The DVD Regimen After Myeloma Progression

Sagar Lonial, MD: When we think about the use of daratumumab, it’s an antibody, and so it lends itself very nicely to combinations across the board. There are very nice data combining it with IMiDs—both lenalidomide and pomalidomide—and the CASTOR trial was a larger experience trying to understand the combination with bortezomib and dexamethasone. What we know from the laboratory suggests that there is some synergistic myeloma cell apoptosis that occurs when a proteasome inhibitor is combined with an anti-CD38 antibody. And some of that may have to do with signaling that occurs in the myeloma cell when daratumumab engages the CD38 receptor that may sensitize cells to the use of a proteasome inhibitor, such as bortezomib.

What we know about this trial overall is that the median progression-free survival for the bortezomib/dexamethasone arm was about what we would expect, somewhere around 8 to 9 months. However, the median progression-free survival for the daratumumab/bortezomib arm was significantly longer with a very, very impressive hazard ratio andPvalue. We also have suggestions that the use of bortezomib/daratumumab may also be able to mitigate some of the impact of high-risk genetics, and that was recently at a couple of meetings. And, where we’re using sequencing, we were able to identify high-risk patients and showed quite nicely that the bortezomib/daratumumab arm did better than even the bortezomib/dexamethasone arm in terms of high-risk progression-free survival. And there are now pretty strong suggestions for improvements in overall survival across the board as well.

Daratumumab in combination with bortezomib/dexamethasone is a very active combination. And, what we know is that the addition of daratumumab to bortezomib/dexamethasone doesn’t really significantly change the adverse event profile from what we see with bortezomib/dexamethasone. Bortezomib is given again, subcutaneously on a twice-a-week schedule. There’s a lot of controversy about whether anybody should get a twice-a-week dosing of bortezomib. I’ll tell you, in our experience both in newly diagnosed, and early relapse, we typically use twice-a-week bortezomib in the beginning to make sure we get a quick response. And then, if patients develop adverse events, like neuropathy, we will then reduce to once a week as our first dose reduction at the sign of grade 1 peripheral neuropathy.

With the use of daratumumab, the only real increase in adverse events that we see are infusion reactions, and the infusion reactions tend to occur with the first or second dose of daratumumab. So, typically, once you get beyond that first cycle of bortezomib in combination with daratumumab and dexamethasone, the incidence of infusion reactions has reduced pretty markedly. And, the use of leukotriene inhibitors as well as corticosteroids, Benadryl, and other things along those lines can also significantly reduce the incidence and grade of infusion reactions associated with daratumumab.

When you think about using this combination, I think it is important to realize that at signs of grade 1 peripheral neuropathy, go ahead and reduce to once-a-week dosing. That’s not what was necessarily done in the clinical trial, but I think we know from a practical perspective, most of us who have used bortezomib for over a decade now know that that early intervention is really key to preventing long-term peripheral neuropathy.

The other pieces that I would throw out as a bit of advice are to make sure that your blood bank knows when patients are started on daratumumab, because we know that daratumumab can interfere with the indirect Coombs test. And, we’ve had patients who occasionally have needed blood. The blood bank doesn’t know that they’ve gotten daratumumab, and they spend 3 or 4 days doing a type and screen, confounded by that false, positive indirect Coombs test. So, making sure that the blood bank knows when a patient has started is important.

And the other is that there is a lot of discussion about the interference of daratumumab with the serum protein electrophoresis. And, what I can tell you is that practically, only happens with patients who are either at a VGPR or at a CR. And if they have an IgG kappa myeloma, there may be interference from daratumumab in the immunofixation. That can be addressed, but in general, those are patients that are doing quite well anyway, and there isn’t really a reason to make a change in their therapy.

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