Natalie S. Callander, MD

What is important for people who are seeing patients with myeloma, perhaps that’s not your primary focus of your practice, but you’re seeing them here and there, is we want to emphasize a couple of things. One is, when those patients first come in the door, we want you to try to use effective therapy right up front, to give those patients the longest duration of response. That can be for a transplant-eligible patient considering a triplet or maybe a quadruplet regimen in patients with high risk. And we do think autologous stem cell transplant still adds in terms of progression-free survival [PFS] and probably depth of response. Then we think that patients deserve some sort of maintenance, whether it’s going to remain 1 drug, such as lenalidomide or bortezomib. There’s a very large trial underway that’s going to add in daratumumab as a possibility for maintenance, but we want to try to take a very good swing. 

For nontransplant eligible patients, there are several good choices. Daratumumab in combination with lenalidomide and dexamethasone as tested in the MAIA trial looks very promising. There is great now 6-year follow-up showing they had not even reached their PFS at that point, but it’s probably going to be at 5 to 6 years. Or the combination of bortezomib, lenalidomide, and dexamethasone. Some people call that VRd [bortezomib, lenalidomide, dexamethasone]-lite, if you’re trimming the doses a little, making the bortezomib weekly. Those are very good introductory choices for patients.

In terms of the relapsed setting, this is where it gets a little trickier. We would all agree, for patients who have a relapse that symptomatic triple therapy is great. We would like to figure out by future trials whether you need to change all the classes or only 1. That is an important question. Again, the NCCN [National Cancer Comprehensive Network] guidelines have a number of different options. I would always encourage somebody to think about a clinical trial for patients too. Where it starts to get a little harder is that third- and fourth-line therapy, and again, there are a number of good choices. We tend to look in the third and fourth line at what kind of [adverse] effects the patients may be experiencing at that point. What kind of cytopenia maybe they’re experiencing; do they have a lot of peripheral neuropathy? What’s their distance from the treatment location? Those kinds of considerations can be important in making a decision for relapsed therapy. I do think CAR [chimeric antigen receptor] T-cell transplant is going to be an option for you to refer patients to. We’re going to have a couple of different CAR T products approved this year, we believe. 

Finally, quality of life and supportive care are important. In this day and age, with COVID-19, we are advocating vaccination for patients, but we don’t want to forget about some of the common things too, such as influenza and pneumococcus. We are recommending COVID-19 vaccinations for our patients. Typically, right now expert opinion is recommending consideration of COVID-19 vaccination 90 days after a transplant, and many of us are trying to vaccinate patients perhaps in a 1- or 2-week hiatus between some of their dosing schedules. In addition, we want to make sure we think about bone health, so we’ve got 2 excellent options, zoledronic acid and denosumab. We also have pamidronate, which can be useful in some situations as well. We also know that patients can experience increased risk of infection in their first few months after diagnosis, and so this is a vulnerable period where we think there should be a lot of vigilance, and in some cases antibiotic prophylaxis can be helpful.

For nontransplant patients, we have a couple of very good choices. The MAIA trial was recently updated at ASH 2020 [the American Society of Hematology annual meeting]. One of the exciting things, using a combination of daratumumab, lenalidomide, and dexamethasone, they presented that even after an average of 48 months of follow-up they still hadn’t reached the progression-free survival median in the daratumumab-containing arm. The projected median PFS is going to be about 5 or 6 years on that trial for that particular arm; so those are really great data. Another choice for transplant-ineligible newly diagnosed patients would be a combination such as bortezomib, dexamethasone, and lenalidomide, particularly with weekly bortezomib, what we would call VRd-lite. And then the TOURMALINE trial using a combination of ixazomib, lenalidomide, and dexamethasone would also be a very reasonable choice for patients who are transplant-ineligible, and particularly those who are looking for a regimen that can be done orally and not require lots of visits to the center.

An active 68-year-old man presented with a 5-month history of fatigue and new onset hip pain

PE: tenderness appreciated on palpation at the hips and lower back

Labs: Hb 10.3 g/dL, calcium 11.4 mg/dL, LDH 190 U/L, creatinine 1.2 mg/dL, albumin 3.9 g/dL, beta-2 microgloblulin 3.9 mcg/mL, M-protein 2.7 g/dL, lambda free light chains 4.1 mg/dL, CLCr 45mL/min 

Skeletal survey showed lytic lesions in the left hip 

Bone marrow shows 42% clonal plasma cells IgG k

Initiated lenalidomide + bortezomib + dexamethasone for 8 cycles

He continued 15 months maintenance lenalidomide

Imaging at follow-up revealed progression of disease 

Selinexor + bortezomib + dexamethasone was initiated

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An expert in multiple myeloma provides clinical pearls for disease management from initial diagnosis through multiple lines of therapy.

