Importance of Achieving MRD Negativity Considered for Transplant-Eligible Multiple Myeloma

Rafael Fonseca, MD

Regarding the case of a 51-year-old man who first presented with pallor and worsening fatigue on exertion and was diagnosed with transplant-eligible multiple myeloma, Rafael Fonseca, MD, the director and chair of the Department of Internal Medicine, and professor of Medicine at the Mayo Clinic Cancer Center in Phoenix, Arizona, discussed available treatment options.

Targeted Oncology^TM: What primary therapies are available to this patient?

FONSECA: The NCCN [National Comprehensive Cancer Network] guidelines for multiple myeloma are broad, with a range of options for patients who are transplant candidates.¹

VRd [bortezomib (Velcade), lenalidomide (Revlimid), dexamethasone] is the preferred regimen, as well as bortezomib/ cyclophosphamide [Cytoxan]/dexamethasone, which we have moved from based on some clinical trials. Combinations do a better job in producing deep responses.

Other recommended regimens include the combination of KRd [carfilzomib (Kyprolis), lenalidomide, dexamethasone], the quadruplet therapy D-VRd [daratumumab (Darzalex) plus VRd], and then other options including oral prednisone, lenalidomide, [ixazomib (Ninlaro)], which with rare exceptions would be used if someone lives incredibly far away or had access to some injectable medication, but it’s hard to justify [its use based on] efficacy.

In your own practice, how frequently do you use cyclophosphamide, bortezomib, dexamethasone (CyBorD) as a frontline treatment, and in which type of patient?

Most patients are started with a lenalidomide-containing combination. The exception to that is patients with aggressive disease where you need to start them on treatment on the same day; for example, patients with severe hypercalcemia or acute renal failure are started on CyBorD.

We’ve used CyBorD for patients with light chain–associated amyloidosis, and if someone could not access or didn’t have the possibility for a [lenalidomide-containing combination], we would use [CyBorD], but this is probably less than 10% of patients.

Although CyBorD is a convenient and easy regimen, the results of the clinical trials show superiority for a lenalidomide-containing regimen, so that’s why we have moved away [from it] for most patients.

What clinical trials have been carried out in patients with newly diagnosed multiple myeloma who are eligible for transplant?

The IFM/DFCI2009 trial [NCT01191060] had patients on VRd with transplant versus VRd alone. It was a sizable clinical trial, with 700 patients.^2,3

The FORTE trial [NCT02203643] focused primarily on patients treated with KRd with transplant versus KRd alone. There was a third [experimental] arm that used KCd [carfilzomib, cyclophosphamide, dexamethasone] that didn’t live up to the standards of the other 2 [arms].^4,5

The CASSIOPEIA trial [NCT02541383] had patients on VTd [bortezomib, thalidomide (Thalomid), dexamethasone] versus D-VTd [daratumumab plus VTd]. Thalidomide is not as applicable in the United States, but the lessons remain. It was carried out in over 1000 patients on either the quadruplet or triplet therapy.⁶

Lastly, a randomized phase 2 trial, the GRIFFIN study [NCT02874742], had patients on D-VRd versus VRd.^7,8

Can you go into more detail on the IFM/DFCI2009 study?

The IFM/DFCI2009 trial was built on the idea that perhaps we could dispense of autologous stem cell transplant [ASCT] as an option for patients with multiple myeloma. It started in 2009, essentially.

Patients would get 3 cycles [of VRd] and then either stem cell collection and transplant [or no transplant] and then followed by 2 more cycles, for a total of 8 cycles. After that, patients were placed on maintenance [therapy].²

The PFS [progression-free survival] was in favor of transplants, so I think that patients who are transplant candidates should consider it [47.3 months vs 35.0 months].

At 8 years, the overall survival [OS] seemed similar, at 62.2% versus 60.2%.3 It’s one of those trials that is like a Rorschach test that people interpret whichever way they prefer People who don’t think much of transplant might say, “You see, the results are about the same.”

