Vescio Debates Quadruplet Versus Triplet Therapy in Newly Diagnosed Multiple Myeloma

Robert A. Vescio, MD

Robert A. Vescio, MD, medical director Multiple Myeloma and Amyloidosis, Program Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, discussed two treatment options for a 51-year-old male patients with newly diagnosed multiple myeloma.

Targeted Oncology™: The standard treatment in general for multiple myeloma is bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone, or the VRd regimen. When would you consider using the cyclophosphamide, bortezomib, and dexamethasone (CyBorD) regimen?

VESCIO: That regimen is more useful in treating amyloidosis. I believe that lenalidomide has been challenging for some patients with amyloidosis, I think mainly because of the clotting that can occur, which can lead to nephrotic syndrome. This is the regimen that I tend to use, but I’m not certain that that’s the best regimen for these patients.

Have you been using carfilzomib (Kyprolis), lenalidomide, and dexamethasone for patients with multiple myeloma as initial treatment?

If the patient is experiencing peripheral neuropathy prior to treatment, I’ll substitute a proteasome inhibitor. Instead of Velcade, I’ll use carfilzomib if they have neuropathy. Given [a preexisting condition], it’s hard to embark on a regimen with bortezomib. It’s not always approved by insurance companies. But when I have used it, it has worked well. Insurance companies sometimes play a role [when deciding on treatment].

Have you encountered diastolic dysfunction in patients when treating with carfilzomib?

I haven’t encountered patients experiencing diastolic dysfunction. I think patients are more likely to develop cardiac dysfunction with carfilzomib over bortezomib. I treated a gentleman with amyloidosis, and he developed reversible cardiomyopathy from the drug. It is definitely something you have to watch out for. Some [patients] get significant congestive heart failure [within] 3 months [of starting] their treatment. It seems that once they get beyond that [period], it doesn’t seem to occur.

What are the data to support quadruplet therapy for newly diagnosed multiple myeloma?

Some studies have looked at typical regimens that use VRd with a stem cell transplant [SCT]. Michel Attal, MD, and colleagues compared VRd with and without SCT to determine whether there was a benefit for SCT [NCT01191060].¹ The standard regimen of VRd and an SCT led to about a 78% VGPR [very good partial response] rate versus 69% without a transplant. Adding a transplant to carfilzomib therapy did not achieve much more of a benefit.

CASSIOPEIA [NCT02541383] evaluated the benefit of adding daratumumab [Darzalex] to bortezomib, thalidomide [Thalomid], and dexamethasone [VTd] versus VTd, so a quadruplet therapy versus a triplet therapy.² The trial evaluated adults less than 65 years of age. The median age of the patients in the trial was 58 years, and most were standard-risk patients. Patients were randomized 1:1 to receive VTd with or without daratumumab.

After 4 cycles, patients received a SCT. This was followed by 2 more cycles of VTd with or without daratumumab. Arm A did not receive daratumumab, and arm B received daratumumab. After this step, patients were randomized again and observed or received daratumumab every 8 weeks until progression.

Please describe the efficacy in the CASSIOPEIA trial.

The primary end point was response, including the response after the transplant. The patients all had the transplant, and then they went on to get more cycles of either VTd or daratumumab with VTd. Then stringent complete remission [sCR] was observed to be higher in the daratumumab arm [29% vs 20%; P = .001]. The CR rate was also improved in the patients who received daratumumab, 39% versus 26%.

The investigators also noted that MRD [minimal residual disease]–negative rates were higher, as well, 64% versus 44% [in patients who received daratumumab].

What was impressive were the higher CR rates and sCR rates if patients received the daratumumab plus VTd, as well as the higher MRD-negative rates. But what was most impressive was the good progression-free survival [PFS] rates for the daratumumab plus VTd arm, with 1.5-year PFS rates approaching 90% and a hazard ratio of 0.47. So it looks promising from those results.

I have a patient who is on this regimen, and he is debating whether to do a transplant, with the whole COVID-19 [coronavirus disease 2019] scenario that we’re dealing with. He asks a lot of questions; I tend to get a lot of those types of patients. I showed him the [PFS] rates, and he was happy to see how well [patients] do if they go ahead with a transplant.

Now, if you start giving patients 4 drugs, the question [of extra adverse effects] remains. It was well tolerated. The daratumumab has some infusion reactions. There are a few patients who had secondary malignancies, which is a continuing concern, but not much else. I think daratumumab adds to bone marrow suppression. So at first, it didn’t seem to make much sense to me that daratumumab, when given as monotherapy, caused a lot of bone marrow suppression. But when it’s added in clinical trials, the rates for grade 3 and grade 4 neutropenia were higher [29% vs 15% for grade 3 and 4, respectively], thrombocytopenia was higher [11% vs 4% for grade 3/4], and lymphopenia was higher [17% vs 10% for grade 3/4].²

Overall, [this] is a well-tolerated regimen. I’ve started to give it more, mainly using it more often for my younger, pretransplant patients.