Clinical Pearls for the Management of MM

The future of treatment in myeloma is going to consist of the introduction of a lot of cellular therapeutic options, and we’re all looking forward to the introduction of CAR [chimeric antigen receptor] T-cell transplants. Both the KarMMa and CARTITUDE-1 trials were updated at this year’s ASH [American Society of Hematology annual meeting], and both of these particular CAR T systems showed great response rates, upward of 85% to 90%, almost 100% in the CARTITUDE trial. They are showing great activity in patients who are refractory to therapy, and the progression-free survival is around 10 to 12 months. We’re going to be seeing that kind of intervention with CAR T moved into an earlier point in myeloma treatment. Of course, there are several studies underway looking at that principle, but we’re waiting for our first CAR T approval, which we think will happen very soon. 

Also, to be introduced are going to be the bispecific antibodies. These are molecules that in some cases target BCMA [B-cell maturation antigen], but there are also other targets emerging, and they do bring together the myeloma cells with a T cell, with the CD3 [receptor] end of this package. There are a few drugs; teclistamab has probably the most advanced data, which were updated at ASH, and showed very exciting data in the use of this drug subcutaneously. There’s also talquetamab and cevostamab; these are 2 other bispecifics targeting different antigens on myeloma cells.

All of these kinds of agents are going to be introduced, perhaps earlier and earlier. What we’re also going to see as we go forth is combinations that we’re familiar with but are being tweaked. For example, some of the drugs such as belantamab might be moved up into the front line to see whether that will improve responses. We are anticipating that we will see some use of selinexor potentially in the upfront area as well. This is going to be an exciting time in myeloma.

Dr. Natalie Callander describes promising new treatment approaches for patients with multiple myeloma.

The Evolving Treatment Landscape in MM

 If a patient such as this, let’s say we used that combination or a different combination, and now maybe another 6 to 9 months go by, and we’re looking at another line. Now we’re looking at third-line treatment. Particularly, if a patient has received an IMiD [immunomodulatory drug] and maybe previously a proteasome inhibitor, your choices are now getting more limited, particularly if you throw in a CD-38 antibody. Now we would be thinking about drugs that do have some activity in this quad-refractory, or in some cases these patients could be penta-refractory, space. That brings up drugs like belantamab. Belantamab is the first B-cell maturation antigen-directed antibody-drug conjugate that was approved last year for use in this kind of quad-refractory patient, so that might be a reasonable choice if the patient has had many different exposures. That drug has about a 30% response rate when used on its own. Many people are familiar with the fact that it does have as one of its cardinal [adverse] effects keratopathy, which can manifest itself as dryness of the eyes and irritation. We are seeing a suggestion that less frequent dosing with that drug may help with that [adverse] effect.

Also, for patients who are very refractory, or quad-refractory would be a drug recently approved, melflufen, [melphalan flufenamide], which is basically melphalan that is packaged in a special way so that the melphalan or the melflufen is internalized into myeloma cells, and then endopeptidases inside the myeloma cell cleave off that melphalan, which can then do its activity. It’s thought to enhance targeting of that drug. This drug was recently approved in combination with dexamethasone for patients with greater than 4 lines of therapy who were quad-exposed. Selinexor is also being tested in several different combinations as part of what’s called the STOMP trial in different backbones. We’re seeing selinexor in that particular trial combined with drugs like pomalidomide, lenalidomide, daratumumab, carfilzomib, and they’re going to have combinations coming up with some of the other drugs that we mentioned, such as belantamab.

One of the neat things about these trials, particularly in data presented this year looking at selinexor in combination with pomalidomide and dexamethasone, the responses were there, of course, in patients who were naïve to both drugs. But in patients who had been pomalidomide-exposed or refractory, there was a response rate that was about 35%, which was exciting. What we’re very excited about in the STOMP trial and all of those different combinations using selinexor, particularly with daratumumab and lenalidomide and pomalidomide, is a couple of things that we’ve seen. No. 1, there haven’t been any unexpected safety signals. We know that selinexor can be associated with GI [gastrointestinal] toxicity that can be managed effectively with a robust antiemetic regimen, but we weren’t seeing any new [adverse] effects that we didn’t anticipate. There was some hematologic toxicity in terms of anemia and thrombocytopenia, but this was manageable and did not result in a lot of discontinuation of the drug for that reason. We are interested though in the ability of selinexor to potentially sensitize patients again to other drugs that they have seen before, so we’re all staying tuned to see what happens.

An expert in multiple myeloma talks through the considerations for treatment selection in the third line for patient with multiple myeloma. 

Considerations for Third-Line Therapy in MM

 Now we’re looking at what to do with this particular individual. He received selinexor, bortezomib, and dexamethasone, which we’ll talk about in just a minute. One concept here for this kind of early relapse is that we do think patients should receive a triplet regimen for salvage. And that’s because, as I mentioned again, this patient is having a short interval before their disease has progressed. We would all agree that triplets have beat doublets in pretty much every study that’s been done, particularly in these early relapse patients with 1 to 3 lines of therapy. We’re now trying to figure out what would be the better combination. Now, what was done in this case was to basically do class switching. You could potentially say, “Could I just add something to that lenalidomide, along with maybe a different drug or an antibody drug?” A lot of people, particularly for an early relapse like this, would feel very comfortable saying, “Let’s do several class switches.” Not just going from an IMiD [immunomodulatory drug] to a different IMiD, but in this case, going to a proteasome inhibitor, and of course selinexor, which has a novel mechanism of action. 

