Considerations for Third-Line Therapy in MM


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

Natalie S. Callander, MD: 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.

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


  • 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

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