CASTOR Study: Daratumumab Plus Vel-Dex in Relapsed Myeloma

Ola Landgren, MD, PhD:When patients relapse, they can have very different ways of relapsing. They can have symptomatic relapse, which is, on average, less common, or they can have biochemical relapses, which is the majority of patients. And I think that’s simply because doctors are following their patients. If the disease comes back, you’re more likely to pick up a new increased level of a protein in the blood before the patient starts developing symptoms. These patients present with symptoms that indicate that this disease probably was pretty fast when it came back. I would think that the blood tests were done every month, every other month, or every 3 months, despite the fact that the patient was followed pretty carefully with short intervals—still going from nothing to today, the patient has symptoms. So, that indicates that the disease kind of took off.

In that context, I think using a 3-drug combination is absolutely the right thing to do for the relapse. In fact, data support even the use of 3-drug combinations in the setting of a biochemical relapse. All the data point in that same direction. Because the patient has kidney failure that’s evolving, it’s not really clinically established kidney failure, but we see that the creatinine is going up. And as I pointed out, the light chains are going up, but probably are driving it. We have to be careful what drugs we use. To use lenalidomide is probably not the best thing for this patient. Therefore, I think using daratumumab in combination with bortezomib and dexamethasone can be given for patients that have even very severe renal failure. It is a very good option for these patients. You fulfill the criteria of using a 3-drug combination, and you pick drugs that are safe from the kidney perspective.

The CASTOR study is a large randomized phase III trial done internationally. It includes almost 500 patients. The 2 arms include bortezomib and dexamethasone. The experimental arm has the additional daratumumab. So, the control arm is the 2-drug and the experimental arm is the 3-drug. The study shows that the progression-free survival at 12 months is more than 60% for the experimental arm, and less than 30% for the control arm. If you look at the median follow-up of a little bit more than 7 months, the median progression-free survival for the experimental arm is not yet reached; for the control arm, it’s around 7 months. These translate into a hazard ratio, comparing the 2 arms, that is in the range of about 0.3. So, in clinical terms, what this tells us is that you reduce the risk of progressing with about 60% in this current study. That’s pretty impressive.

The CASTOR study will definitely change the treatment paradigm for multiple myeloma in the United States. Patients will be treated with the combination of daratumumab, bortezomib, and dexamethasone starting off with the first relapse—and subsequent relapses as well. The CASTOR study focused on patients with 1, 2, or 3 prior lines of therapy, and the new approval by the FDA allows the use of this combination from that first relapse. There’s no doubt that this is going to be commonly used in clinic around the country.

Bortezomib has well-documented toxicity in terms of peripheral neuropathy. A pretty high proportion of patients have pretty advanced peripheral neuropathy when the drug is given intravenously. We no longer use the drug intravenously. We give it subcutaneously, but still patients develop peripheral neuropathy. Typically, we say that grade 3 and higher is a big problem, but I do think when it comes to peripheral neuropathy, even grade 2 peripheral neuropathy is clinically not an easy thing for patients to live with. So, that’s a major limitation of that drug.

Dexamethasone is a drug we use in combination with many other drugs. We don’t think about that as being a troublemaker, but a lot of patients have problems with dexamethasone. They have sleeping problems, they have mood variations, they gain weight, they have increased blood pressure, the bones are becoming thinner, and a lot of other things happen as well.

Daratumumab, which is the new drug added to this combination, has very amazingly limited toxicities. Usually, only infusion reactions are attributed to the first infusion. After that, even for patients who do have infusion reactions the first time, most patients have no infusion reactions later. And for patients who do not have infusion reactions the first time, they rarely have infusion reactions later. There is no known evidence that the drug has any cumulative toxicities either. So, it is a drug that has very limited toxicities.

My personal experience using the combination from the CASTOR study, including daratumumab with bortezomib and dexamethasone, is that it’s a very efficacious therapy. It is quite tolerable, and I think it’s a very good option for patients who have one or more relapses. There are other options where you can use daratumumab, such as in the POLLUX study. The POLLUX study includes lenalidomide and dexamethasone in addition to daratumumab. In my practice, I tend to use more of the lenalidomide/dexamethasone in addition with daratumumab. But there are instances when I choose the CASTOR study combination with bortezomib and dexamethasone added to daratumumab—examples could be patients who have some kidney failure or patients who have a tendency of blood clots—because lenalidomide cannot be given safely for patients with renal failure and it also increases the risk for thromboembolism.

Case Scenario 1:

January 2015

• The patient is a 61-year-old male who was diagnosed with ISS stage II MM.
• Performance status 0.
• At diagnosis bone marrow shows 40% light chain restricted plasma cells, FISH cytogenetics show hyperdiploid phenotype.
• M-spike of 3.2 g/dL IgG kappa, serum free light chains kappa 60 mg/dL, lambda 1.5 mg/dL, ratio=40
• Bloodwork show beta-2 microglobulin=4.2 mg/dL, Hg=8.2 g/dL, creatinine=0.9 mg/dL.
• PET/CT shows multiple focal bone lesions in upper and lower extremities and in L2 and L3.Bone lesions have increased SUVs.
• Based on these data and diagnosis of standard risk he was started on 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 10 mg.

April 2016

• Patient was experiencing back pain, loss of appetite and weight loss.
• Blood work show beta-2 microglobulin=4.0 mg/dL, Hg=9 g/dL, creatinine=1.5 mg/dL.
• M-spike is 0.5 g/dL, serum free light chains kappa 60 mg/dL, lambda 0.6 mg/dL, ratio=10.
• Performance status 1.
• Based on these criteria he was diagnosed with standard-risk multiple myeloma.
• He was started on daratumumab, bortezomib, and dexamethasone.