But on the other hand, as the data mature with this and other trials, it seems as if transplant adds OS, [same as] with the FORTE trial, but these data are still evolving, and we need many years of follow-up.

It was initially thought that achieving MRD [minimal residual disease] status, whether that was with or without transplant, was the goal and that the results would be similar. Being MRD negative is better than being MRD positive, but some would argue you still see a difference between the MRD negativity quality of those who get a transplant versus thWhen the status of patients according to their ability

The outcomes according to treatment and MRD status show that transplant [improves outcomes] in PFS [not reached vs 29 months].

When the status of patients according to their ability to achieve MRD negativity and their risk classification are compared, patients who are MRD negative with standard- risk genetic features do best. Interestingly, the next group are patients who are MRD negative who had high-risk cytogenetic features, who do even much better than those who have standard-risk markers but remain MRD positive. Last are those who are MRD positive and have high-risk features. One can argue that achievement of MRD-negative status can overcome some of the limitations of high-risk genetic features.³

The lesson is that it doesn’t matter when you achieve MRD negativity. If you achieved it before maintenance or even 1 year after maintenance, the outcomes were similar, so that PFS was not reached at both 29 and 20 months for those who were not MRD negative.

We’ve learned quite a bit from [the IFM/DFCI2009] clinical trial, and we’ll continue to monitor it as time goes by. But it seems as if achievement of MRD is important. The MRD quality seems to be slightly better with transplant, and it doesn’t matter when one achieves MRD.

How did patients do on the FORTE study?

Another important trial, FORTE is a 3-arm trial presented at ASH [American Society of Hematology] 2020.^4,5

The first arm is KCd, then ASCT plus more KCd. The second arm is KRd, then ASCT followed by more KRd. The third arm is just KRd straight for 12 cycles [of treatment].

There is a second randomization, and after completion of the induction and consolidation period, patients were randomized to receive either lenalidomide alone or lenalidomide plus carfilzomib. KCd with ASCT seems to have worse PFS compared with the other 2 treatment arms. Originally, it appeared the PFS was going to be very similar between the KRd alone versus KRd with ASCT [arms], but as we follow patients longer, it seems as if the KRd plus ASCT does have the edge over the other 2 treatment arms.

A direct comparison of just KRd and ASCT versus KRd alone again shows that there is an advantage for the transplant [HR, 0.64; P = .023].

The idea is that as long as patients get more of a better treatment, they will do better. For the second randomization, patients who have completed the induction phase, transplant, and consolidation phase have the second randomization to either lenalidomide or lenalidomide plus carfilzomib.

There is a little bit of an edge for the 2 drugs versus 1 drug. At 36 months, the PFS is 75% for the 2-drug arm versus 66% for the 1-drug arm [HR, 0.63; P = .026].

Hopefully, in the future, a more intensive induction and more rapidly achieved MRD can make us treat patients for a shorter [duration]. What really becomes clear is that you have to do the best job possible to put the patients into an MRD-negative status.

What was the efficacy of the CASSIOPEIA trial in these patients?

The CASSIOPEIA study is a phase 3 trial. It’s a very large 1:1 randomization, over 1000 patients on VTd versus D-VTd.⁶ We don’t use thalidomide in the United States, but the randomization is pretty powerful. So we can infer some of the implications of this for our clinical practice.

Patients were randomized to 4 cycles of either [VTd or D-VTd for the induction phase, followed by] stem cell mobilization and transplant and then 2 more cycles of either VTd or D-VTd for [the consolidation phase]. Then there’s a second randomization of [responsive patients to either] observation or daratumumab every 8 weeks until progressive disease. The early metrics might predict what happens down the line; the stringent complete response [sCR], which is the primary end point, was at 29% for D-VTd versus 20% for VTd [odds ratio, 1.60; 95% CI, 1.21- 2.12; P = .001].

[The difference in percentage] doesn’t seem like a lot, but it’s statistically significant, and when you start adding these absolute points in percentages, they add up over time. When they looked at the different subgroups, [attainment of sCR] appeared to be more common with D-VTd.

