Berdeja Compares Later-Line Therapies in Multiple Myeloma

Jesus G. Berdeja, MD

As part of a virtual Case Based Peer Perspective event, Jesus G. Berdeja, MC, director of Myeloma Research, Sarah Cannon Research Institute, in Nashville, Tennesee, discussed the treatment options for stage II multilple myeloma, based on a case of a 71-year female patient.

Targeted Oncology™: Is this patient experiencing a biochemical or clinical relapse?

BERDEJA: This patient is not just having a biochemical relapse. I think we all see patients who we’re following on maintenance, and all of a sudden, their M protein is rising. The light chains are rising, but there are no symptoms or no other findings that warn you that disease is clinically progressing. In this patient’s case, she has become anemic, and she’s fatigued. Clearly this is not just a biochemical relapse. This is a clinical relapse. That’s definitely a reason to start treatment and not delay.

Would you recommend imaging for this patient to confirm relapse?

In terms of imaging, the guidelines are not perfect. Traditionally, we have been doing skeletal surveys, and the truth is, skeletal surveys are terrible. It takes about 40% bone destruction before you see it on x-rays. Most of the patients will be symptomatic before you pick it up on x-ray. We’ve been moving away from that. There’s a lot of literature, especially coming from Europe, that suggests that a low-dose CT scan is preferable [to an x-ray] and is relatively cost-efficient. It’s quick, and you can see the whole skeleton quickly. It provides a significant improvement in sensitivity over a skeletal survey. If we were in Europe right now, you would order a whole body low-dose CT.

In the United States, radiologists have not figured out how to perform a low-dose CT by itself and get reimbursed for it, so we cannot order a low-dose CT. The next best thing is the PET/ CT [scan]. The CT part of the PET is the low-dose CT. It’s important that you get a whole body PET/CT, not just standard PET. You want the radiologist to read the CT portion and give you the skeletal findings.

The PET portion adds more than just the low-dose CT. Lesions will show up , and then you can follow the patient, because the PET portion of a PET/CT can be used follow response.

In general, for a patient [who needs] a new baseline to assess for new disease, I would say I would do a PET/CT. If your PET/ CT shows something of concern or is equivocal, [if it] shows a particular area where the patient’s hurting or is having obviously cord compression or something to that effect, when you need to visualize the bone and the soft tissues around it, the MRI is much more sensitive than the PET/CT. That’s when I would use an MRI instead of a PET/CT.

Have you experienced difficulties getting a PET/CT approved by the insurer?

Getting an insurer to cover a PET CT should not be a challenge. One way to ensure that the studies get approved is to include the code for bone metastases. If you include that code with the diagnosis of myeloma, then it never gets declined [by] insurance.

That might save you some calls to the insurance [company]. So far, I’ve been pretty lucky. I have not heard that people are getting declined anymore.

What would you choose for this patient after progression on lenalidomide? The good news in myeloma is that there are a lot of active regimens. The bad news is that none of these regimens has ever been compared head to head. So you have to decide which of these regimens makes sense.

What we know from the data is that, in general, triplet therapy is better than doublet therapy. If at all possible, you should always be treating your patient on a triplet instead of a doublet. And the third drug is always dexamethasone. The bottom line is every time you compare a triplet to a doublet, regardless of the line of therapy, the triplet always wins. So the question is, you know, how much better is it?

From my experience, what I consider to be the strongest combination is the daratumumab [Darzalex], lenalidomide, and dexamethasone based on results from the POLLUX study [NCT02076009].¹ The investigators reported a significant benefit in progression-free survival [PFS], which was not reached after a median follow up of 13.5 months [HR, 0.37; 95% CI, 0.28- 0.53; P < .001].

The majority of these patients in the trial were lenalidomide naïve, which is not our patient population. For the most part, most of our patients in the first line are going to have lenalidomide somewhere along the way, whether it was just part of their introduction or even their maintenance, as is the patient in this case, who is now progressing on lenalidomide maintenance.

How does the clinician decide which regimen to pick?

It’s going to have to come down to several things. One is what [treatments] have been used before? What was the patient’s tolerance, how well did they respond, and for how long did they respond?

If you give someone VRd and they progress on treatment or within 3 months, you’re probably not going to want to go back to those drugs—whereas if someone received this regimen 3 years prior and now they’re just on low-dose lenalidomide maintenance, you might think they’re still sensitive to those drugs. In that case, you might consider going back to those drugs. That’s definitely an important part of the picture here.

The other [factor to consider] has to do with the toxicity and the patient’s tolerance. If a patient developed a severe neuropathy with bortezomib, you’re probably not going to want to go back to an agent that causes peripheral neuropathy again. Or, if the patient has a really hard time with cytopenias with the IMiDs [immunomodulatory drugs], you may want to stay away from the IMiDs for the next line. That’s basically the kind of thing you need to consider when choosing the next regimen. I think another thing [to consider] is the patient’s wishes.

You would also consider if the patient just wants to maintain things and keep things from getting worse, compared with wanting a robust response. If the patient reads up on all the different [cancer] blogs, and they want MRD [minimal residual disease], and they want the best combination, that’s a different patient than your patient who may want to just not feel sick with the disease. Or your patient may say, “I can’t make those trips to the clinic every week, so I would rather have an oral combination.” I think those are the kind of things to consider.

