Multiple Myeloma

Ajai Chari, MD, associate professor Medicine, Hematology, and Medical Oncology, The Mount Sinai Hospital, discussed the case of a 51-year-old patient with multiple myeloma during a Targeted OncologyTM Case-Based Roundtable.

Targeted OncologyTM: What are the data for using autologous stem cell transplant (ASCT) in patients such as this?

CHARI: Some brief data from the IFM/DFCI2009 study [NCT01191060] that had VRd [lenalidomide (Revlimid), bortezomib (Velcade), dexamethasone] for 3 cycles, after which they got ASCT in the consolidation phase or got more VRd, then lenalidomide maintenance for a year. These are the French data. In the United States [DFCI (Dana-Farber Cancer Institute)] version, the lenalidomide is given until progression of disease [PD].1,2

[After 44 months of follow-up], the control arm without ASCT had a 36-month median PFS [progression-free survival] vs 50 months for the ASCT arm, so an extra 14 months. After 90 months of follow-up, the PFS didn’t change much, and the OS [overall survival] rate is not different [either], at 60.2% without ASCT vs 62.2% with ASCT.1,2 This is important because people make their decisions based on OS.

I would say that, although we always look for OS end points, our outcomes in myeloma are getting so good. If you’re going to wait for an OS end point to make treatment decisions, you’ll be waiting a long time because this was with a long follow-up of 90 months.

In 90 months, there wasn’t an OS difference, despite a significant PFS difference, which speaks to the impact of salvaged therapies. Although we can risk stratify multiple myeloma, there are high-risk patients who relapse and might be able to demonstrate OS outcomes, but not for the typical patients with multiple myeloma. The FDA routinely accepts PFS as a surrogate end point, particularly for less heavily treated patients and those with newly diagnosed multiple myeloma [NDMM], because of the prohibitive duration of follow-up. Sometimes people talk about molecular data and whether somebody should get a particular treatment. In the IFM/DFCI2009 study, relative to the hazard ratio, ASCT was better in all patients. Although [there was] a wide confidence [interval in those with high-risk cytogenetics], which is not surprising because they had [only approximately] 40 patients.

I don’t think ASCT harms patients. But [to know] whether it overcomes patients, you need well-designed prospective studies with an adequate number of patients.

There’s a lot of debate about the use of MRD [minimal residual disease] status, especially coming from chronic myeloid leukemia, where you have these deep molecular remissions, and you may think this is really practice-changing. The ASCT arm always does better than the arm without ASCT.

Whether you’re looking at standard-risk or high-risk [cytogenetics] based on transplant, standard-risk seems to do better.2 That’s an important update.

What do you consider the standard-of-care regimen for induction?

In speaking to the potential utility of MRD, the FORTE study [NCT02203643] from the Italian group is a very important study. They used a 1:1:1 randomization. There were several questions being asked, [such as] what the best induction regimen was. It was 4 cycles of KCd [carfilzomib (Kyprolis), cyclophosphamide, dexamethasone] for 1 arm vs 4 cycles of KRd [carfilzomib, lenalidomide, dexamethasone] for 2 arms.3

All 3 arms got mobilized, 2 arms got ASCT, and 1 KRd arm did not get ASCT, but went on with 8 more KRd cycles. The dosing of carfilzomib is 36 mg/m2 twice weekly. Keep that in mind because many of you [probably] do weekly chemotherapy, but here it is twice weekly for an entire year. That’s a pretty dose-intensive regimen, and we need to think how many patients, physicians, and nurses would adhere to a year of chemotherapy twice weekly. The other 2 arms received ASCT followed by KCd or KRd consolidation, and the second 1:1 randomization was to either KR or R alone maintenance.

Francesca Gay, MD, PhD, presented some updated [data at the American Society of Hematology 2020 meeting and later published in Blood].4 Interestingly, after a 1-year follow-up, there was no big difference between the ASCT and the non–ASCT arms. This is one of the limitations of MRD because it is a surrogate, but OS and PFS can also be difficult, and MRD doesn’t preclude you from needing to follow up patients with these survival-based end points that are being used as surrogates.

