Treatment of Symptomatic Disease Progression in Multiple Myeloma

Paul G. Richardson, MD:I think, in the context of symptomatic disease progression, rather than tinkering with dose and other things, I tend to be more active and taking on a combinatorial approach. And I think in someone like an elderly patient like this who’s frailer, the integration of a well-tolerated proteasome inhibitor makes great sense. The use of a next-generation IMiD, like pomalidomide, is clearly an appropriate way to go. And then, of course, now with the advent of the monoclonal antibodies, the judicious choice of an appropriate antibody may also be an important other avenue for the patient to consider.

   The very good news around pomalidomide and renal dysfunction is that unlike lenalidomide, which is renally cleared, pomalidomide is not renally cleared. It’s primarily metabolized through the liver. So, in that context, pomalidomide use in renal insufficiency is perfectly appropriate. In my own practice, I monitor platelet count, I monitor how the patient is doing overall. But my dose adjustments for pomalidomide certainly can be much more conservative than they are for lenalidomide, where we have clear guidelines that you must reduce dose and frequency. The same does not apply to pomalidomide. In fact, some of the studies have shown that clearly you can use full-dose pomalidomide. My own practice is to start at 2 mg daily and sometimes go to 3 mg and 4 mg daily, but I always think in terms of just seeing how things go perhaps before immediately getting up to the full dose. Having said that, studies suggest that you can use up to 4 mg without difficulty as long as you’re careful to observe platelet count and other parameters of any potential toxicities. Again, its efficacy in renal dysfunction has been well established now, given the current studies that have been completed, as well as now the larger clinical experience in the setting since pomalidomide’s approval.

   So, as I mentioned, when we think about pomalidomide dosing in renal failure, it is, in my view, worth thinking about dose, not so much for hematologic side effects necessarily—although those are important to monitor, particularly platelet count—but most importantly for nonhematologic side effects, like fatigue. Having said that, my own experience with pomalidomide, in the context of renal dysfunction, has been quite favorable. And I usually explore a dose range of between 2 and 4, depending how the patient’s doing. I typically use 3 weeks on and 1 week off.

   I think, in terms of when we think of what appropriate drugs could be used, that we could add to the pomalidomide platform in this particular patient. I think the really exciting news is we have plenty of options. Now, these range from bortezomib administered subcutaneously weekly. Again, because of the frailty of this patient, I would be cautious about carfilzomib. Ixazomib is also an excellent choice. We have preliminary data showing it to be well tolerated, the dose up to 3 mg and even 4 mg weekly in a MTD (maximum tolerated dose) study of selected patients combining pomalidomide and ixazomib. This is administered, as I mentioned, weekly on days 1, 8, and 15, every 28 days. So the ixazomib platform is particularly attractive in an older patient.

   I have to also say that monoclonal antibodies can be very helpful, and daratumumab is obviously tremendously active. Elotuzumab, too, is clearly an excellent choice. And we have data now for pomalidomide and daratumumab that are very favorable in terms of responses. We also have preliminary data on pomalidomide combined with elotuzumab, showing that it’s a very well tolerated platform and very active, as well.

   Now, I think in that same context, when you think about pomalidomide and cyclophosphamide, it’s an excellent combination. Very nice work from colleagues like Dr. Rachid Baz at Moffitt [has] clearly shown that you can put these drugs together and see great activity. I personally am a little bit careful with cyclophosphamide in the frailer patient. I do find it useful, but one has to be careful about blood counts and monitoring blood counts and ensuring compliance, particularly if you’re using oral cyclophosphamide in this context.

   I think, in summary, these two cases illustrate very nicely how pomalidomide-based salvage therapy can be effective in the younger patient after autologous stem cell transplant and can be very helpful, too, in the older patient, particularly when, in the frailer older patient, tolerability profile really, really matters. And the absence of really serious nonhematologic toxicities for pomalidomide as an agent of choice in relapsed, relapsed-refractory disease, I think is one of the most attractive aspects of its use. Also, the fact that as an IMiD, it’s working when both lenalidomide and thalidomide have failed.

   What I like particularly about pomalidomide is our ability to combine it very safely with other drugs. Pomalidomide and bortezomib, pomalidomide and carfilzomib are very active and effective combinations, as well as pomalidomide and ixazomib. And now, of course, the evidence that pomalidomide combined with monoclonal antibodies can be very attractive, as well.

   Finally, I’d make one comment that is particularly interesting. The combination of pomalidomide with histone deacetylase (HDAC) inhibitors has been really promising in a variety of studies, both with some of the newer generation agents, like AC241 or AC1215, and, of course, with the approved HDAC inhibitor, panobinostat.

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.