During a Targeted Oncology case-based roundtable event, Yvonne A. Efebara, MD, MPH, discussed the role of triplet and quadruplet systemic therapies for newly diagnosed multiple myeloma and the use of autologous stem cell transplant.
Targeted Oncology™: What are the available triplet and quadruplet regimen options for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM)?
EFEBERA: In the [National Comprehensive Cancer Network] guidelines, VRd [bortezomib (Velcade), lenalidomide (Revlimid), dexamethasone] is the preferred regimen. It doesn’t state whether it is for high-risk or standard-risk patients, and that is based off the phase 3 randomized study that was done before. Other recommended regimens are KRd [carfilzomib (Kyprolis), lenalidomide, dexamethasone], D-VRd [daratumumab (Darzalex), lenalidomide, bortezomib, dexamethasone], and IRd [ixazomib (Ninlaro), lenalidomide, dexamethasone].1
For other regimens useful in certain circumstances, especially in patients who are admitted in the hospital with renal failure, I use daratumumab plus CyBorD [cyclophosphamide (Cytoxan), bortezomib, and dexamethasone], which can be given inpatient.1 Cyclophosphamide is a great drug to start, then once the patient gets discharged—maybe after cycle 2— you can switch to lenalidomide.
What data support early transplant in transplant-eligible patients with NDMM?
Many [oncologists] are familiar with the IFM 2009 study [NCT01191060], which was done in conjunction with the DETERMINATION trial [NCT01208662] that was presented at the 2022 ASCO [American Society of Clinical Oncology] Annual Meeting as a plenary session and published in the New England Journal of Medicine on June 5, 2022.2,3 [However], there are some differences between the studies.
In the era of novel agents, is autologous stem cell transplant still a first choice as part of the initial treatment in patients with NDMM?
[In IFM 2009], patients received the triplet VRd therapy in both groups for 3 cycles, then stem cells were collected using chemomobilization, which we generally don’t do at OhioHealth, but that’s what they do in Europe. Patients were [randomly assigned] to continue the treatment for up to 8 cycles or go through transplant and then received lenalidomide maintenance.4
The only difference between the IFM 2009 study and the DETERMINATION study is that the lenalidomide maintenance in Europe was for 12 months compared with the DETERMINATION trial, which was until disease progression. There were differences in the median progression-free survival [PFS]. In the IFM 2009 study at the initial analysis after 44 months of follow-up, the median PFS was better in the transplant arm by at least 14 months, so it was 36 months in the VRd alone arm and 50 months in the VRd plus transplant arm.4
There was a 90-month follow-up where the median PFS was 47.3 months in the transplant arm compared with 35 months in the VRd alone arm, so [there was an approximate] 12-month benefit for transplant.5 Just like in many other trials, the overall survival [OS] was not statistically different between the groups because there are so many options at relapse. One can do another transplant, depending on the time, or do a new daratumumab-based, pomalidomide [Pomalyst]-based, or carfilzomib-based regimen. The subgroup analysis showed benefit in the transplant arm.
For the subgroup analysis by minimal residual disease [MRD] status, [patients who were] MRD negative had a benefit whether they [did] or did not have transplant, [which is] an improvement in PFS compared with patients who [did] or did not have transplant but were MRD positive. The MRD negativity rate of 10-6 after 5 years of follow-up was 30% in the transplant arm compared with 20% in the nontransplant arm.5
Can you explain the rationale for those in the IFM 2009 trial who did not receive transplant but received 12 months of lenalidomide maintenance?
That is the standard in Europe. It was France, Belgium, and Germany that participated. It’s 12 months of maintenance. The medical system there is run by the government, and that’s what they dictated. The second primary malignancy [rate] in this group was 7% to 8% in the transplant arm compared with 4% in the nontransplant arm. So still, there’s a little bit of a higher second primary malignancy rate. As a result, the Europeans decided [patients should receive] 12 months of maintenance.
What was observed in the DETERMINATION trial?
The DETERMINATION trial was presented at ASCO as a plenary session.2 It had the same eligibility criteria as IFM 2009. The 2 trials were supposed to go together, but Europeans enroll very quickly in clinical trials. The IFM 2009 trial was completed in 2.5 years, with [more than] 300 patients in each arm, whereas the DETERMINATION trial took 5 to 6 years to complete. The follow-up was long, but that was because there was no end point. Lenalidomide maintenance in this case was given until disease progression in both arms.
The median follow-up was 76 months—almost 7 years. There was a big difference in the median PFS at 67.5 months for the transplant arm compared with 46.2 months for the nontransplant arm. The 5-year OS rate was not different because there were many [therapy] options at relapse, but that is almost a 22-month difference in PFS.3 This study also enrolled 1 of the largest Black populations; [approximately] 19% of the patients were Black, so a subset analysis study and publication will be coming out of that. It will be interesting to see, as I was part of the study. It looks like the Black patients did just as well with transplant vs without transplant, but we must assess the high-risk vs the standard-risk population and see [whether] it matches up.
But overall, the subset analysis in terms of FISH analysis showed that the high-risk patients all benefited. For the R-ISS3 [Revised International Staging System 3] group, it was pretty much equal between the transplant and nontransplant patients.
