Keith Stewart, MB, ChB:Our next case is a 77-year-old African American gentleman who presented in 2013 with newly-diagnosed multiple myeloma with intermediate-risk features. Because of frailty and comorbidities, he was not considered a transplant candidate and went on to receive lenalidomide at the reduced dose of 15 mg daily for 21 out of 28 days, along with weekly dexamethasone. After about 2 years of therapy on lenalidomide and low-dose dexamethasone, the patient began to show signs of biochemical progression with a rising M (monoclonal) spike, but remained asymptomatic. At that point, his physician increased his lenalidomide dose to the full dose, at 25 mg daily. About 4 to 5 months after increasing his dose of lenalidomide, the patient presented to the hospital feeling unwell, with increasing back pain and fatigue. He had signs of high-risk disease, with a high beta-2 microglobulin, a low albumin, and bone marrow confirmed relapse with 30% plasma cells. He was now high-risk myeloma progressing on lenalidomide and was started on a combination of pomalidomide, cyclophosphamide, and dexamethasone.
The staging of myeloma still predominantly revolves around checking some routine blood tests, looking for signs of end organ damage, including anemia, hypercalcemia, renal failure, or bone disease. In terms of prognostication, we’ve tended to treat earlier. And there are some patients who we used to consider as having smoldering myeloma who will now be treated on the basis of either the presence from a bone lesion, a very high rate serum kappa/lambda free light chain ratio, or a very high M spike. Those patients will be considered high-risk smoldering myeloma and be referred for therapy. Also, bone marrow plastocytosis of over 60% would fall into that criteria.
Other things that become very important in prognosis include the international staging system, which revolves basically around the beta-2 microglobulin. A high beta-2 microglobulin, over 5.5, is considered high risk. A low albumin, less than 4, is also considered to be a high-risk feature. The absence of both of those features is low risk, or stage 1; the presence of both is high risk; and the rest is an intermediate if only one of them is abnormal. We can further refine this by using cytogenetics based on a bone marrow test using fluorescence in situ hybridization, or FISH. There are eight different genetic types of myeloma, some of which can fall into the high-risk category, some of which are intermediate-risk, and some of which are lower-risk. This patient presented with some intermediate risk features.
This gentleman is 77 years old and somewhat frail, limiting our treatment options to some degree. I do agree with the treatment he received, which was lenalidomide and dexamethasone. Phase III clinical trials have shown that this combination is superior to melphalan-based therapy, either MPT or MPR, which is melphalan-prednisone and lenalidomide. In fact, the use of melphalan has gone out of fashion in the United States, although use of melphalan-prednisone or bortezomib is still quite common in Europe and other countries. So, I do agree with lenalidomide and dexamethasone in this case. One option would have been to add bortezomib in this gentleman, but he seems to have done quite well with just the two drugs, and I think, given his frailty, that is appropriate.
Clearly, given this gentleman’s frailty and potential problems with side effects and toxicity of drug, I think the option to use lenalidomide at lower starting dose was appropriate. Almost all patients with myeloma will develop drug resistance over time. The mechanisms for such resistance are not terribly well described for the proteasome inhibitors, although sometimes we will find mutations of proteasome subunits. Resistance to steroids also is somewhat vague, but again, mutations in the glucocorticoid receptor can occur. The mechanism of action of the immune modulator drugsthalidomide, pomalidomide, and lenalidomide—is much better understood today. Those drugs all work by targeting the same protein, which is called cereblon, and cascading a series of events once they bind to that protein that result in the degradation of important survival factors in multiple myeloma. It turns out that in relapsed patients who are refractory to those drugs, the mutations in the cereblon pathway are really quite common.
Case Scenario 2: