Triplet Regimens for Relapsed Multiple Myeloma

Ravi Vij, MD:Often, the question that is asked is when a patient relapses is whether he should be given a 2-drug regimen or a triplet regimen. That certainly has become established in the frontline setting, especially for transplant-eligible patients. I think that the data from multiple clinical trials, which we have discussed, shows that the use of a triplet leads to better disease control, in terms of depth of response.

So, I think that I, whenever possible, would like to use a triplet for patients, and this patient could tolerate a triplet of ixazomib (Ninlaro) with lenalidomide (Revlimid) and dexamethasone, or if he had been totally asymptomatic, even elotuzumab (Empliciti) with lenalidomide and dexamethasone. However, there are some patients, especially over the age of 80, who are still not candidates for a 3-drug therapy. For them, often we move from a serial 2-drug regimen at the beginning to a 2-drug regimen at time of relapse. For an octogenarian, it is not uncommon for me to start a patient with lenalidomide and dexamethasone, and then when he progresses, the patient may go to just a 2-drug regimen of ixazomib with dexamethasone. Though not FDA approved, it is a valid choice of therapy.

Then they often want still an oral therapy beyond that, and then going to pomalidomide (Pomalyst) and dexamethasone at that point is often what I end up doing. Also in this situation, the use of single-agent daratumumab (Darzalex) is an option when patients are older and you do not want to subject them to the toxicity of treatments. That is a regimen that has single-agent activity. So, you have to look at the patient to decide whether it should be a 3-drug regimen or a 2-drug regimen, but certainly, if possible, giving a 3-drug regimen is best.

The TOURMALINE-MM1, study which led to the FDA approval of ixazomib with lenalidomide and dexamethasone, was a large phase III study that compared the 3-drug regimen to a 2-drug comparator, lenalidomide and dexamethasone. This study showed that the progression-free survival, which was a primary endpoint of this study, was superior with the use of the 3-drug regimen. Also, what was shown was that in subset analysis, the study showed benefit even for patients with high-risk disease: patients who had 17p deletion—who are considered the highest risk subset—and also those that had other high-risk features, including translocation (4;14), (1q+). All those patients seemed to benefit by the use of the 3-drug regimen compared with the 2-drug regimen.

So, I think that for this patient, who has high-risk chromosomal features, ixazomib with lenalidomide and dexamethasone would be a very appropriate treatment option. It is often perceived that for high-risk chromosomal features, the only things that are going to work are really the intravenously administered drugs, but that is not what is supported by data. The TOURMALINE-MM1 study showed that even in the high-risk subgroup, an all-oral regimen was appropriate.

The use of ixazomib, lenalidomide, and dexamethasone for the high-risk population is supported by subset analysis of the TOURMALINE-MM1 study. What we saw in a publication inBloodjust recently is that those patients who had high-risk chromosomal features, including 17p deletion (4;14) and translocation (1q+), actually seemed to have a greater benefit with the 3-drug regimen, compared with the lenalidomide and dexamethasone control, compared with the whole group of patients in the trial. Although everybody benefited, it seemed that those who had high-risk features had the maximum benefit.

Transcript edited for clarity.

CASE: A 72-year-old Caucasian Man With Relapsed Multiple Myeloma

September 2016

• Patient history: At the age of 72, a Caucasian man was diagnosed with multiple myeloma; R-ISS stage I
• Other relevant history includes hypertension and difficulty walking up stairs
• He was treated with lenalidomide/dexamethasone and achieved a VGPR
• Treatment duration was 9 months; patient subsequently discontinued therapy 12 months ago

June 2018

• On routine follow-up, patient complains of increasing problems with fatigue, and has rising levels of M protein
• Laboratory results:
  • Hb, 9.6 g/dL
  • Ca²⁺9.2 mg/dL
  • Creatinine, 0.8 mg/dL
  • M-protein, 3.0 g/dL
  • 30% plasma cells in bone marrow
• Cytogenetics/FISH: del(17p)
• ECOG PS: 2