Landgren Spotlights Safety Considerations for Carfilzomib Quadruplet in Newly Diagnosed Myeloma

When administering the novel weekly 4-drug regimen comprised of carfilzomib (Kyprolis), lenalidomide (Revlimid), dexamethasone, and daratumumab (Darzalex; KRd-D) in newly diagnosed patients with multiple myeloma, factors like prophylactic medications and optimal fluid administration must be considered, according to C. Ola Landgren, MD, PhD.

“[We need] to really be on [the top of our] game and know what is needed. If you are going to deliver these good drugs, you need to have the right supportive drugs,” Landgren underscored. “[It’s] the same thing [with fluid]. If you give half a liter of fluid before and after the infusions with carfilzomib, you are going to run [the risk of] congestive heart failure…You have to give the optimal fluid and have the right prophylactic medicine. Attention to [these details] is very important.”

In an interview with OncLive^®, Landgren, the inaugural leader of the Experimental Therapeutics Program at Sylvester Comprehensive Cancer Center, Miami Health System, discussed key safety considerations with a novel carfilzomib quadruplet regimen in patients with newly diagnosed multiple myeloma, the clinical implications of the phase 2 MANHATTAN trial (NCT03290950), and next steps for this research.

OncLive^®: What was the tolerability of the 4-drug regimen examined in MANHATTAN and what factors should be considered to ensure the appropriate management of patients who receive it?

Landgren: One thing that is sometimes a little bit overlooked is the attention to detail [that is needed] for [optimal] clinical management; [this includes] how [drugs] are delivered and all the other surrounding [factors], such as the different types of prophylactic medications, as well as fluid administration, and careful assessment of patients. Many times, people tend to forget about this. The older drugs were less effective, but they were, at the same time, potentially a little bit easier to give. The newer drugs are more effective and better, but many of them [require] more attention. You have to have good anticoagulation if you are going to use good drugs.

Are any next steps planned for this research?

Yes. These results are the best we have ever seen in the newly diagnosed setting. Beyond the efficacy [observed], in terms of the high rates of minimal residual disease [MRD] negativity, we also did not see the high rate of peripheral neuropathy that you see with bortezomib [Velcade]. That is also one thing that we get used to; no one is hiding it [or] lying about it, because it happens all the time, but we kind of stop thinking about it. If you go back and look through the data, the bortezomib studies have been around for 15 years or so. Many patients who are treated with this therapy, maybe up to half, experience chronic peripheral neuropathy in [their] fingers and toes, which is something they will have to manage for the rest of their life; it impacts [them] every day. [Patients] have to be on medications and some even require a walker. Not every patient will experience this effect, but it is not a trivial proportion of patients [who] do.

With the regimen, you do not see that because carfilzomib does not cause peripheral neuropathy; that is important. For that reason, we felt that this [regimen] has to go forward to be validated and tested in a large study. We have already launched the large, randomized 2 ADVANCE study [NCT04268498]; this is open to newly diagnosed patients and compares this new therapy with the standard of care.

What are the clinical implications of the MANHATTAN trial? What should be taken away?

[These data] show that you can achieve very deep responses in patients with a modern therapy in the absence of a bone marrow transplantation. Once-a-week dosing is a very reasonable schedule for a defined period of time. I do not know that going forward every patient will need 8 cycles. If you look at the time to reaching MRD negativity, [some] patients reach negativity after just 1 to 6 cycles. The median time [to MRD negativity] is around 6 cycles. As such, thinking about getting an injection and infusion once a week—3-weeks-on and 1-week-off for this number of cycles—compared with other options like bone marrow transplantation and all the toxicities [that come with it], such as sustained peripheral neuropathy, [this approach is worth it]. If you look at the value proposition of receiving a modern 4-drug combination with such a high rate of MRD negativity, it really pushes the field forward and provides a new option for patients with newly diagnosed disease.

Data demonstrate that if you use the best drugs in every line of therapy, that means that you will lose fewer patients for the next line [of treatment]. If the disease relapses and comes back [because] patients were not treated properly, some will have so much disease that they will not make it to the next line [of therapy]. The emphasis on using optimal drugs in every line is there, and it starts with the first line.

The last thing I want to say is that this is not for every patient; unfortunately, [this regimen is] not for every doctor either. [To give this,] you must pay attention to detail. You have to be on top of the anticoagulation and the intravenous fluids. In my practice, I do an echocardiogram of the heart and an electrocardiogram for every patient before I start [my patients] on therapy. I would also assess the blood pressure and would adjust that, [if needed]; if it is too high, I would treat that. If there are any concerns, I would be more careful with these types of therapies. However, if you do not see [these issues], which is true for many patients, and no other underlying comorbidity [is observed], this is an excellent therapy.