Based on median PFS, the winner—by far—is the KRd plus ASCT, then the arm with 12 cycles of KRd [KRd12], then KCd plus ASCT. KRd12 without ASCT did better than KCd.4 This is an important take-home message because it confirms the older IFM2013-04 study [NCT01971658] that VTd [bortezomib, thalidomide (Thalomid), dexamethasone] was superior to VCd [bortezomib, cyclophosphamide, dexamethasone] by efficacy. It seems a better partner for a PI [proteasome inhibitor] is [an immunomodulatory drug (IMiD)], whether in Europe you use thalidomide [or] in the United States you use lenalidomide.

It seems like the IMiD plus PI combination is better. I still think there may be slight exceptions for somebody who is admitted in the hospital with renal failure or cord compression, and you need to start treatment immediately. You may have some issues with getting [an IMiD]. In the real world, just because you start somebody on a [cyclophosphamide]-based regimen, doesn’t mean with the next cycle you couldn’t switch, but in the European policy, they’re pretty much locked into it.

[The] first message is [that] the KRd is superior. The second message is [that], although MRD [initially] suggested relatively comparable results—with the notable exception that even early on there would seem to be a benefit for high-risk patients going to transplant— with a longer 45-month follow-up, ASCT with KRd did the best and was statistically significantly better than the non–ASCT group.

Pretty much everybody benefited from ASCT, so KRd with ASCT is favored, and the HRs are well below 1 [across the board], with a few crossing the 1 threshold because, again, smaller numbers. The message here is [that] if KRd 36 mg/m2 twice weekly for an entire year did not beat ASCT, then that gives us pause as to the utility of MRD as a surrogate for decision-making and the importance of how you get to a particular remission.4

Now we have both the French data for VRd with ASCT with a 90-month follow-up and KRd with a 45-month follow-up, and both studies show that, even in 2021, ASCT has not gone away. If you want to displace ASCT, I argue that you need to show that novel regimens are doing better than it. Not only have we not seen that they’re not doing better but they are also not keeping up with it, so we still have work to do. We’ll see what the newer regimens are, but we should still be considering ASCT, [especially] for patients below age 70.

One of the tricky parts is, for patients over age 70 or 75, you need to reduce the melphalan [Alkeran] dose typically to condition for the ASCT. Then you are in a [murkier] situation.

The second randomization was the KR vs R, and the KR [seemingly] did better across all subgroups, showing the utility of doublet maintenance therapy.

The carfilzomib dosing for the maintenance is 36 mg/m2 on day 1, 2, 15, and 16. So it’s still 4 visits per month, which is a big ask, but it is an option for patients.

Can you discuss trials looking at quadruplet therapy?

In the CASSIOPEIA study [NCT02541383], everybody was transplant eligible. All patients received 4 cycles of VTd or VTd plus daratumumab [Darzalex; D-VTd], stem cell collection, ASCT, then 2 cycles of consolidation with VTd or D-VTd.5

There was an important difference in the United States version of this study. In the CASSIOPEIA study, there’s a possibility a patient could get daratumumab up front in induction and consolidation but not get it in maintenance. In the United States version, it is daratumumab throughout, and there is no double randomization. Another difference is, in this study, the daratumumab maintenance started off every 8 weeks. That’s important because we now have pharmacokinetic data, and we all know daratumumab is a monoclonal antibody, but the trough level is quite below where we think efficacy is maintained. In the United States study, daratumumab also started off at 8 weeks, then it was modified to go to monthly for every-4-week dosing of maintenance. Those are the 2 major differences other than [lenalidomide use in the United States one].

The CASSIOPEIA study was a large study with 1000 patients that had 2-part end points. One randomization before induction, and [the second randomization before maintenance].

What was the efficacy in the CASSIOPEIA trial?

The [first] primary end point was stringent complete response [sCR], and that was favorable. It was 29% for the quadruplet arm vs 20% for the triplet arm, which was statistically significant [P ≤ .001].

MRD negativity status was 64% in the quadruplet arm vs 44% in the triplet arm, which was also statistically significant [P < .0001]. The take-home message is [that] we currently have deeper responses with the addition of daratumumab. Everybody seemed to benefit in [the subgroup analysis], except the high-risk patients.

In the high-risk population, there was a difference between improving, overcoming, and hurting. The addition of daratumumab didn’t overcome high-risk, but it also did not hurt those patients. The high-risk group remains an unmet need, and we still need to do better. With continuing therapy, both arms have a deepening of response, but the quadruplet arm always seems to do better.

Source :

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