Melissa Alsina, MD, reviewed the treatment options for transplant-eligible multiple myeloma based on the case of a 52-year-old male patient.
During a virtual Targeted Oncology Case-Based Roundtable event, Melissa Alsina, MD, professor of Medicine, Blood and Marrow Transplant Program and head, Multiple Myeloma Transplant, Program at Moffitt Cancer Center, reviewed the treatment options for transplant-eligible multiple myeloma based on the case of a 52-year-old male patient.
Targeted OncologyTM: What is this patient’s prognosis?
ALSINA: High-risk multiple myeloma remains a significant treatment challenge. These patients usually do poorly no matter what. [As a result], there are clinical trials in development that target this patient population differently. For example, there is a study looking at chimeric antigen receptor T-cell therapy for patients with newly diagnosed high-risk multiple myeloma. If you get those [patients], perhaps they can be directed to more novel approaches= than just the standard that we use for most patients.
Monoclonal gammopathy of undetermined significance has not been shown [to increase the risk of multiple myeloma], but definitely [in] smoldering myelomas, having abnormalities increases the risk of progression. For example, if a patient has translocation 4;14, [they] probably have a 50% [chance] of progressing to multiple myeloma if they have smoldering myeloma in the first 2 years, as opposed to the first 5 years. We [do not treat] those patients differently but may consider [enrolling them in] a clinical trial.
Would you order additional molecular testing in this situation?
Most of us are now looking at minimal residual disease [MRD] with ID by clonoSEQ, which is an FDA-approved test. MRD is becoming important in multiple myeloma. That would be the only additional testing that I would order [for] the bone marrow in most patients.
How do you define young patients?
We define them histologically over chronologically. We [consider] comorbidities and how the patients are doing as opposed to [their] age.
What are the options for primary therapy of myeloma in transplant-eligible patients?
The National Comprehensive Cancer Network [NCCN] guidelines [for the treatment of multiple myeloma are] quite complicated.1 There are a lot of regimens for primary therapy in transplant candidates, [including]: RVd [lenalidomide (Revlimid), bortezomib (Velcade), dexamethasone], KRd [carfilzomib (Kyprolis), lenalidomide, dexamethasone], RVd-D [lenalidomide, bortezomib, dexamethasone, daratumumab (Darzalex)], and IRd [ixazomib (Ninlaro), lenalidomide, dexamethasone]. Sometimes it’s hard to [choose a regimen], but the standard one is RVd.
What clinical studies have assessed the impact of systemic therapy coupled with stem cell transplantation in patients with newly diagnosed multiple myeloma?
There are [several] different studies in patients with newly diagnosed myeloma. The studies looked at different regimens and compared [patients who underwent a stem cell] transplant [and those who did not].
The IFM 2009 study [(NCT01191060) provided insight regarding] early versus late transplant.2 Patients were randomized to receive RVd followed by transplant [and] a few cycles of [consolidation therapy] or continuous RVd. The median follow-up was 44 months. [Results from an] 8-year follow-up analysis were recently presented at the 62nd American Society of Hematology [ASH] Annual Meeting and Exposition.3 It was shown that if a patient received a transplant, [they] had a better response post hospitalization and very good median progression-free survival [PFS]. [Response] was sustained at 8 years. It was even sustained when a patient relapsed if they did not [undergo] a transplant at the time. Also, a higher percentage of patients had MRD negativity in the transplant arm [79% compared with those who did not receive a transplant (65%)].2 These results support transplant, [or having a patient undergo a] transplant early on.
Then there was the FORTE trial [NCT02203643], and [updated results were] also presented recently at ASH.4,5 This trial compared KRd followed by transplant and KRd alone. There was another [arm] that consisted of KCd [(carfilzomib, cyclophosphamide, dexamethasone) followed by transplant]. KRd was better in terms of response and PFS.4 Median PFS for patients given KRd without transplant was 57 months and had not been reached at the time of this follow-up in [those given KRd who underwent a transplant].5
The CASSIOPEIA study [NCT02541383] compared daratumumab, bortezomib, thalidomide [Thalomid], and dexamethasone [VTd-D] versus VTd.6 This study was done mainly in Europe because VTd is not a regimen that we use a lot [in the United States]. When adding the fourth drug, there was a better response. Median PFS has not been reached [in] either arm, but we see a better [overall response] and [a higher percentage of] very good partial responses [VGPRs] with the addition of [daratumumab]. These results led to the FDA approval of this combination, here and in Europe.
