Looking at Long-Term Impacts of Treatment in Patients With Newly Diagnosed Multiple Myeloma

Leo Shunyakov, MD

Oncologist/Hematologist

Central Care Cancer Center

Bolivar, MO

Case Summary:

• Woman, aged 54 years
• Hemoglobin, 7.0 g/dL; β2-microglobulin, 6 mg/L; albumin, 3.2 g/dL •
• Calcium, 11.3 mg/dL; lactate dehydrogenase, 200 U/L; creatinine clearance, 45 mL/min/1.73 m2
• Bone marrow: 22% monoclonal plasma cells
• Serum κ free light chain: 240.0 mg/L
• Serum monoclonal protein: 5 g/dL
• Cytogenetic (fluorescence in situ hybridization and karyotyping) abnormalities: none
• ECOG performance status: 1
• PET-CT: multiple bone lesions in vertebrae without extramedullary disease
• Diagnosis of Revised International Staging System (R-ISS) stage 2/R2-ISS stage 3 IgG κ multiple myeloma; patient identified as being transplant eligible

Q: What are the National Comprehensive Cancer Network guidelines for primary therapy in patients who are candidates for transplant?

SHUNYAKOV: For preferred regimens, [RVd: lenalidomide (Revlimid), bortezomib (Velcade), dexamethasone] and [KRd: carfilzomib (Kyprolis), lenalidomide, dexamethasone] are mentioned. In “other recommended regimens” is the quadruplet daratumumab [Darzalex] plus RVd [D-RVd], which does give us a choice, although this regimen is not category 1. Among other choices, listed as “useful in certain circumstances,” we even have a D-KRd option, possibly reserved for patients with highest-risk disease and able to tolerate the intensive quadruplet.¹

Q: To what extent have investigators explored the role of transplant in younger, transplant-eligible patients with newly diagnosed multiple myeloma?

There are 2 main studies that assessed this. One… was a French study published in 2017² [in the New England Journal of Medicine] and presented again in 2020 with 90 months of follow-up.³ Th is was the IFM 2009 study [NCT01191060], and the schema was very simple. Patients who were randomly assigned to [the fi rst arm received] RVd for 3 cycles, stem cell collection, and then an additional 5 cycles of RVd. Patients in this…arm did have an opportunity to get transplant.

In fact, close to 80% of those patients ended up getting transplant. Patients in the other arm…received 3 cycles of RVd, stem cell collection, and bone marrow transplant with melphalan [Evomela, 200 mg/m²], followed by 2 consolidation cycles of RVd. In [both arms], lenalidomide, [10 to 15 mg per day], was given just for 1 year.^2,3

That was the difference between this trial and the DETERMINATION trial [NCT01208662], where lenalidomide maintenance was given indefinitely or until patients developed progression, intolerable toxicity, [or both].⁴

On the initial read at 44 months, there was a 14-month difference in progression-free survival [PFS],² [and there was a 12.3-month PFS difference at the 90-month follow-up3]. The 8-year overall survival [OS] rates did not show a statistically significant difference.³

In the subgroup analysis, minimal residual disease [MRD] negativity was achieved by more patients who received transplant than by those who received RVd alone [approximately 30% vs 20%, respectively]. The worst-performing groups were patients who were MRD positive after this initial induction therapy.

In fact, in this study, patients did not get assessed for MRD early. The assessment was done at close to 1 year. So it is hard to tell what significance MRD has for our day-to-day management. What is also interesting is that the MRD-positive transplant arm was still performing a little better than the MRD-positive RVd arm [at a median follow-up of 89.8 months].³

What this study tells us is that there was a high MRD negativity rate with transplant. Also, [transplant] does translate into better PFS by approximately 1 year; however, we still do not have OS benefit, even with 8 years of follow-up.^2,3

Q: What were the design and results of DETERMINATION?

