A 68-Year-Old Man with Multiple Myeloma - Episode 2

Second-Line Options After ASCT in MM

April 14, 2021
Natalie S. Callander, MD

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

Natalie S. Callander, MD: 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.

This transcript is edited for clarity.

A 68-Year-Old Man with Multiple Myeloma

Initial Presentation

  • An active 68-year-old man presented with a 5-month history of fatigue and new onset hip pain
  • PMH: HTN, medically controlled
  • PE: tenderness appreciated on palpation at the hips and lower back
  • ECOG PS 1


Clinical workup

  • 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 
  • Hepatitis B and C negative
  • Skeletal survey showed lytic lesions in the left hip 
  • Bone marrow shows 42% clonal plasma cells IgG k
  • FISH: del(17p)
  • Diagnosis: R-ISS stage II MM

Treatment

  • Initiated lenalidomide + bortezomib + dexamethasone for 8 cycles
  • He underwent ASCT 
  • He continued 15 months maintenance lenalidomide
  • Imaging at follow-up revealed progression of disease 
  • Selinexor + bortezomib + dexamethasone was initiated