Dhakal Discusses Important Considerations for Treating Newly Diagnosed Multiple Myeloma

Binod Dhakal, MD, MS

Associate Professor of Medicine

Medical College of Wisconsin

Milwaukee, WI

Targeted Oncology^TM: What data are most important to you in selecting treatment, including transplant, for newly diagnosed, transplant-eligible patients with multiple myeloma?

DHAKAL: I would say the most important study in the context of modern therapy was the IFM 2009 trial [NCT01191060].^1,2 All the studies prior to that, or even in the modern era, used either doublet [therapies] or different triplets, [treatments that are] not used in the United States, or [at least] not the standard clinical trials. This is the 1 study that tried to establish the role of transplant with triplet induction; [the triplet was] VRd [bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone].

At the same time, this [study] also tried to answer the question of whether we can delay transplant in [some] patients. Or do we need to do earlier transplant? There were about 700 patients in this French study, the IFM 2009, and all were transplant eligible. Transplant eligibility was decided based on multiple factors. Eligible patients were aged 65 years or less. Based on that, the patient population was not representative of what you see in the United States.

[The IFM 2009 study included 2 arms: VRd without transplant and VRd with transplant.]¹ Induction therapy with 3 cycles of VRd was given to [patients in] both arms. After [induction therapy, both arms] underwent stem cell mobilization with cyclophosphamide [Cytoxan] plus granulocyte colony-stimulating factor, followed by stem cell collection, [but only the VRd with transplant arm received a stem cell transplant]. Consolidation therapy included melphalan [Alkeran] at 200 mg/m² in the transplant arm, followed by 2 cycles of VRd [with a lower dexamethasone dose than in the induction phase].^1,2 Consolidation therapy in the [nontransplant arm was] another 4 to 8 cycles of VRd with a lower dose of dexamethasone, but without melphalan.

Then [patients in] both arms went on to lenalidomide maintenance for about 1 year. [Salvage therapy with a second-line treatment was allowed in patients with disease progression in both arms]. Following second-line treatment, salvage stem cell transplants were allowed in both arms, which gives us data for patients with early transplants [during the study and those who had delayed transplants as salvage therapy].

[There are both] early data [at approximately 3 years] and 8-year follow-up data.^1,2 [The data at 3 years showed a] median progression-free survival [PFS] of 50 months. At the 8-year [follow-up], [which is the latest follow-up data we have and were presented at the American Society of Hematology (ASH) Annual Meeting], the duration of survival was pretty much comparable [to other data], as long there was a delayed transplant arm.^2,3 Basically, this shows that patients with early vs late transplants are going to have similar survival, but if you transplant early, there is a chance that the disease will remain in remission much longer; it was significantly much longer than in the delayed transplant arm. If you look at the study in more detail, it was designed for the patients who had a first relapse. They were mandated to get the first transplant at relapse. However, [only] 79% of the patients were able to get the first transplant at relapse, for several reasons.

In the subgroup analysis, they determined minimum residual disease [MRD] status by flow [cytometry] initially; later, they also did next-generation sequencing at the 10^-6 level of sensitivity.^2,3 The MRD-negative rates in the transplant arm were much higher, almost 10% higher, than in the VRd-alone arm.

[For patients who underwent] transplant early, the chance of a deep response, including the highly sensitive MRD-negativity rates, was also much higher [than in the late] transplant arm. We have several studies that show that achieving MRD negativity post-transplant is prognostic of [a good] outcome. Given the fact that many patients can achieve MRD negativity after transplant, I think that early transplant is probably a better option [in terms of achieving a deep response].

Based on these data, how do you make decisions regarding when to perform transplantation?

That is the critical question: whether to delay the transplant or do the transplant early.^1-3 Given that there was similar survival in the early vs delayed transplant subgroups, there is variability across institutions in terms of when transplant is performed. If you ask me, I prefer to do transplants early just based on the IFM study; the patients achieved deep responses and higher MRD-negativity rates.

Also, if you wait, about 21% of patients won’t be able to get the transplant at the later stage. For those reasons, I tend to do transplants early, particularly with high-risk patients, because MRD negativity becomes even more important for them than for standard-risk [patients]. The other study that was just recently published, the Italian FORTE study [NCT02203643], also tried to further confirm the benefit of transplant, even with current induction regimens.^4,5

KRd [carfilzomib (Kyprolis), lenalidomide, and dexamethasone] was the key induction regimen [in this study], and there were 3 arms. One was KCd [carfilzomib, cyclophosphamide, and dexamethasone] for 4 cycles, followed by stem cell transplant.

Then, [patients received] 4 cycles of the same [regimen for] consolidation, followed by [a second] randomization [for maintenance therapy], which was lenalidomide monotherapy vs carfilzomib plus lenalidomide. In addition to establishing the benefit of transplant vs no transplant, the study aimed to compare the benefit of doublet vs monotherapy maintenance in the current setting.

Patients in the second arm received 4 cycles of KRd and then, like the first group, they underwent stem cell transplant. After another 4 cycles of KRd consolidation, they were randomized to lenalidomide vs carfilzomib plus lenalidomide.^4,5 The last group didn’t undergo transplant; they had 4 [cycles of] KRd induction, and 8 [cycles] of KRd consolidation. Then there was a second randomization [for maintenance therapy].

The primary end point was the response rate [of the treatment], in terms of the PFS.^4,5 The transplant plus KRd arm had superior PFS compared with the patients who received 12 cycles of KRd, and both were substantially superior to the KCd plus transplant arm.

There is no doubt that using 3 drugs, especially immunomodulatory drug [IMiD] and proteasome inhibitor combinations, is superior to the cyclophosphamide-based regimen with the proteasome inhibitor and transplant. What this trial also established is that transplant continues to drive the benefit in the current setting. The subgroup analysis [data from the] first randomization [showed that the] transplant plus KRd group had the greatest benefit in almost all settings, including high-risk cytogenetics.

Additionally, data [showed that] the KRd transplant group and the [group that received 12 cycles of KRd] achieved the same rates of MRD negativity, about 55% or 56%, after consolidation.⁵ But the data also showed that among MRD-negative patients who had a transplant, about 90% were able to sustain the MRD negativity, which was significantly higher than in the KRd-only group.

That showed that transplant not only helps patients achieve deep responses but also helps them sustain those responses over time. Again, this is a very important end point that we need to look at specifically in patients with aggressive disease and high-risk patients. This study established, even more strongly, the benefit of transplant despite using effective induction with the KRd treatment, despite achieving a very deep response and higher MRD negativity rate.

What other data do you believe are important for combination drug regimens in treating transplant-eligible patients with myeloma?

The second part of the study [looked at] maintenance,^4,5 and this is the first time that we established the benefit of [using] doublet maintenance in myeloma. In the randomization, 356 patients were randomized to either the KR or lenalidomide [maintenance groups].

Response rates, MRD negativity rates, and PFS were higher in the patients with the KR maintenance, so [this study] showed the benefit of the doublet maintenance in this patient population. The subgroup analysis showed that all the subgroups benefited, including patients with high-risk cytogenetics. The 3-year PFS rate from the second randomization was 75% in the doublet group vs 66%, and that is statistically significant [hazard ratio (HR), 0.63; P = .026).

The FORTE results established the benefit of adding a proteasome inhibitor, carfilzomib, to an IMiD as maintenance for all patients. Then the CASSIOPEIA study [NCT02541383] was conducted, and the results were presented a couple of years ago. This trial was mainly done in Europe and was 1 of the large, phase 3, randomized studies that tried to establish [the benefit of] the addition of a monoclonal antibody like daratumumab [Darzalex] in transplant-eligible patients.⁶

What were the design and results of the trial?

About 1100 patients enrolled in the trial; all were transplant eligible, and 1085 patients were randomized 1:1 to 2 groups. One group received bortezomib, thalidomide [Thalomid], and dexamethasone, or VTd. The other group’s regimen was dara- VTd, that is, daratumumab with VTd induction for 4 cycles. Then they underwent stem cell collection [and transplant], followed by 2 additional cycles of consolidation with VTd or dara-VTd. Then there was a second randomization, just like in the FORTE trial, but here they were randomized to either single-agent daratumumab or just observation.⁶ People ask why these patients were just put on observation, but I think in Europe at that point in time, observation was still the standard of care. Then they received follow-up care after that.

The primary end point, which was the stringent complete response rate, was significantly higher in the dara-VTd arm at 29% compared with the VTd arm at 20% [overall response, 1.60; 95% CI, 1.21-2.12; P = .0010 (dara-VTd); P = .001 (VTd)].⁴ If you look at PFS, there was a significant benefit of adding daratumumab to VTd [HR, 0.58; 95% CI, 0.47-0.72; P < .0001]. The median overall survival was not reached, and the HR favored the dara-VTd group in this study. In the subgroup analysis, VTd was favored in all subgroups, except for patients with stage III disease or high-risk cytogenetics.

MRD negativity was assessed by 2 assays: next-generation flow [cytometry] and next-generation sequencing with a sensitivity of 10^-5.⁶ The addition of daratumumab to the VTd backbone increased the MRD negativity rate, which was significantly higher than in the VTd-only arm. Deep responses could be achieved, and they translated into a greater PFS benefit with the addition of a monoclonal antibody in the up-front setting.

The PFS curve is a very important result from CASSIOPEIA.⁶ The addition of daratumumab [to VTd] benefited everybody. The dara-VTd-dara group, dara-VTd followed by daratumumab maintenance [group], and dara-VTd [followed by] the observation [group] all had similar benefit compared with the patients treated with VTd and observation only. Those [with the worst results were the] patients who just got VTd.

The addition of daratumumab benefited everybody. This study also yielded a very important observation: if we have daratumumab and then you add that either at the time of induction or at the time of maintenance, you really don’t need to put it during maintenance. The benefit that you derive from daratumumab initially or later on is pretty much similar. The question that remains concerns the benefit of daratumumab as a long-term or ongoing treatment as maintenance in this patient population. But if you look at the MRD-negativity data, dara-VTd followed by daratumumab [maintenance] had the highest MRD negativity rate, 64.2% at 10^-5 sensitivity; this is much higher than in the VTd-only arm, which was about 35.8%.

However, observation alone vs daratumumab maintenance vs VTd-dara had pretty comparable rates at 57% and 56%, respectively. Though we didn’t see a PFS benefit in the dara-VTd group compared with the observation arm, the rates of MRD negativity were much higher, and with longer follow-up you might see a difference with the daratumumab arm in both induction and maintenance.

Was there a relevant study that focused on mostly US patients?

The US counterpart, the phase 2 randomized GRIFFIN study [NCT02874742], [used lenalidomide instead of thalidomide].⁷ The design was similar to the CASSIOPEIA study, enrolling transplant-eligible patients. The age cutoff was 70 years, and the creatinine clearance rate had to be at least 30 mL/min. Patients were randomized to dara-VRd vs VRd. There was only 1 randomization; this [study did not have] a second randomization [for the maintenance phase], unlike the CASSIOPEIA and FORTE studies.^4-7 Patients were randomized to [1 arm that received] 4 cycles of dara-VRd as induction [or a second arm that received] 4 cycles of VRd.

[Both groups then received a transplant] and [subsequently went on] to consolidation for 2 cycles [with the same regimen they received pretransplant]. Following this, patients [received maintenance therapy], with the dara-VRd arm receiving dara-lenalidomide vs [the VRd arm, which received] just lenalidomide. The primary end point was the stringent complete response rate. The transplant rate was slightly lower in the VRd arm due to early discontinuation, probably because of disease progression or adverse effects. The patients’ [treatment was then up] to 4 cycles [of maintennance therapy]. [Patients who had the] addition of daratumumab to the VRd backbone [had an] increased depth of response.⁷

The complete response rate and the [very good partial response] rate were both increased. All the responses, including the deep responses, [were greater] in the dara-VRd arm, at a 13.5-month median follow-up. Now we have [24-month] follow-up [data], and the bottom line is that if you add daratumumab, you increase the depth of response in these patients.⁸

[At the 24-month follow-up], they measured MRD-negativity by next-generation sequencing at 10^-5 [sensitivity], and the dara-VRd arm had significantly higher MRD-negative rates.⁸ So at this 10^-5 [sensitivity, the MRD negativity rate in the dara-VRd arm was] about 64%, [and it was] about 30% in the VRd arm after 2 years of maintenance [P < .0001]. Over time, the [data showed that] MRD-negativity rates continued to increase and get better. The responses continued to deepen with time, which is very impressive with the MRD negativity rates in the dara-VRd arm.

Are there subgroup analyses that are relevant from these studies?

The subgroup analysis showed that the dara-VRd arm benefited most of the patients, as in CASSIOPEIA.^6,8 But there were some groups that perhaps didn’t derive much benefit, or maybe high-risk groups need more than just dara-VRd.⁸ The stage III revised International Staging System [ISS] group didn’t derive as much benefit as the standard-risk patients. They did derive some benefit, but not as much as the standard-risk patients.

This is something of a patient population with unmet need, where we probably need a little bit more than just dara- VRd. We talked about MRD negativity, but we also know that having 1-point MRD negativity may not be that important if you cannot sustain that MRD negativity. [The GRIFFIN investigators looked at] sustained MRD negativity at more than 6 months and at more than 12 months.^7,8

At both time points, the sustained MRD negativity was much higher in the dara-VRd arm, at 48% at more than 6 months and a similar rate, 44%, at more than 12 months. Going back to the [issue of] transplant-sustained MRD negativity, dara-VRd not only achieved a deeper response but also helped to maintain that response in this patient population. The latest follow-up result that we have [is PFS in the intent-to treat-population], which is 38.6 months.⁸ There was a trend toward a PFS benefit with dara-VRd. Similar to what we saw in the CASSIOPEIA study, adding daratumumab to the front-line not only increased the depth of response and the rates of MRD negativity, but with longer follow-up, it also has a potential survival advantage or PFS advantage in this patient population.^6,8 The HR [for PFS] was 0.46 [95% CI, 0.21-1.01], but I think with longer follow-up, it’s very likely that we’re going to see a benefit in the dara-VRd arm in this patient population.

_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. 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}

_{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. Abstract presented at the 2020 American Society of Hematology Annual Meeting; December 5-8, 2020; Virtual. Accessed May 12, 2022. https://ash.confex.com/ash/2020/webprogram/Paper134538.html}

_{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. Laubach JP, Kaufman JL, Sborov DW, et al. Daratumumab (DARA) plus lenalidomide, bortezomib, and dexamethasone (RVd) in patients (Pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): updated analysis of GRIFFIN after 24 months of maintenance. Blood. 2021;138(suppl 1):79-82. doi:10.1182/blood-2021-149024}