Which studies investigated carfilzomib-based regimens in this setting?
The FORTE trial [NCT02203643], which was done mostly in Europe, compared 2 regimens with transplant. These were KCd [carfilzomib, cyclophosphamide, dexamethasone] followed by transplant, then consolidation vs KRd for 4 cycles, and then transplant followed by consolidation vs KRd without transplant for 12 cycles. There was a second randomization for the whole group to lenalidomide maintenance vs carfilzomib/lenalidomide maintenance. With the first randomization, for the KRd plus transplant group, 4-year PFS rate was 69%, superior to KRd without transplant, which was 56%, and then superior to KCd with transplant, which was 51%. There was a PFS significance with the groups.6 For KRd [without transplant] vs KCd plus transplant, the P value was .45 [HR, 0.88; 95% CI, 0.64-1.22], so KRd without transplant did just as well as the KCd with transplant.6 This just shows that adding an immune modulator is important to the induction regimen. The subset analyses all showed benefit in the transplant arm.
The second randomization with the maintenance arm with lenalidomide vs carfilzomib/lenalidomide also favored the carfilzomib/lenalidomide arm compared with the lenalidomide alone arm. I’m most interested in patients who received KRd with transplant and then were [randomly assigned] to the lenalidomide arm vs carfilzomib/lenalidomide arm. That subset analysis is not yet available. There are [approximately] 120 patients in each arm. It will be something of importance to know for patients who received the KRd [whether] it made any difference whether they received carfilzomib/lenalidomide or lenalidomide maintenance. The subset analysis all favored the carfilzomib/ lenalidomide arm. The 3-year PFS rate from second randomization did favor the carfilzomib/lenalidomide arm at 75% vs 65% on the lenalidomide alone arm [HR, 0.64; P = .026].6
What data support the use of a quadruplet regimen in transplant-eligible patients with NDMM?
The GRIFFIN trial [NCT02874742] was a phase 2 trial. The other studies were phase 3. This is a small study. For the other studies, the primary end point was PFS, but for this one, it was MRD negativity. It had approximately 100 patients in each arm up to the age of 70 [who were randomly assigned] to D-VRd vs VRd, then transplant followed by consolidation in both arms for 2 cycles. Patients in the D-VRd arm received daratumumab/lenalidomide maintenance. Daratumumab was given for 2 years as a maintenance, then they continued lenalidomide until disease progression.
Patients on the VRd arm [received] lenalidomide maintenance until disease progression. The primary end point was stringent CR [complete response] and MRD. Fifteen percent of patients were high risk.7 The stringent CR rate 2 years after maintenance was 66% in the D-VRd arm compared with 47% in the VRd arm [Table8].
The total CR rate, including stringent CR, was 82% in the D-VRd arm compared with 61% in the VRd arm. They did have a median follow-up of 24 months, with a cutoff at 38.6 months, which was presented at the [64th American Society of Hematology Annual Meeting and Exposition].8 There was an increase in the MRD negativity as they went through their treatment. At 2 years of maintenance, the MRD negativity rate was 64% in the D-VRd arm vs 30% in the VRd arm.8 The subset analysis for the MRD assessment regardless of stage and age all favored the D-VRd arm, including the high-risk cytogenetics patients. A sustained MRD negativity lasting more than 6 months and more than 12 months both favored the D-VRd arm compared with the VRd arm.
The median PFS was not yet reached. At 2 years, the PFS rate was 91.6% in the D-VRd arm compared with 89.7% in the VRd arm. Then the 3-year PFS rate was 88.9% in the D-VRd arm compared with 81.2% in the VRd arm, but the P value was not statistically significant. As we get close to 5 years, we may see a significance, or we may not. The 3-year OS rate was not different between the 2 groups.8
The most common adverse effect was grade 3 and 4 neutropenia, which was higher in the D-VRd arm, and thrombocytopenia and leukopenia, which were almost twice as much as in the VRd arm. Interestingly, there were fewer discontinuations in the D-VRd arm compared with the VRd arm.7 Both the IFM 2009 and DETERMINATION studies were very large studies, with over 300 patients in each arm, and were phase 3 trials. The GRIFFIN trial had 103 and 104 patients in [the VRd arm and D-VRd arms, respectively]. Sometimes phase 2 trials can have good results, but things don’t pan out in a [confirmatory] phase 3 study. There is an ongoing phase 3 study [Perseus; NCT03710603] in Europe, looking at D-VRd vs VRd.
1. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 5.2022. Accessed October 13, 2022. https://bit.ly/3fa9Yx5
2. Richardson PG, Jacobus SJ, Weller E, et al. Lenalidomide, bortezomib, and dexamethasone (RVd) ± autologous stem cell transplantation (ASCT) and R maintenance to progression for newly diagnosed multiple myeloma (NDMM): the phase 3 DETERMINATION trial. J Clin Oncol. 2022;40(17_suppl):LBA4. doi:10.1200/JCO.2022.40.17_suppl.LBA4
3. Richardson PG, Jacobus SJ, Weller EA, et al. Triplet therapy, transplantation, and maintenance until progression in myeloma. N Engl J Med. 2022;387(2):132-147. doi:10.1056/NEJMoa2204925
4. 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
5. 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
6. 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
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 DW, 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