Management of Myeloma Biochemical Progression

Sagar Lonial, MD: This is a case of an elderly, frail gentleman who presented with symptomatic myeloma. He was initially started on lenalidomide and dexamethasone with appropriate reductions in the lenalidomide dose based on renal function, as well as overall performance status. He had about a 2-year duration of remission, had biochemical evidence of progression, and then the dose of lenalidomide was increased to 25 mg, that worked for about another year. He then had, again, clear progression with new bone lesions as well as significant increase in the protein.

I think the management of this case is really relatively straightforward. For a true frail, transplant-ineligible patient, I think the standard does continue to remain the use of lenalidomide and dexamethasone. I think the doses that were used were reasonable doses. There is some question now about whether a triplet, such as VRd—the addition of bortezomib to lenalidomide and dexamethasone—has become a standard for these patients, based on the recent SWOG study. I think that that is an important consideration, but given how frail this patient was, I’m not sure that I would have jumped in with a triplet combination at that time point. There are modifications that can be done to the VRd regimen, such as RVd-lite, which is presented by the Massachusetts General Hospital group. That also may be a consideration. But, again, unless somebody doesn’t have high-risk genetics—and he didn’t appear to have high-risk genetics—I think the doublet of lenalidomide/dexamethasone is a pretty reasonable therapy.

I think a major question that’s going on in the field right now is about how to handle patients who have biochemical progression. This is something that we’re starting to see a lot more of, and we’re paying a lot more attention to it because patients are on continuous therapy, and are coming in to the office much more frequently than they were, say, 10 or 20 years ago. And there is, again, a bit of a split. There are those in the myeloma working group who say biochemical progression is a short harbinger to clinical progression; you shouldn’t wait. There are those of us in the working group I’m a part of who say the path to progression can be variable, and that patients can have long-term biochemical progression without any evidence of symptomatic relapse. And, so, you should watch it to get a sense for tempo of relapse. I will tell you, Ajay Nooka from our group actually looked at this very question from our own data set. We had predicted that patients with high-risk genetics would biochemically progress very quickly, and so there wasn’t a reason to start where a standard-risk would progress relatively slowly, and those patients could be watched. It turns out we were both wrong—patients’ progression has nothing to do with their genetics, although the tempo and way in which they initially presented may color that decision a little bit.

I think that certainly the idea of continuing on therapy for patients who have only biochemical progression is a reasonable thing to do. We know that increasing the lenalidomide dose from 10 mg or 15 mg up to 25 mg doesn’t typically give you long-term disease control. In this case, it did; it probably gave us about 1 year. But in general, I think we know that what we tend to do in these situations is just maintain the current dose and wait until we see either rapid progression or evidence of symptomatic progression.

I think that the data around the use of increasing the dose of lenalidomide, in the context of progression, are relatively soft data. There were some unpublished data from the French that suggested that when patients progressed on lenalidomide maintenance at 10 mg going up to 25 mg, the addition of dexamethasone may give you a short-term benefit. Those data have never been published. There are other series that have reported similar outcomes where it may be a short-term response, but it’s typically not a long-term response. And you don’t know how much of that is an increase in the lenalidomide dose versus adding the dexamethasone back in, which may do the same thing.

Transcript edited for clarity.

Multiple Myeloma in an Older Patient Who Develops Symptomatic Progression

December 2013

• A 77-year old African American male was diagnosed 24 months ago with stage III multiple myeloma and was 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

• He reported feeling tired but continued to do well functionally
• Laboratory findings:
  • Hb, 11.4 g/dL
  • Creatinine, 1.0 mg/dL
  • M-protein rose from 0.6 g/dl→1.2 g/dl→1.5 g/dl
• Lenalidomide was increased to 25 mg daily; M-protein returned to normal

December 2016

• The patient was hospitalized 2 months ago for pneumonia and now complains of increasing back pain, fatigue, and weakness
• Laboratory findings:
  • M-protein, 2.1 g/dl
  • Serum beta-2-microglobulin, 6.2 mg/L
  • Albumin, 2.1 g/dL
  • Creatinine clearance of 32 ml/min
• Skeletal survey shows new compression fracture in the L4/L5 vertebrae
• Bone marrow biopsy shows 30% involvement by abnormal appearing plasma cells, confirmed by CD138+ IHC stain
• Performance status, ECOG 2
• The patient was treated with daratumumab, weekly subcutaneous bortezomib, and dexamethasone