Finally, we have the GRIFFIN study [NCT02874742], which looked at RVd-D versus RVd.7,8 [Postconsolidation responses were] better with daratumumab. For MRD negativity, it’s quite impressive—62.5% with daratumumab versus 27.2% without.
What were the major efficacy findings in the IFM 2009 study?
The IFM 2009 study assessed RVd alone versus RVd and transplant.2 A higher [percentage] of patients in the transplant group experienced complete remission [59%] versus 48% with RVd alone. Responses were better after induction and consolidation.
[Among] patients who were MRD negative, those who had a transplant [had a greater probability of PFS than those who] got RVd alone.9 This group also did better than the patients who were MRD positive and underwent a transplant. MRD-negative status has a positive outcome on PFS, so it’s also important to assess. In either case, when patients are MRD positive or negative, transplant is better than RVd alone.
When you look at a patient’s risk, those who were MRD negative and standard risk did [best].9 Patients who were MRD negative and high risk did much better than a high-risk patient who didn’t reach MRD negativity. There are many trials going on now trying to use MRD negativity as a goal of therapy and adjusting therapy to get a patient to that point.
In the FORTE trial, what were the key efficacy results?
The FORTE trial [consisted of] 4 cycles of KCd or KRd for induction.4 Then patients underwent a transplant or continued with KRd and received consolidation therapy. The first end point was VGPR after these 4 cycles of induction. The secondary end points included percentages of patients achieving a VGPR and MRD before maintenance. Patients were then randomized to carfilzomib and lenalidomide or lenalidomide alone as maintenance. Patients who received KRd [induction therapy], a transplant, and KRd [consolidation therapy] had an MRD negativity of 58% and a VGPR rate of 89%. For those who received KRd alone, [the VGPR rate was] 87% [and MRD negativity was 54%]. These groups were very similar in terms of response.
Patients who were high risk, R-ISS 2 and 3, [had the same VGPR rate (86%)] with either regimen.5 [However,] PFS] was different. Early relapse was lower [in] the transplant group [8%] versus patients who [received 12 cycles of] KRd alone [17%]. There was no difference [in the rate of early relapse] in patients who had R-ISS 1 [disease among the 2 groups]. A multivariate regression analysis showed reduced risk of early progression in patients who underwent a transplant after KRd [induction].
[After a median follow-up of 45 months from the first randomization], median PFS had not been reached for patients who received KRd followed by a transplant.5 Median PFS for patients who received 12 cycles of KRd without transplant was 57 months. [Median PFS was] 53 months in the group given KCd and underwent a transplant. This shows that PFS seems to favor KRd followed by transplant.
[Results from a subgroup] analysis [demonstrated the PFS benefit of KRd and transplant compared with KRd alone regardless of] patient risk, LDH level, or ISS.5 For the maintenance phase, PFS also favors patients who got the combination of carfilzomib and lenalidomide versus lenalidomide alone. The 3-year PFS rate was 75% with carfilzomib and lenalidomide versus 66 with lenalidomide.
What was the impact of quadruplet therapy in the CASSIOPEIA study?
Quadruplet therapy has been [examined], and data show that compared with triplet therapy, it makes an impact in terms of response and PFS in some studies. The CASSIOPEIA study assessed VTd versus VTd-D for 4 cycles.6 Patients then underwent a transplant and received 2 more cycles of therapy. [Subsequently], patients were randomized for observation or daratumumab every 8 weeks [until disease progression or] for 2 years.
