Treatment Options in Relapsed/Refractory Multiple Myeloma

Thomas Martin, MD: Let’s talk about relapsed and refractory myeloma. When somebody has evidence of relapse, what do you look at to try to help you decide what treatment to give?

Yvonne Efebera, MD: The cytogenetics. I try to do a bone marrow biopsy. How long from the initial transplant, or diagnosis if they were transplant-ineligible, did they relapse? Time from initial diagnosis or time from transplant to relapse? Are they now on maintenance? Some patients may say, “I haven’t been on maintenance treatment.” Were they on maintenance, and what was the maintenance at the time of relapse? Did the cytogenetics change? Were they standard risk and then they become high risk? Of course, there are comorbidities; how well are they going to tolerate treatment, a 3-drug versus a 2-drug treatment based on their comorbidities? Those are some of the things I look at in terms of reusing initial induction treatment. If a patient had a good response, VGPR (very good partial response), CR (complete response), and had stayed on for 4 or 5 years and has been disease-free for 3 or more years, I can safely use the initial induction treatment. Will they be eligible for a second transplant? If they’ve gone 3 or more years from their first transplant, there are data out there for second autologous transplant if they have cells and are able to collect cells. Always think of a clinical trial for patients who are high risk and patients who relapse within a year from their transplant or even 2 years. Those are considered super high risk. I am a big fan of allotransplant. Those are things I also put in my equation. Are they eligible for an allotransplant? How about you?

Thomas Martin, MD: We have so many agents to choose from. We have the 3 major classes: we have the proteasome inhibitors (PI), the immunomodulatory drugs, and now the monoclonal antibodies. Typically, it is a ping-pong approach between those 3 classes of drugs. Which ones are you going to compare? I agree, refractoriness to an agent is the important thing in my mind when we’re starting off for the first therapy after their initial induction. A lot of our patients are on continuous lenalidomide. I will not bump up the dose of lenalidomide and add another agent. That is not a great regimen. I switch at that point. Typically, it’s a class switch. If they’re lenalidomide refractory, I either go to the next-generation—IMiD (immunomodulatory imide drug), such as pomalidomide—and typically add something to that. There are good combinations. Daratumumab/pomalidomide is one of my favorite ones, but sometimes I’ll also choose carfilzomib or pomalidomide. For whatever reason, if they’ve had toxicity to the IMiD and they’re lenalidomide refractory, I might switch completely and just give a PI plus daratumumab or a monoclonal antibody, even bortezomib if they haven’t had it for a while plus daratumumab. There are more recent data with using carfilzomib with the CD38 antibodies; some of those studies are quite convincing, that combination is really good in the lenalidomide refractory population. How about you?

Yvonne Efebera, MD: How did this patient relapse? Patients can have what they call biochemical progression where they’re totally asymptomatic. You’re looking at the numbers, and the time for progression is when the monoclonal protein is 500 above the nadir, or their light chains are at least 100 points above the nadir in terms of the units—mg per L or 10 mg per dL above their nadir. I’ve had patients who, just by a chemical progression, are totally asymptomatic and on lenalidomide maintenance, 5 mg. I increase the lenalidomide and add dexamethasone; I’ve had patients 2 years on that regimen without any progression. It all depends on the nature and symptom of the progression. If they’re not refractory to lenalidomide, I would do it.

Again, the timing from their initial treatment, VRd/DARA (bortezomib, lenalidomide, dexamethasone plus daratumumab) base, or DARA (dexamethasone) base is actually my most second-line choice, either DRd (daratumumab, lenalidomide, dexamethasone), DARA/POM/D (daratumumab, pomalidomide, dexamethasone). Some patients like all oral drugs, so IRd (ixazomib, lenalidomide, dexamethasone) is a good option for a patient who doesn’t want any IV and/or just likes the oral. If they’re refractory to lenalidomide, then KRd (carfilzomib, lenalidomide, dexamethasone) would be good. Of course, the daratumumab/Velcade, daratumumab/pomalidomide, carfilzomib/pomalidomide, elotuzumab/pomalidomide, CyBorD, daratumumab/carfilzomib/dexamethasone, isatuximab/pomalidomide/dexamethasone were approved for both PI and the IMiD refractory setting. It could be either second-line or third-line prior regimen.

As you go down the road, you have the panobinostat, Velcade/dexamethasone, selinexor, and VD PACE for the younger patient with really aggressive disease that you want to cytoreduce right away. Those are other options. There are so many options you can switch back and forth with. If we’ve used so many lines of therapy and they’ve progressed on 3 drugs, I can just remove 1 drug and add a different drug to the regimen. Say if they’re on carfilzomib/POM/DEX, I will just remove the carfilzomib and add daratumumab because POM is more tolerable, so we’ve done that. Again, it’s all patient-directed and depends on the tolerability by patient.

Transcript edited for clarity.