Do you take into consideration whether the patient is potentially eligible to go through a second ASCT?

If your patient is potentially interested in a second transplant, that’s the patient who wants aggressive therapy. I would defi - nitely be choosing a more aggressive regimen for them. The only caveat, I would say, is second transplants are even more controversial to me than which therapy to choose.

A salvage transplant, which means a transplant you do at the time of relapse, as opposed to a transplant [in] tandem when you do it back to back with the first, seems to benefit patients who had at least a PFS of 2 years following their initial transplant. The data suggest that’s the time frame to consider salvage transplants. But those studies were done before the age of maintenance.

If the patient has received maintenance after the initial transplant, then you’d expect the patient should remain at least 3 or 4 years in remission before being considered for a salvage transplant. If the patient relapses 2 years after, I probably wouldn’t be too quick to go for a salvage. But let’s say your patient does relapse, like this patient, after 5 years. If you have cells stored, I think it’s reasonable to consider.

Some patients have a hard time with continuing therapy. So if the patient is going to be able to continue their therapy, that may be a patient you want to take to transplant. In that case, I think you will get control much longer than if they just stop therapy after 6 months and then go on no therapy or a break.

What are the new agents or combinations available for previously treated myeloma?

The ICARIA-MM trial [NCT02990338] resulted in the approval of the combination of isatuximab pomalidomide, and dexamethasone by the FDA.² Isatuximab is an anti–CD38 antibody very much like daratumumab. This study was conducted with patients who’ve had at least 2 prior lines of therapy and then had lenalidomide and at least 1 proteasome inhibitor. These are patients who are CD38 naïve and pomalidomide naïve. So 307 patients were randomized 1:1 to pomalidomide and dexamethasone or pomalidomide and dexamethasone with isatuximab. Isatuximab was given intravenously on days 1, 8, 15, 22 for the first cycle.

After that, the dose is given every other week….A little bit different from daratumumab, where daratumumab is administered weekly for 8 weeks and then every other week and then every other week for 8 doses, and then once every 4 weeks. So initially, this is given less frequently. But in the long term, daratumumab is given less frequently than isatuximab. The patients had a median of 3 prior lines of therapy in this study. Ninety percent of them were lenalidomide refractory; 76% were proteasome inhibitor refractory; and 73% were considered double refractory.

The primary end point was PFS. The cohort that received isatuximab and pomalidomide had a PFS of 11.53 months compared with the control, which had a PFS of 6.47 months [HR, 0.596; 95% CI, 0.436-0.814; P = .001] in these patients who were mostly third line and above.

How did patients in the subgroup analysis respond?

Every subcategory of patient benefited from the addition of isatuximab, including patients who were over age 75. They had a significant benefit to the addition. And that’s a good point, not just with this antibody; with most antibodies I find that, at least toxicity-wise, they don’t seem to add too much. So I think we could give it to our patients who are a little more frail.

In patients who had high-risk cytogenetics, there was a benefit. Also, the patients who were lenalidomide refractory benefited from the triplet because you would think the pomalidomide by itself should be helpful but adding the third drug helped.

What was the overall survival in this study?

Patients who received the triplet therapy lived longer, 72%, compared with the control, 60%, with a hazard ratio of 0.68 [95% CI, 0.461-1.023; P = .0631]. In terms of responses, adding the third drug led to an increase in overall response rate but you also see a deepening of the response rate. Only 7% of patients had a VGPR; 2% had a CR or better. For the isatuximab combination, 27% of patients have VGPR, 5% had CR [FIGURE].²

What is the safety profile?

In terms of safety, there was nothing too dissimilar between the 2 cohorts. However, 38% of patients had infusion reaction of all grades, mostly grade 1 and 2. Rarely, you had grade 3/4 infusion reaction. This is better than daratumumab.

Patients experienced neutropenia and thrombocytopenia, but not too dissimilar between both groups, which tells you that for the most part it is the pomalidomide, which as we all know is hard on the marrow. All of the toxicities were similar.

How does the dosing for isatuximab compare with daratumumab?

A daratumumab infusion takes 8 hours. The first dose of singleagent daratumumab takes about 7 hours on average. There’s split dosing that you could do but the patient is there for 4 hours on 2 different days. Moving forward, the dose goes down to 2 to 3 hours. I think you could probably go down to about 2 hours, maybe even 90 minutes for some patients.

With isatuximab, given that the first infusion is much shorter, it’s only a little over 3 hours. Then, after the initial dose, most patients don’t have reactions. Infusions are about 2 hours and then down to 75 minutes thereafter. So it’s definitely a userfriendlier antibody for our nursing staff in the clinic. Much to the chagrin of isatuximab, now we also have subcutaneous daratumumab. I think that’s something that you also need to take into account.

_References:

_{1. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(14):1319-1331. doi:10.1056/NEJMoa1607751}

_{2. Attal M, Richardson PG, Rajkumar SV, et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet. 2019;394(10214):2096-2107. doi:10.1016/S0140-6736(19)32556-5}