The other trial that is getting a lot of [attention] is the GRIFFIN trial [NCT02874742].3 It hasn’t been fully published yet. The regimen [in that trial] is VRd with or without daratumumab. That’s the easiest way…of thinking about it.

When you administer VRd for a patient, do you choose the day 1, 4, 8, and 11 regimen or the once-a-week regimen?

I tend to use it once a week for most patients, unless there’s some immediate need, such as if the patient is in the hospital with renal failure, and I’ve put them on CyBorD. Then I’ll maybe give the day 1, 4, 8, and 11 regimen to get a quick response.

For convenience, the once-a-week regimen is good for patients who do not want to drive. It also results in less neuropathy for the patient. I have patients who have received bortezomib 8 or 10 years ago, and they’re still complaining about the [subsequent] neuropathy.

In GRIFFIN, patients followed the day 1, 4, 8, and 11 regimen. They all had a transplant after 4 cycles. They went on to have more consolidation, followed by a maintenance regimen with either lenalidomide alone or lenalidomide plus daratumumab.

We don’t have the final answers yet, but what we do have is response rates, and the investigators reported that by the end of consolidation, all patients had responded, and during maintenance, there was a 63% sCR rate. I’ve never seen that in any other clinical trial. It looks promising.

Post consolidation, the overall response rate was 99% in patients who received daratumumab versus 91% for patients who did not. It’s still good without the daratumumab. Response rates continued to improve over time, as you might anticipate with very good response rates in the daratumumab-containing arm. The MRD-negative rates were high, with 68.8% of patients in the daratumumab arm and 32.3% of patients in the control arm reported.

The adverse effects were well tolerated and comparable between the 2 groups. There was more grade 3/4 neutropenia in the daratumumab arm [32% vs 15%] and more thrombocytopenia [16% vs 8%] and not much else that was different.

Do oncology centers still use tandem transplants for patients in this setting?

There are still cancer centers that conduct tandem transplants. It’s difficult to carry out a great randomized trial, however. The early data suggested that [patients] who are not in remission benefited by doing the tandem transplant. The past couple of [patients] I’ve done it for were those who didn’t seem to respond well to their initial therapy, and then the transplant itself was profoundly effective for them. It was clearly their best treatment, and they tolerated it reasonably well. I think you have to be a pretty good salesman to persuade [patients] to undergo 2 transplants, though.

Would you consider a bortezomib-free regimen in non– high-risk patients?

I would still use a proteasome inhibitor until proved otherwise for those patients who have the high-risk features—those with translocation(14;20), translocation(14;16), or the 17p deletion abnormalities in their myeloma cells. It does seem the proteasome inhibitors work best in them. But maybe we could get by without proteasome inhibitors in other patients? It’s a good thought.

What kind of schedule do you use for dexamethasone?

I give it weekly because I usually give bortezomib weekly. So if they take Velcade, I try to give dexamethasone the day they get bortezomib. It helps with nausea and reduces some of the adverse effects they get from the bortezomib. So I tend to base dosage on the frequency of the bortezomib. This is similar with carfilzomib, whether it’s once-a-week or twice-a-week regimens. The patients are coming in for infusions anyway, so I tend to give it with the drug. But I don’t think there’s a right answer to that.

Are you comfortable switching patients from Ninlaro (ixazomib) to Velcade, given the current COVID-19 environment?

I have not done that; I’ve kept patients on treatment. I guess my colleagues and I were focused on transplant versus no transplant during [COVID-19]. We’re back up to doing transplants. So far, so good. I know the Dana-Farber [Cancer Institute] made changes to move [patients] to oral regimens.

I had one woman who had her transplant right before this all happened, and then her husband, who travels for his job, came down with it. He tested positive. She had undergone a transplant 1.5 months prior.

She shipped him out of the house, and he recovered, and she never got sick. I didn’t test antibody titers for her. So it’s kind of strange; the whole process is kind of hard for me to understand. I haven’t had anybody get significantly ill from it, but I also had only 1 person get COVID-19, and he’s not on treatment.

_References:

_{1. Attal M, Lauwers-Cances V, Hulin C, et al; IFM 2009 Study. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376(14):1311-1320. doi:10.1056/NEJMoa1611750}

_{2. Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study Lancet. 2019;394(10192):29-38. doi:10.1016/S0140-6736(19)31240-1}

_{3. Voorhees PM, Kaufman JL, Laubach JP, et al. Daratumumab, lenalidomide, bortezomib, & dexamethasone for transplant-eligible newly diagnosed multiple myeloma: GRIFFIN. Blood. Published online April 23, 2020. doi:10.1182/blood.2020005288}