When you’re looking at first-line treatment, again, for transplant-eligible patients, one thing we take into account is risk. Many people, because of some of the preliminary data from trials such as GRIFFIN and from trials coming from Europe such as CASSIOPEIA, would say a 4-drug regimen may be coming up as a new alternative, particularly for patients with high-risk disease. That would include an antibody drug along with that backbone, whether in the CASSIOPEIA trial it was bortezomib, thalidomide, and dexamethasone, and in the GRIFFIN trial it was bortezomib, dexamethasone, and lenalidomide. One caveat to the quadruple approach as we do know from the recently published SWOG 1211 study, this was not a transplant study, but patients who received elotuzumab in combination with bortezomib, lenalidomide and dexamethasone, did not seem to fare better than just with the triplet on its own.

More and more we’re moving to consideration of the addition of a fourth drug or an anti-CD38 antibody in patients who have the highest risk disease. Now, for patients who want to stay active, we do know that there are some oral regimens you could consider. These are probably a bit of a softer recommendation based on NCCN [National Cancer Comprehensive Network] guidelines for newly diagnosed myeloma. People have tested the combination in the recent TOURMALINE trial, looking at ixazomib added to lenalidomide and dexamethasone. That seems to be a very convenient as well as well-tolerated combination. Lenalidomide has been combined with cyclophosphamide and dexamethasone as well. There are some oral options out there if a patient really was in a situation where they could not get to the treatment center, which was particularly a situation we saw a lot last spring and summer here in the United States.

This choice for this patient is reasonable. The recently reported out ENDURANCE trial that compared 9 months of induction with either bortezomib, lenalidomide, and dexamethasone, or carfilzomib, lenalidomide and dexamethasone, would have excluded this kind of patient because of that high-risk cytogenetics. But as I mentioned, that SWOG study did not reach that conclusion, at least with that combination.

When you’re looking at a relapse, as we’re talking about with this particular patient, there are a number of issues to keep in mind. This man is relatively young and presumably, although we weren’t told this, he is maybe employed and working, so coming up with a regimen that fits a person’s lifestyle is a very important consideration. There are a lot of choices here that would potentially support the use of an anti-CD38 antibody such as daratumumab. That drug certainly is one that people would feel very comfortable bringing in in combination with either bortezomib or possibly pomalidomide. As I mentioned, there is sometimes that issue about going from 1 different class to 2 different classes. There are times when patients can be retreated with the same drugs. The NCCN guidelines usually ask us to consider a patient who has not progressed on that line of therapy, so to include that, but also at least 6 months of good control of their myeloma previously before you would consider retreatment.

Now, in this case, this patient received selinexor, bortezomib, and dexamethasone, and that selection is based on some very exciting data from the BOSTON trial, in which patients who had had 1 to 3 lines of previous therapy were randomized to receive either bortezomib, dexamethasone in a dose-intensive fashion, so days 1, 4, 8, and 11 of the bortezomib, and dexamethasone twice for each dose of bortezomib in the control arm. That was compared to once a week bortezomib with selinexor and dexamethasone in the experimental arm. What this study showed, which was really one of the first studies, a phase 3 randomized study to use once-a-week bortezomib, is a couple of things. One, the response rate with a triplet was considerably better, with around a 75% response rate, and in addition, as everyone who uses bortezomib is familiar with, peripheral neuropathy can be an issue with this drug. The patients who received the selinexor combination had a lower incidence of peripheral neuropathy, which was very exciting to see. 

Now, there is some experience you have to learn about if you’re choosing selinexor. One thing is that because the drug does have some issues with gastrointestinal toxicity, that may be because the drug does penetrate the blood-brain barrier, you must think about aggressive treatment with, say, a serotonin agonist such as ondansetron, or also the use of a drug like olanzapine can be helpful. And be aggressive at the use, don’t just wait for a patient to develop [adverse] effects; you want to try to go out after them initially. The other thing that we’re learning with selinexor is that the dosing schedule may be very important here, in that the higher doses do seem to be more difficult for a patient to tolerate, and using a lower dose tends to mean that the patient will stay on the drug longer. More of the trials that we’re going to see with selinexor are going to do that.

Dr. Natalie Callander provides insight on selection of second-line therapy after transplant patients with multiple myeloma.

Natalie S. Callander, MD | Authors

Articles

Clinical Pearls for the Management of MM

The Evolving Treatment Landscape in MM

Considerations for Third-Line Therapy in MM

Second-Line Options After ASCT in MM