

TARGETED ONCOLOGY:Would the patient's anemia be one of those determining factors?

Landgren:I would say no. The anemia is most likely due to the disease activity. It would be a mistake if you think to hold back therapy because of the anemia. Just like many other diseases that we are treating, the disease causes the anemia. The way to get rid of the anemia is to be more aggressive and get rid of the disease.

If the anemia was profound, if the patient had symptoms from it, or if it was numerically profound anemia, I think that would be a reason to consider doing transfusions with blood. If that's not the case, I would not hold back on that. I would anticipate the hemoglobin to normalize as you get the disease under control.

TARGETED ONCOLOGY:What would the role of transplant be in this patient?

Landgren:As I indicated, the old paradigm that is still around is to use combination therapy followed by chemotherapy melphalan, where you need the stem cells, which is also referred to as a transplant, even though it is chemotherapy. Then use maintenance therapy. That has been the paradigm that has been around for more than 30 years. You have what people historically refer to as induction, consolidation, and maintenance therapy. For that reason, the melphalan chemotherapy with stem cells has a role in that standard-of-care setting.

I do think that there is emerging data from ongoing and already published studies suggesting that deep response to therapy could also be used to guide the use of therapy. I would envision that using very powerful combination therapy upfront could lead to a deep sustained response. It may not necessarily have to be back to back followed by the chemotherapy melphalan with stem cells. I know that is a controversial statement, but there is not a lot of literature to prove that you must give the melphalan. Those studies are ongoing and there are emerging data that is beginning to question that paradigm. The new ideas are interesting and we will see what the new literature tells us going forward.

The patient was treated with lenalidomide [Revlimid], carfilzomib [Kyprolis], and dexamethasone [KRd] for 6 cycles, followed by autologous stem cell transplant [MEL 200]. She then started maintenance therapy with ixazomib [Ninlaro], lenalidomide, and dexamethasone.

TARGETED ONCOLOGY:Why was KRd given for this patient?

Landgren:There are 2 major triplet combinations available that you can give based on current paradigms that are reimbursed if you use a chromosome inhibitor, an IMiD, and a steroid. One of them is RVD, and the other is KRd.

The first was initially approved by the National Comprehensive Cancer Network [NCCN] guidelines in 2008 when the presentation was given by the Dana-Farber group at the American Society of Hematology meeting. In 2010, there was a phase II trial with about 40 patients that was published in the journalBloodwhich supported the use of this triplet drug combination. For very many years it was based initially on an abstract and then a phase II trial. It was not until the beginning of 2017 that an old study by the property group SWOG was published with randomized phase III study. That study has a lot of limitations and the data is not very clean. Nevertheless, it shows that the 3-drug combination is better than the 2-drug combination, which was lenalidomide and dexamethasone.¹

The use of the triplet combination was based on single-arm data for very many years. At this point, KRd is also approved by the NCCN guidelines and phase II single-arm data [based on] 2 studies, 1 of them was with 53 patients and the other 1 was with 45 patients. That’s over 100 patients, which is more than initial phase II data for the other combination. There is no phase III data available yet for this combination. I think that this combination, from a clinical experience, seems to be more powerful with deeper responses. More patients are minimal residual disease—negative and it seems to be more durable.

There was recently a publication of a final analysis for that therapy in the relapsed setting. The study, ASPIRE, showed that the combination translated into an OS benefit that was significant, 8 months longer.²It is a more powerful therapy, at least with regards to deeper responses in more patients.

TARGETED ONCOLOGY:What kind of follow up would you suggest for this patient?

Landgren:The patient here was treated according to what we were informed, with 6 cycles of KRd, followed by melphalan chemotherapy with autologous stem cell transplant. According to the notes, the patient was then started on the combination of ixazomib, lenalidomide, and dexamethasone as the continued maintenance therapy.

That triplet combination is an oral drug combination that is FDA approved as a second-line treatment. I think it is reasonable for a patient who is young and has high-risk disease to think of a 3-drug combination. But, there is no randomized data proving that lenalidomide maintenance alone versus ixazomib, lenalidomide, and dexamethasone has significantly different PFS outcomes. That is not known in randomized studies. It is reasonable, given the historical data for the signatures of 17p deletion in high proportions of cells, or adverse.

Additionally, the patient could probably be monitored with blood tests. You could start [the treatment] and, after a month, if the patient is doing fine and the labs are fine, you could then check again in 2 months. In my clinical practice, I would be okay checking the labs every 2 to 3 months if the patient was agreeable to that. If the patient wants to come once a month I would certainly be okay with that too. But there is certainly no clinical necessity to push for that, 2 to 3 months is fine, followed with labs when the patient comes.

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

Landgren:That's a good question. Relapse includes a lot of different types of scenarios. If the scenario is that the disease is very slow-growing and it is a biochemical relapse, and the patient is doing fine, which may be unlikely in this case, I think you could consider using daratumumab maybe in combination with lenalidomide and dexamethasone. That is approved for patients who have been previously exposed to prior lines of therapy. If the carfilzomib and lenalidomide plus transplant was one, and there was a decision to start him on ixazomib, lenalidomide, and dexamethasone as the second line, we could build on that to do lenalidomide, daratumumab, and dexamethasone. There are certainly a lot of other options as well, and it is complicated to cover all of the scenarios. If the patient has renal failure, you may think of cyclophosphamide in combination with bortezomib or carfilzomib. There are many other scenarios.

If the relapse is more aggressive and happened after a shorter period of time, maybe after only 6 or 12 months, as a contrasting example to slow relapse, I would probably do a bone marrow biopsy to see what we are dealing with. Let’s say the bone marrow now shows 80% or 90% [plasma cells], that would be a situation where you would have to act quickly and you have to do some powerful therapy to get the disease under control.

Typically, what I would consider doing would be 4 days back to back inpatient therapy in combination with dexamethasone, cyclophosphamide, etoposide [D-CEP] or dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide, bortezomib [VDT-PACE]. All of these regimens are based on old-school, 1970s or 1980s, therapies, which basically kill the cells across the board. If you administer them as infusions for 4 days back to back, I would anticipate seeing, after 3 additional weeks or so, that the disease has responded. If that works, and the patient has tolerated it well, I would even consider doing it for a second round. I think you could expect to have a high likelihood of getting the disease under control.

TARGETED ONCOLOGY:What do you do from here?

Landgren:That is a very difficult question to answer because there are so many different scenarios. You would need to stay on combination therapy. You could argue that you could do a chromosome inhibitor without the combination. I have certain drugs that I have experience with that are quite powerful. Carfilzomib did a good job in the beginning; if the treatment works to control the disease, I would probably think to do carfilzomib with cyclophosphamide. I have used that in combination with lenalidomide and dexamethasone. As an outpatient therapy, that could work for many of these patients. There are certainly a lot of other combinations, and you could also consider doing clinical trials. We have ongoing clinical trials where we offer chimeric antigen receptor T-cell therapy. That would be a great option for this patient as well. That would be due to availability and what the patient is interested in.

References:

1. Durie B, Hoering A, Rajkumar V, 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: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract 25.
2. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma.N Engl J Med.2015;372:142-152.