Treatment Options in Asymptomatic Biochemical Relapse in Multiple Myeloma

Paul G. Richardson, MD:In terms of treatment options for these variety of different relapses, I think it’s very important to spend some time on them. If you have biochemical progression only, it’s very reasonable to try and make changes within the drug class, such as an IMiD switch as we’ve talked about from, say, lenalidomide to pomalidomide. You can increase the dose, although to be honest, my own experience with that has been somewhat limited in terms of benefit. I’m not sure that necessarily increasing the dose always is associated with benefit. And, in fact, there may be better approaches, such as adding another drug.

   Similarly, of course, it’s very important to know the role of steroids. Adding steroids to IMiDs synergizes. Having said that, and particularly in an elderly frail patient, that may not be possible or feasible. The monoclonal antibodies have changed their considerations here to some extent. And, for example, use of elotuzumab—which has been clearly shown, when combined with lenalidomide, to be highly active—is one very reasonable approach to always bear in mind in this setting.

   But biochemical relapse is one thing. And we talked about that also with the younger case earlier, where we might use ixazomib or we might use bortezomib every 2 weeks. For the more aggressive relapses, one needs to think about more aggressive therapy. And, obviously, in a younger, fit patient, carfilzomib/pomalidomide is one excellent choice, as we’ve already discussed. In an older patient like this who’s 77, I would be careful about the use of a potent proteasome inhibitor, like carfilzomib, for the following reason. We have data from a variety of studies looking at carfilzomib-based therapy that suggest there may be some challenges with its use in older, frailer patients. In my own clinical experience, it’s been fatigue and also some of the vascular toxicities, such as hypertension, which one has to be careful about. Having said that, there may be settings in which carfilzomib is perfectly appropriate, particularly if a patient is challenged by significant neuropathy.

   So, in this particular case of this patient, he has not had prior exposure to a proteasome inhibitor, so it’s a very rational choice to think about. And he’s not had prior exposure to bortezomib. So, the use of bortezomib in this case would be very rational, I think, for a variety of reasons. On the one hand he has renal dysfunction. On the other hand, he also has a significant bone disease. So, the use of a proteasome inhibitor is clearly appropriate, in addition to an IMiD.

   And as we discussed, the question would then be: what would be the best choice? As I’ve mentioned, he’s not had prior bortezomib, so this would be reasonable. Ixazomib would be another excellent choice. Carfilzomib would also be very appropriate if he had a very aggressive progression. But as I mentioned, we have to be somewhat careful because in the elderly, carfilzomib can be quite challenging for a variety of reasons: fatigue, vascular toxicities, and so forth. But having said that, it’s still a very reasonable class of drug, or a particular drug, to think about combining with pomalidomide.

   The rationale for maintaining an IMiD beyond progression is based upon the fact that there are certain backbone drugs that are very critical to our management. And so I think that in this context, for example, the use of pomalidomide-based therapy after lenalidomide failure is well established from our prospective trials in which lenalidomide failure was associated with clinical benefit from pomalidomide use.

   These studies show that in relapsed refractory disease after prior exposure to bortezomib, and being refractory to lenalidomide, we were able to salvage patients consistently at a rate of about a third. That obviously means that we had to do more for the two-thirds in whom benefit wasn’t seen, and there we have very strong combinatorial strategies, as I’ve already discussed. But I think the important message is that even when lenalidomide fails, pomalidomide will salvage. Now, why we, in our own practice, are very enthusiastic about the use of the IMiD-based platform is because they constitute a backbone agent. They have immunomodulatory properties as a driving force, but they also have other properties that make them very attractive as myeloma therapy. And what’s particularly important is that synergy with other classes, be it a proteasome inhibitor, be it an antibody. And, indeed, for that matter also, a histone deacetylase inhibitor would be considered. These drugs partner very well with the IMiDs and are highly synergistic.

   When we think about the first step in this patient with biochemical progression, which was the increasing dose of lenalidomide, I think it’s an area where there are studies that have suggested that this can be helpful. But my own practice is to do that with some degree of caution. I think that lenalidomide at 15 mg in an older patient is an adequate dose. When you go higher in a patient like this, and he’s 77, and especially as he has some evidence of renal dysfunction, I would be a little careful. Remember, lenalidomide is cleared by the kidney, and some of the side effect profile may change when you increase the dose, particularly in this older, frailer patient. Having said that, there is evidence that you can increase [the] dose from 10 to 15, up to 25, and add a steroid and see the restoration of response. And arguably, in selected patients who are tolerating their lenalidomide very well, that’s a reasonable thing to try. My own personal practice is if I do that and I see any evidence that there’s either an increase in toxicity and/or not the kind of activity I want to see, I’ll be very quick to move on to a next-generation IMiD and also bring in another class of drug to restore response.

Case Scenario 2:

December 2013

• The patient is a 77-year old African American male who was diagnosed 24 months ago with stage III multiple myeloma and not eligible for transplant based on his level of frailty. His cytogenetics were classified as intermediate risk.
• He received treatment with lenalidomide (15 mg daily) and low-dose dexamethasone.

December 2015

• IgA monoclonal protein spike seen on SPEP. M-protein level has risen to 0.6 g/dl.
• He continued to do well functionally.
• Lenalidomide was increased to 25 mg daily.

May 2016

• The patient now complains of increasing back pain, fatigue and weakness. He was hospitalized two months ago for pneumonia.
• Abnormal laboratory findings show:
  • Serum beta-2-microglobulin level, 6.2 mg/L
  • Albumin level of 2.1 g/dL.
  • Creatinine clearance of 32 ml/min
• Skeletal survey shows lytic lesions in the L4/L5 vertebrae.
• Bone marrow biopsy shows 30% involvement by abnormal appearing plasma cells, confirmed by CD138+ IHC stain.
• ECOG performance status is 2.
• The patient was started on pomalidomide, weekly cyclophosphamide, and low-dose dexamethasone.