MRD-negative status was also more common in patients who had the 4 drugs, at 64% versus 44%, which again was highly significant [P < .0001]. All the response rates on VTd versus D-VTd were compared. The MRD-negative rates [based on] both flow [cytometry] and next-generation sequencing were also recorded.

Importantly, [the PFS rate for] D-VTd is close to 90% at 33 months, which is a pretty good result. The outcomes show durable control of the disease.

What trial results have shown a potential benefit for quadruplet therapy in transplant-eligible patients with newly diagnosed multiple myeloma?

The GRIFFIN clinical trial is a randomized phase 2 [study with] the primary end point being sCR again. They were trying to prove whether 4 drugs [D-VRd] are better than 3 drugs [VRd].⁷

There were 4 cycles [for the drug induction phase], followed by transplant, and then 2 more cycles for the consolidation [phase]. There is a maintenance phase depending on whether you started with daratumumab. So you use daratumumab/lenalidomide, and if you didn’t, then just lenalidomide for maintenance.

An update was presented at the ASH 2020 meeting by Kaufmann JL et al.⁸ For the response categories, the sCR of the 4 drugs [was compared with] the sCR of the 3 drugs. It’s almost 20 absolute percentage points of difference between the 4 drugs and the 3 drugs [47.4% vs 63.6%; P = .0253]. We have seen across the board for most clinical trials that the depth of the response is associated with a longer duration of disease control, so a better PFS.

For the subgroup analyses of sCR and MRD negativity rates in the VRd versus D-VRd arm, most of the markers favor the 4-drug combination.⁹ This applies irrespective of the sex, age, [ISS disease] stage, and type of myeloma but with the exception of patients with high-risk [cytogenetics]. It’s hard to make an argument against something being used in higher-risk myeloma, but those are the data that we have.

For the GRIFFIN study, we have the PFS rate for the 4 drugs, which is close to 95% of the patients after 3 years and a bit less for the 3 drugs [90.8% at 24 months]. The OS rate is similar for both D-VRd and VRd [94.7% vs 93.5% at 24 months].

Some of the toxicities we would be looking for are signals of the addition of daratumumab. Not surprisingly, infusionrelated reactions are seen in 6% of patients; perhaps a bit more diarrhea, although the numbers are small, but overall, they seem quite comparable with both treatment arms.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 4.2021. Accessed May 12, 2021. https://bit.ly/3fa9Yx5}

_{2. Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376(14):1311-1320. doi:10.1056/NEJMoa1611750}

_{3. Perrot A, Lauwers-Cances V, Cazaubiel T, et al. Early versus late autologous stem cell transplant in newly diagnosed multiple myeloma: long-term follow-up analysis of the IFM 2009 trial. Blood. 2020;136(suppl 1):39. doi:10.1182/blood-2020-134538}

_{4. Gay F, Cerrato C, Petrucci MT, et al. Efficacy of carfilzomib lenalidomide dexamethasone (KRd) with or without transplantation in newly diagnosed myeloma according to risk status: results from the FORTE trial. J Clin Oncol. 2019;37 (suppl 15):8002. doi:10.1200/JCO.2019.37.15_suppl.8002}

_{5. Gay F, Musto P, Scalabrini DR, et al. Survival analysis of newly diagnosed transplant-eligible multiple myeloma patients in the randomized Forte trial. Blood. 2020;136(suppl 1):35-37. doi:10.1182/blood-2020-136907}

_{6. 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}

_{7. Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;136(8):936-945. doi:10.1182/blood.2020005288}

_{8. Kaufman JL, Laubach JP, Sborov D, et al. Daratumumab (DARA) plus lenalidomide, bortezomib, and dexamethasone (RVd) in patients with transplant-eligible newly diagnosed multiple myeloma (NDMM): updated analysis of Griffin after 12 months of maintenance therapy. Blood. 2020;136(suppl 1):45-46. doi:10.1182/blood-2020-137109}

_{9. Perrot A, Lauwers-Cances V, Corre J, et al. Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma. Blood. 2018;132(23):2456-2464. doi:10.1182/blood-2018-06-858613}