The schema was similar to that of the IFM 2009 trial. Patients in the first arm were treated with RVd, followed by stem cell collection, followed by RVd, for a total of 8 cycles. In the other group, patients did proceed with bone marrow transplant, and after that they had 2 cycles of consolidation. And in both groups, they proceeded to a lenalidomide maintenance.⁴ It is important to note that this trial enrolled patients younger than 65 years.4 Whenever we have a patient in front of us who might be 70 years… the DETERMINATION study results do not necessarily apply…. But, unquestionably, at 76 months of followup, there was a marked improvement in PFS [for the transplant group vs the group that did not receive a transplant].

It was almost like continuing lenalidomide indefinitely increased the gap between those 2 arms. The PFS improvement in the transplant arm was 21 months, and it was 67.5 months vs 46.2 months for the transplant and nontransplant arms, respectively [HR, 1.53; 95% CI, 1.23-1.91; P < .001].⁴ One of the other possible reasons for this improvement could be that very few patients in [the] RVd-only arm [20%] ended up getting delayed transplant vs 80% in the [IFM 2009 study].² The 5-year OS, even with longer follow-up, was still similar between the 2 studies [80.7% vs 79.1% for the transplant and nontransplant arms, respectively]. Essentially, it was identical.⁴ Now, the number of patients in the DETERMINATION study was small, but for patients with high-risk cytogenetics, we see an HR of 1.99 in favor of transplant. Transplant did make more of a difference for patients in the high-risk group. In the standard-risk group, there was also some improvement in median PFS.

The interesting, and somewhat unexpected, subgroup analysis showed that for patients with [R-ISS] stage III disease the HR was close to 1.0 [0.96], which is counterintuitive, and it clashes with the fact that high-risk patients derived more benefit from transplant, although the number of patients was very small [28 and 21 patients in each group].4 But given the absence of OS [benefit], it allows some of the opinion leaders to say that maybe we should be transplanting most of our patients with high-risk cytogenetics, especially those with ultrahigh-risk cytogenetics, and possibly give [the] option to our patients with standard risk.

However, it is only some of the opinion leaders who say that. Many transplanters are firmly convinced that this 21-month improvement in PFS is worthwhile even with the toxicities and some transient decline in quality of life for about 3 to 6 months after the transplant. That was such an important study, and unexpected; with such a long follow-up, we still don’t see an improvement in OS. Still, this was a great study, but [given] the comparator arm, with 70% of us using D-RVd as an induction, [the data] might already be outdated, as happens with many trials in myeloma. By the time the data are presented, the standard of care has moved ahead.

If patients in this study did achieve MRD, it didn’t matter whether they received RVd or had a bone marrow transplant; their survival [median PFS, 33.4 months vs 50.6 months for RVd alone and RVd plus transplant, respectively] was superior to those who had not achieved MRD at [59.2 months vs 53.5 months, respectively]. The worst survival was in patients who received RVd alone and who did not achieve MRD.

Q: What was the key result of the FORTE trial (NCT02203643)?

This was a complex trial, and it showed the inferiority of induction with carfilzomib, cyclophosphamide [Cytoxan], and dexamethasone [KCd] to induction with KRd, and, ultimately, it showed that transplant still makes a difference.⁵ The regimen of KRd followed by transplant had the best 4-year PFS rate at 69% compared with 56% for [12 cycles of] KRd, and even lower for KCd [51%].

The subgroup analysis showed that all subgroups of patients benefited from KRd followed by transplant.⁵ And then there was a second randomization [for a trial of KR vs R maintenance], and that was interesting. Most of us are thinking that we could do better than just lenalidomide maintenance. There was significant improvement in PFS when KR was used, compared with R, with an HR of 0.64, and a 3-year PFS rate of 75% with carfilzomib vs 65% with lenalidomide alone.⁵

Q: What effect have the results of the GRIFFIN trial (NCT02874742) had on the use of daratumumab with RVd?

The GRIFFIN trial has made a lot of impact, and that is why, probably, some of us are using D-RVd as an induction therapy. This trial enrolled transplant- eligible patients who were younger than 70 years… and who had a creatinine clearance [rate of at least 30 mL/min/1.73 m²].

