A 51-year-old man presented with pallor and worsening fatigue on exertion and was later diagnoses with multiple myeloma.
During a Targeted Oncology Case-Based Roundtable event, Luciano J. Costa, MD, PhD, associate director for Clinical Research, O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, discussed a 51-year-old man diagnosed with standard risk, stage II multiple myeloma.
Targeted OncologyTM: What are the National Comprehensive Cancer Network (NCCN) guidelines for primary therapy in transplant-eligible patients with multiple myeloma?
COSTA: According to the NCCN, the combination of bortezomib [Velcade], lenalidomide [Revlimid], and dexamethasone [VRd] is a preferred regimen. Other recommended regimens are carfilzomib [Kyprolis], lenalidomide, and dexamethasone [KRd]; daratumumab [Darzalex] plus bortezomib, lenalidomide, and dexamethasone [dara-VRd]; and ixazomib [Ninlaro], lenalidomide, and dexamethasone, which is an interesting choice. Several other combinations [are listed as “useful under certain circumstances”], including bortezomib, cyclophosphamide [Cytoxan], and dexamethasone.1
What data influence your decision to combine VRd therapy with transplant?
Our practice is greatly influenced by the [IFM/DFCI2009] trial [NCT01191060], in which [all patients received] 3 cycles of the classic VRd regimen [with bortezomib given twice a week, followed by stem cell collection]. Half of the patients then received an autologous transplant, 2 cycles of VRd consolidation, and 1 year of lenalidomide maintenance. The other arm received [no transplant] but [did receive] 5 cycles of VRd, followed by 1 year of maintenance, [with transplant recommended upon progression]. The primary end point was progression-free survival [PFS].2
Median PFS [at the 44-month follow-up] was 50 months vs 36 months, favoring the transplant arm [HR, 0.65; P < .001]. Overall survival [OS] is not different between groups at the present time, [although it is important to remember] that about 70% of the patients in the no-transplant arm [did eventually receive] an autologous transplant.3 [Subgroup analysis of cytogenetic risk groups suggests there was] a greater benefit for standard-risk [patients than for high-risk] patients, but it is hard to make many conclusions about high-risk patients because of their small number.
Regarding minimal residual disease [MRD], patients who were MRD negative at the beginning of maintenance did far better than patients who were MRD positive [median PFS, not reached (NR) vs 29 months, respectively]. The same [trend was observed] for [patients whose MRD status was assessed] after 1 year of maintenance [median PFS, NR vs 20 months, respectively]. Among the MRD-negative patients, the transplant patients did better than the patients who received VRd alone; the same [trend was observed], of course, for MRD-positive patients. Keep in mind that this trial did not assess MRD prior to transplant [but only] after induction, transplant, and consolidation. Even then, only 30% of the patients in the transplant arm and 20% of the patients in the VRd-only arm were MRD negative.4 Although it is possible that a patient could become MRD negative after 3 cycles of VRd, it is highly unlikely.
What data support combining a KRd regimen with transplant and using carfilzomib plus lenalidomide for maintenance therapy?
Another very important trial is the FORTE trial [NCT02203643]. Initially, patients were randomly assigned to 3 arms. In the first arm, patients received induction with carfilzomib, cyclophosphamide, and dexamethasone [KCd]; this was followed by transplant and then 4 more cycles of KCd. In the second arm, patients received 4 cycles of KRd, followed by transplant and 4 more cycles of KRd. In the third arm, patients received 4 cycles of KRd; then, after stem cell collection [but no transplant], patients received 8 [more] cycles of KRd.
This study answers 2 very important questions: Is lenalidomide a better partner to carfilzomib than...cyclophosphamide? [This is addressed by comparison of the first and second arms.] And can transplant be replaced with 4 cycles of KRd? This is [addressed by] comparison of the second and third arms. Finally, there was a second randomization, and patients received either lenalidomide or the combination of carfilzomib plus lenalidomide for maintenance therapy.5,6
The results of this trial were clear. The second arm, which received KRd plus transplant, did the best; at 3 years, 78% of the patients exhibited PFS. In contrast, this percentage was 58% for KCd with transplant and 66% for KRd alone. Lenalidomide [was shown to be] a far better partner to carfilzomib than was cyclophosphamide [HR, 0.53; 95% CI, 0.37-0.77; P < .001]. [This study also showed that] 4 extra cycles of KRd cannot replace transplant [KRd plus transplant vs KRd alone, HR, 0.64; 95% CI, 0.44-0.94; P = .023]. Finally, subgroup analysis showed that the benefit [of transplant] was [consistent among subgroups] that were defined by ISS staging [stage I vs stage II/III], cytogenetic risk [standard vs high], and LDH level relative to the upper limit of normal [ULN; ≤ ULN vs > ULN].6
The second randomization, which compared 2 maintenance regimens, is more intriguing. The percentage of patients exhibiting 3-year PFS was greater in the carfilzomib-lenalidomide arm than in the lenalidomide arm [75% vs 66%, respectively; HR, 0.63; P = .026]. The PFS benefit [of the doublet was consistent] across all subgroups. [Finally, in the doublet arm, 46% of MRD-positive patients became MRD negative by the end of consolidation vs 32% in the lenalidomide arm (P = .04)].6
What other data inform the treatment of patients with newly diagnosed MM?
