CASTOR Study: Therapy Options in Relapsed Multiple Myeloma

Cristina Gasparetto, MD:This patient relapsed within 1 year of transplant with a quite aggressive relapse. His bone marrow biopsy at time of relapse was overwhelmed, was replaced by 70% of myeloma, and now cytogenetic was positive for the deletion of 70, which is a high-risk feature, unfortunately, for this patient. He also had new lytic lesions, anemia, slight elevation of renal function, so he really clearly had the clinical relapse and aggressive relapse. This patient, after transplant, was placed on lenalidomide maintenance of 50 mg. And despite the maintenance, and despite the fact that he was in remission, he progressed very rapidly. So, I think it will be appropriate to change the class of therapy by going from an IMiD to a proteasome inhibitor combination. If this patient didn’t have such an aggressive relapse, like what we call a “biochemical relapse”—where we see the numbers going up, but we don’t have any evidence of end-organ damage—I would have probably felt more comfortable to increase the lenalidomide and add a different agent, such as daratumumab, or a proteasome inhibitor. But because their now aggressive PDT causes relapse, I think it makes sense to change the combination, the treatment strategy, completely.

This patient was treated, as I mentioned earlier, with RVD induction therapy followed by transplant, and then by maintenance with lenalidomide of 50 mg. He relapsed aggressively within 1 year of transplant. Using a combination with the lenalidomide will probably make me very uncomfortable. So, switching to a proteasome inhibitor combination is more appropriate. The daratumumab/bortezomib/dexamethasone was in the CASTOR study, and it was published recently in The New England Journal of Medicine showing incredible results. This study was a phase III randomized study where patients with relapse or relapse refractory disease were randomized 1:1 to receive bortezomib/dexamethasone—which, for many years, has been one of the backbone treatments in the relapsed setting—versus bortezomib/dexamethasone/daratumumab. We have adjunction of these powerful drugs. The daratumumab is a monoclonal antibody in an IgG kappa—targeting CD38, which is present in the old myeloma cells and other hematopoietic cells. And the daratumumab as a single agent was approved by the FDA at the end of last year because of the results of a large study showing that the overall response with a single agent was about 30% in patients with relapsed refractory disease to multiple lines of therapy. So, it’s an effective powerful drug.

In the CASTOR study, daratumumab was combined with the backbone, bortezomib/dexamethasone, and clearly showed an improvement on the outcome. The follow-up in the study was not really long. It was only 7.4 months. But with the short follow-up, it was clear that the adjunction of daratumumab improved the outcome of the combination with higher numbers of patients responding with a long progression-free survival. Hopefully, with a longer follow-up, we’ll see a survival advantage as well. Also, it’s very well tolerated. Daratumumab/bortezomib/dexamethasone is clearly a good combination in the relapsed setting based on the results on this study. One of the advantages of this combination is the safety profile. We are all familiar with the toxicity of bortezomib and dexamethasone, and by adding the daratumumab, it doesn’t really look like it’s increasing the toxicity profile. In fact, in the study, patients had maybe a little more thrombocytopenia and neutropenia, but it was not excessive. In terms of known hematologic toxicity, we are always concerned with peripheral neuropathy with bortezomib.

There was an increased incidence of peripheral neuropathy overall, all grades, but not necessarily an increased incidence of grade 3 and 4 neuropathy. So, overall, the toxicity profile of the combination was very similar to bortezomib/dexamethasone alone. But as I mentioned, the addition of the daratumumab clearly had, in overall response, progression-free survival, and hopefully, we will see a survival advantage, as well, in this population of patients. Now patients’ role in the study were already previously exposed to bortezomib, but they were not bortezomib-refractory and that is a very important point.

I have used this combination, daratumumab/bortezomib/dexamethasone, in my clinic. And, as mentioned, it’s well tolerated. Daratumumab is given once a week for the first 3 cycles with this particular regimen, and infusion can be long. About 50% of patients will experience an infusion reaction during the first infusion, but generally, it’s otherwise well tolerated. And then, after cycle 3, daratumumab is given every 3 weeks, so it’s becoming a more tolerable, less cumbersome combination treatment regimen for patients, which is very important. So, I have used these combinations and it’s very well tolerated.

Case Scenario 1:

January 2015

• The patient is a 61-year-old male who was diagnosed with ISS stage II MM.
• Performance status 0.
• He was treated with lenalidomide, bortezomib, and dexamethasone (RVD) induction.
• He achieved a partial response with RVD.
• He then had an autologous stem cell transplantation and achieved MRD negativity.
• He was started on lenalidomide maintenance of 15 mg.

April 2016

• Patient was experiencing back pain, loss of appetite and weight loss.
• Upon relapse cytogenetics showed a 17p deletion detected by FISH, demonstrating progression of his disease.
• Beta-2 microglobulin=4.0 mg/dL, Hg=9 g/dL, creatinine=1.2 mg/dL, multiple bone lesions, bone marrow biopsy=70% plasma cells.
• Performance status 1.
• Based on these criteria he was diagnosed with standard-risk multiple myeloma.
• He was started on daratumumab, bortezomib, and dexamethasone.