This study did enroll some of the high-risk patients; 15% of the patients were high risk. Patients were randomly assigned to D-RVd or RVd. After transplant, patients received…2 cycles [of consolidation] and then maintenance [with D-R or R]. It is important that D-R was given for 2 years as maintenance. It was not indefinite; it was just for 2 years, [and only some common adverse events were seen (Table⁶)].

Q: How did the 4-drug regimen compare with the 3-drug regimen with respect to MRD negativity?

As you know, for MRD conversion rates, some physicians use a threshold of 10^–4, but most who do MRD with 10^–5, and in the new trials, there is a goal to…use 10^–6. [In this study, multiple thresholds were applied.]

In terms of achieving MRD, [the 4-drug regimen was more effective]. And, although we do know from the previous trials that deeper MRD usually correlates very strongly with longer PFS,^3,4 with this…approach, using quadruplet regimens throughout induction [and] consolidation, and doing maintenance with a doublet of D-R, we still don’t [have confirmation] that there is better PFS in patients who achieve deeper MRD. But, from the bulk of the data, we may expect that MRD negativity will translate into a longer PFS.

It is also interesting that with the daratumumab-based regimen, the median time to MRD negativity was remarkable, almost 3 times faster [8.5 months compared with almost 3 years with RVd], and this is despite patients getting bone marrow transplants in both of those groups.⁷

We don’t know for sure whether MRD translates into better PFS with a quadruplet regimen. But certainly, the PFS at 50 months of follow-up [87.2% vs 70.0% for the quad and triplet regimens, respectively] suggests that adding daratumumab early on, and later, does make a difference. It is fascinating that we do not see a separation of the survival curves until after 2 years.

It is hard to tell whether it is the initial induction or the subsequent consolidation and maintenance that [is] making the difference. But the MRD transitions, at every point of treatment, showed that there was further… deepening of the responses, and PFS at 3 years was 89% with the quadruplet vs about 81% with the triplet, and the difference in PFS increased at 4 years [87% vs 70%]. Of course, it is a small trial, but 87% PFS at 4 years is a result that we haven’t seen [with any other regimen].

Q: Can a physician start with daratumumab plus lenalidomide after the transplant?

That question is why we have the ongoing Perseus trial [NCT03710603], which is testing this hypothesis. And, of course, we have an ongoing trial testing D-R vs R alone as maintenance. We don’t have definitive answers, but [the data tend to] suggest that daratumumab does play a significant role. If you think about it from the point of view of the disease, we all know that the disease is much more sensitive early on, so the deeper the remission we achieve early on, the smaller the likelihood resistant clones develop.

REFERENCES

1. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 3.2023. Accessed April 30, 2023. bit.ly/44vsHJQ

2. 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

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. Richardson PG, Jacobus SJ, Weller EA, et al; DETERMINATION Investigators. Triplet therapy, transplantation, and maintenance until progression in myeloma. N Engl J Med. 2022;387(2):132-147. doi:10.1056/NEJMoa2204925

5. Gay F, Musto P, Rota-Scalabrini D, et al. Carfilzomib with cyclophosphamide and dexamethasone or lenalidomide and dexamethasone plus autologous transplantation or carfilzomib plus lenalidomide and dexamethasone, followed by maintenance with carfilzomib plus lenalidomide or lenalidomide alone for patients with newly diagnosed multiple myeloma (FORTE): a randomised, open-label, phase 2 trial. Lancet Oncol. 2021;22(12):1705-1720. doi:10.1016/S1470-2045(21)00535-0

6. 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

7. Sborov DW, Laubach J, Kaufman JL, et al. Daratumumab (dara) + lenalidomide, bortezomib, and dexamethasone (RVd) in patients with transplant-eligible newly diagnosed multiple myeloma (NDMM): final analysis of GRIFFIN. Presented at: 19th International Myeloma Society Annual Meeting; August 25-27, 2022; Los Angeles, CA. Abstract OAB-057.