The data from the CASSIOPEIA trial [NCT02541383] answer a simple question: Does adding a monoclonal antibody like daratumumab to a triplet improve PFS in patients who are going to undergo an autologous transplant? Patients received either bortezomib, thalidomide [thalomid], and dexamethasone [VTd] followed by mobilization, autologous transplant, and then 2 more cycles of VTd or the same [regimen] with the addition of daratumumab [dara-VTd]. Remember, this was done mostly in parts of the world where lenalidomide was not approved as part of initial or maintenance therapy. Then, following a second randomization, patients were either observed until progression or treated with daratumumab every 8 weeks until progression.7
The primary end point was stringent complete response [CR], which was superior in the arm that received the quadruplet therapy compared with that observed in the triplet arm [29% vs 20%, respectively; odds ratio, 1.60; 95% CI, 1.21-2.12; P = .0010]. The rate of MRD negativity with a 10-5 sensitivity threshold was 64% in the quadruplet arm vs 44% in the triplet arm [P < .0001].
The responses tended to get better with each phase of therapy. [In both arms], the responses were good after induction, and they improved after transplant [and improved again] after consolidation. That improvement was even [more] pronounced when patients received the experimental quadruplet therapy. It is important that [the experimental therapy] improved the overall performance of the regimen but did not replace autologous transplant. [There was] a similar increment in the depth of response [after] transplant in both arms, although the dara-VTd arm was already performing better [at the time of transplant], and there was also an improvement in PFS that favored the dara-VTd arm [HR, 0.47; 95% CI, 0.33-0.67; P < .0001].7
The GRIFFIN trial [NCT02874742] was similar but had some key differences. This trial used VRd instead of VTd because lenalidomide is approved for newly diagnosed [MM] in the United States, and RVd is the standard of care in the newly diagnosed setting. Patients received 4 cycles of VRd [with or without daratumumab], followed by transplant and 2 more cycles of consolidation [with their same assigned regimen]. There was also not a second randomization in this trial. Patients who received VRd continued with lenalidomide maintenance for 2 years; patients who received dara-VRd continued with daratumumab plus lenalidomide for 2 years of maintenance. The primary end point was stringent CR.8
Similar to the CASSIOPEIA study, the results of this study showed improvement in the quality of response as [the study progressed] from induction through transplant, consolidation, and then 12 months of maintenance. The improvement that [resulted from] transplant [was observed] in both arms, but at each of phase of therapy, the dara-VRd arm outperformed the VRd arm [eg, at 12 months, the percentage of patients exhibiting CR or better was 81.8% in the quadruplet arm vs 60.8% in the triplet arm; P = .0014].9
Subgroup analysis of stringent CR greatly favored the dara-VRd arm [across subgroups defined by sex, age, ISS staging, MM type, cytogenetic risk, and ECOG score]; no subgroup received greater or lesser benefit [than any other].10 Results also showed that the likelihood of achieving MRD negativity [with a 10-5 sensitivity threshold] was greater in the dara-VRd arm than in the VRd arm [62.5% vs 27.2%, respectively], with no subset of patients deriving a greater or lesser benefit [than any other].9
This study was much smaller [than the CASSIOPEIA study]. While CASSIOPEIA had several hundred patients,7 GRIFFIN only had a little over  patients in each arm.9 At 24 months, the PFS remains very high in both arms, and the same [is true] for OS, [although the data are] not mature yet.
Of course, with the addition of agents, toxicity increases. In every randomized trial in which daratumumab11 or any other anti-CD38 monoclonal antibody [is added to a regimen], there is an increase in neutropenia and a small increase in thrombocytopenia, and the same was seen here in the dara-VRd arm vs the VRd arm [neutropenia of any grade, 57.6% vs 35.3%, respectively; thrombocytopenia of any grade, 43.4% vs 35.3%, respectively]. There was also an increased tendency to have infection in the quadruplet arm than in the triplet arm [of any grade, 90.9% vs 61.89%, respectively]. For most of the other toxicities, including neuropathy, gastrointestinal toxicity, and pain, there was really no difference between the 2 arms.9,12
What conclusions can be drawn from a comparison of these trials?
When the results of the [IFM/DFCI2009] trial, the FORTE trial, the CASSIOPEIA trial, and the GRIFFIN trial are compared, the [greatest percentage] of patients with a very good partial response or better [was observed in] the dara-VRd arm of the GRIFFIN trial. [We should remember] that although the populations in those trials were similar, they were not equivalent. But [overall], I think [a cross-trial comparison shows] that the depth of response is improved by transplant and by adding daratumumab to a triplet, while in the CASSIOPEIA trial, [adding daratumumab] also improved the duration and the quality of the response.
1. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 1.2022. Accessed October 15, 2021. https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf
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 vs 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. 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
5. 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
6. 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
7. 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
8. Voorhees P, Kaufman JL, Laubach J, et al. Daratumumab + lenalidomide, bortezomib & dexamethasone improves depth of response in transplant-eligible newly diagnosed multiple myeloma: GRIFFIN. Paper presented at: 17th International Myeloma Workshop; September 12-15, 2019; Boston, MA. Accessed October 17, 2021. http://imw2019boston.org/images/Abstracts/17th_IMW_Abstract_Book_FINAL_V2.pdf
9. 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
10. Roussel M, Moreau P, Hebraud B, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab for transplantation-eligible patients with newly diagnosed multiple myeloma (CASSIOPEIA): health-related quality of life outcomes of a randomised, open-label, phase 3 trial. Lancet Haematol. 2020;7(12):e874-e883. doi:10.1016/S2352-3026(20)30356-2
11. Darzalex. Prescribing information. Janssen; 2021. Accessed October 18, 2021. https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX-pi.pdf
12. 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