Treatment of Myeloma Relapsed Disease

Ajai Chari, MD:For this patient, daratumumab/VD (bortezomib and dexamethasone) would be a very reasonable option because of her lenalidomide maintenance progression, and because she does have a known history of high-risk disease. Some practical considerations in treating with daratumumab/VD are, number 1, daratumumab is a relatively long infusion, so it’s important to be prepared for that. What we can do, as physicians, is have the labs drawn ahead of time (perhaps the day before). We did that, routinely, on clinical trials. The good thing is, we don’t really need a lot of labs to dose these drugs because daratumumab is not significantly affected by hepatic or renal function (although the label has only been studied to a clearance of 30 mL/min). Similarly, bortezomib physicians have a lot of experience with this.

But, some considerations include getting the labs drawn ahead of time; having the orders pre-signed (so it’s not a last minute scramble); alerting the pharmacy and nursing staff that this is a first dose of daratumumab; having the patient arrive early so that everybody has that benefit of time; starting the infusion in a prompt fashion (with pharmacy having mixed the drug); giving those premedications, perhaps even at the same time that the pharmacy is instructed to mix the drug; and starting the drug early, not late in the day. And then, infusion-related reactions are common. It’s 50%, but most of the time it’s grade 1 or grade 2. It just means that we have to hold the drug, sometimes, and give additional pre-medications, rechallenge, and, potentially, re-escalate. But, all of that is only possible if you have time. If you’re practicing in a busy community practice with a 9 to 5 schedule, and this patient doesn’t start until 12, you’re going to probably end up wasting a lot of drug. The patient won’t get completed on their therapy.

Another strategy that, again, has been done in studies as well, now, is split-dose daratumumab. If you are a community center that’s very pressed for time and you can’t complete it in the first day, split it into 2 bags (8 mg/kilo on day 1 and day 2), that way you have the benefit of not wasting the drug if the patient has a significant reaction. And then, you can do the second dose on the next day. Those are very important, I think, practical considerations.

It’s also important to remember, for those hospitals that may give daratumumab as an inpatient procedure, the drug is only stable for 15 hours. So, unlike other monoclonal antibodies that may be stable, longer (and we can sometimes just run it at a very low rate overnight), this drug could potentially expire depending on when it was hung. Then, there are 2 other practical considerations. One is the implication for blood banking. Daratumumab’s target is CD38, which is primarily on myeloma cells but red cells also express CD38. We know, now, that if you give a patient daratumumab and you send a Type and Screen specimen to the bank, post-daratumumab, it will look (to them) that this patient has a lot of antibodies to a lot of antigens, because every red cell will be coated with daratumumab.

The way to deal with that is, number 1, in all of our chemotherapy template orders on the day 1 dosing, we put, “Please send blood bank a specimen for type and screen.” And, we inform them that this is a pre, first-dose daratumumab patient. That way, the blood bank is alert. In our center, for example, they do extended testing—either phenotyping or genotyping. That way, they know that when this patient comes back, even if the type and screen is raising these weird antibody questions, they know what the patient’s blood type was, definitively, pre-daratumumab.

If somebody got daratumumab and that was not done, the other strategy is to use enzymes to strip away daratumumab from their red cells (using DTT [dithiothreitol] or trypsin). This makes the red cell naked again (without the daratumumab coating), and they can do their standard type and screen. The implication of that is certain antigens like Kell will also be stripped, so the blood bank will have to give Kell-negative blood as well. Blood banking is an important thing that physicians should know about, and patients should also know about it. They should have a card such that if they go to a local emergency room for perhaps trauma or a motor vehicle accident, the facility will also be aware of what’s going on.

Luckily, even though this occurs, there’s very little concern. We just published a paper revealing that there’s really no hemolytic reactions or transfusion reactions. It’s more of an artifact. And the biggest import of this is that you can delay transfusions in terms of finding the right product. The other practical implication of daratumumab (and I would broaden this to all of the monoclonal antibodies, whether it’s daratumumab or elotuzumab), checkpoint inhibitors, and all of these antibodies, is that they are typically IgG (immunoglobulin G) kappa antibodies. Why is that important? Well, in myeloma, we test paraproteins to assess response. So, if you’re making paraproteins for the myeloma, but are also giving exogenous antibody, how do you determine what is coming from what? Is it the patient or the antibody?

That can be difficult to determine. Luckily, in community practice, it probably won’t make a big difference. The main implication of these interferences is going to be significant when patients should be reaching very low levels of disease where the M-spike is nearly gone and we’re looking at either the difference between an M-spike of 0.1 and 0.2, or 0, or immunofixation-positive versus immunofixation-negative. At this low level of disease, it can be difficult to determine whether it’s the exogenous antibody or the myeloma protein. This is, obviously, only applicable to IgG kappa patients. So, if it’s an IgA (immunoglobulin A) lambda, and we know that if it’s an IgG kappa being picked up, it’s coming from the exogenous antibody.

One strategy that has developed is the daratumumab interference assay, where an anti-idiotypic antibody is added to the sample. And then, that moves daratumumab out of the way so you can see if there is any endogenous myeloma protein left. That hasn’t yet been done with all of the antibodies, but it is important for community doctors to be aware of because, perhaps somebody who is in CR (complete response) is going to be called “not in a CR,” and it may just be a low-level interference?

The final important thing to think about for daratumumab/VD is, for both the proteasome inhibitors and for daratumumab, acyclovir or valacyclovir (for Shingles prophylaxis) is recommended. It’s been known that proteasome inhibitors can reactivate Shingles in 20% of patients, and the Shingles vaccine, which is a live vaccine, is not yet recommended for hematologic malignancy. Therefore, prophylaxis is the way to go. It’s also important to remember that these are renally cleared, so the dosing of those medications needs to be adjusted for renal dysfunction.

So, this is a patient who was diagnosed with symptomatic myeloma. She got RVD (bortezomib, lenalidomide, and dexamethasone) induction, transplant, and lenalidomide maintenance. And, fortunately, in spite of having a high-risk translocation t(14;16), her remission lasted 5 years. Luckily, we have many options to choose from at the time of relapse. Really, there’s not a right answer, but the daratumumab/VD combination would be a great option and likely would give her a long remission duration.

Transcript edited for clarity.

Biochemical Progression of Stage II Myeloma

July 2011

• A 61-year-old Caucasian female was diagnosed with stage II multiple myeloma
• Genetic testing showed t(14:16)
• At the time she was treated with lenalidomide, bortezomib, and dexamethasone (RVD) induction therapy followed by autologous stem cell transplantation
• She achieved a near complete remission with RVD and transplant
• Based on her high-risk cytogenetics, the patient was placed on lenalidomide maintenance therapy

August 2016

• On routine follow up, the patient reports having mild fatigue but continues to work full-time; she has grade 1 neuropathy
  • M-protein, 1.3 g/dL
  • SFLC, kappa, 150 mg/L
  • Hb, 10.3 g/dL
  • Creatinine, 1.3 mg/dL