About 85% of patients were standard risk and 15% were high risk.6 The primary end point for the initial part of the study was stringent complete response [sCR], and the primary end point for the second part was PFS. The sCR rate was 29% with quadruplet therapy versus 20% with [triplet therapy]. Significantly [more] patients who received VTd-D [achieved] MRD negativity [64%] than those given VTd [44%; P < .0001]. PFS favored VTd-D, resulting in the approval of this combination for patients with newly diagnosed multiple myeloma [in the United States] and Europe. A subgroup analysis showed that PFS favors VTd-D in all groups, except patients with stage III disease and those with high-risk cytogenetics, highlighting that high-risk myeloma still remains a challenge.6
What were the key efficacy takeaways from the GRIFFIN trial?
GRIFFIN study data were presented at ASH [in 2020].8 This was a phase 2 randomized study where transplant-eligible patients and patients just given diagnoses were randomized to receive RVd-D or RVd for 4 cycles.7 Patients underwent a transplant and then received consolidation therapy with RVd-D or RVd for 2 more cycles. [They subsequently went] right into maintenance with daratumumab and lenalidomide versus lenalidomide. The primary end point was [sCR] at the end of consolidation therapy. The secondary end points included MRD negativity, CR, and a response rate of [at least a] VGPR. Like [a typical] patient population, they had newly diagnosed myeloma, 15% were high risk, median age was 60, and 14% were ISS stage III.
The responses deepened over time.8 This is something that we’ve seen in multiple clinical trials; sCR at the end of induction—so, after 4 cycles—was 12% [with D-RVd]. At the end of transplant, 21%; at end of consolidation, 42%; and then after 12 months of maintenance, 64%. As we continue treating these patients, the responses get better. In all these cases, the rate of an sCR was [higher] when we added daratumumab. At the end, the sCR rate was 64% versus 47%.
When you add daratumumab, MRD [negativity rates improved compared with RVd], 62% versus 27%, [respectively].8 Among all patients who were MRD evaluable, 78% [given D-RVd were MRD negative] versus 39% [given RVd]. It’s interesting data regarding MRD negativity with the addition of daratumumab. [MRD negativity is] definitely an important factor for long PFS.
A subgroup analysis by 12 months of maintenance, the therapy cutoff for both groups, assessed sCR and MRD negativity. It favored D-RVd in almost all groups, except ISS stage III. D-RVd improved MRD negativity in most subgroups.8
There was not a significant difference in overall survival [OS]. This is very common in myeloma because of all the different added therapies. PFS rate at 12 months [appeared] the same, but at 24 months it [starts] separating, favoring D-RVd.8
How do you attempt to get patients to MRD-negative status?
If I have a patient who is MRD positive 3 months after transplant, regardless of whether they are high risk or not, I would use a proteasome inhibitor and an immunomodulatory drug as maintenance to get the patient to MRD [status].
We’ve seen in multiple studies that to get to a deep response in myeloma takes time. It’s not something that happens quickly. As you keep treating these patients, [there’s a greater] chance of getting deeper responses. We usually look at 3 months after transplant, and then at year 1 and year 2. We do it yearly after that with next-generation sequencing, which is FDA approved.
When comparing a 4-drug regimen with a 3-drug regimen, how do you gauge what regimen is most effective?
In the majority of the trials, the difference in survival is very hard to measure. In the IFM trial, [at the] 8-year follow-up, survival has not changed. But the PFS [advantage] is clear. The CR rate is clear. The MRD negativity rate is clear.
I think all these therapies are for better OS. I [lead] by that. I celebrate when I see better PFS and better MRD [negativity] and the treatment response according to those. Many of these therapies are being approved based on better PFS.
How did the addition of daratumumab affect the adverse event (AE) profile in the GRIFFIN study?
Adding daratumumab [to the regimen does not produce a lot of changes in] the most common AEs.7 It’s not too toxic. Grades 3 and 4 nonhematologic AEs [were] low for both RVd and D-RVd. The [incidence of] cytopenia increased with the [addition of] daratumumab, and all these patients needed to be on prophylaxis.
1. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 5.2021. December 10, 2020. Accessed March 22, 2021. https://bit.ly/3fa9Yx5
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 followup 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