Fonseca Considers Transplant and Quadruplet Regimens in Multiple Myeloma

Rafael Fonseca, MD

During a Targeted Oncology Case-Based Roundtable event, Rafael Fonseca, MD, director, Innovation and Transformational Relationships, chair, Department of Internal Medicine and interim Director at the Mayo Clinic Cancer Center in Phoenix, AZ, discussed the case of a 51-year of man with multiple myeloma.

Targeted Oncology^TM: What are some primary therapy options recommended by the National Comprehensive Cancer Network (NCCN) for transplant-eligible patients with multiple myeloma?

FONSECA: Sometimes it’s difficult to [choose] a primary therapy for transplant candidates. Within the NCCN guidelines, the combination of bortezomib [Velcade], lenalidomide [Revlimid], and dexamethasone [VRd] is preferred.¹ Other recommended regimens include the carfilzomib [Kyprolis], lenalidomide, and dexamethasone combination [KRd] and the daratumumab [Darzalex], bortezomib, lenalidomide, and dexamethasone combination [D-VRd]. The combination of cyclophosphamide, bortezomib, and dexamethasone, listed as “useful in certain circumstances,” is appropriate [when there is] renal failure and even amyloidosis.

What data support the use of stem cell transplant in conjunction with the VRd regimen?

The IFM 2009 study [NCT01191060] addressed the role of stem cell transplant as part of a [first-line] treatment regimen for transplant-eligible patients with multiple myeloma. In this study, [treatment with] VRd plus stem cell collection and transplant was compared with VRd plus stem cell collection but no transplant. All patients were given a maintenance regimen of lenalidomide, 10 to 15 mg, for 12 months. Although there was no apparent difference in 8-year overall survival [OS] rate between the nontransplant and transplant groups [60.2% vs 62.2%, respectively; HR, 1.03; 95% CI, 0.80-1.32; P = .81], the early indicators for median progression-free survival [PFS; 35.0 months vs 47.3 months, respectively; HR, 0.70; 95% CI, 0.59-0.83; P < .001] favor a regimen that includes stem cell transplant.^2,3

How did minimal residual disease (MRD) status and cytogenetic risk status affect PFS?

MRD was measured after transplant and MRD negativity was associated with [greater PFS], but among both MRD-negative and MRD-positive patients, the results seem to favor transplant.⁴

[The data also suggest] that it doesn’t matter when the patient achieves MRD negativity as long as they achieve it. For those who achieved MRD negativity at the start of maintenance therapy and for those who achieved MRD negativity after 1 year of maintenance therapy, the outcomes were [essentially] the same; [for patients whose MRD status was analyzed after 1 year of maintenance therapy and who were followed up at a median of 38 months after completion of maintenance, PFS was not reached for those who were MRD negative and was 20 months for those who were MRD positive].⁴

The results also showed differential PFS [among patients when they were subdivided] according to their cytogenetic classification [high risk vs standard risk]. MRD-negative patients with high-risk genetic markers [exhibited superior PFS to that of] MRD-positive patients with standard-risk markers.4 In other words, MRD status [was more important than] cytogenetic risk category. This suggests that achieving MRD negativity will become an important goal of therapy. Now, in this study they achieved a [slightly better result] with transplant, but I would suggest that this was agnostic to the treatment used; it’s possible that patients will be able to get results that are just as good without transplant.

Are there data to support the use of transplant in conjunction with the KRd regimen?

[In contrast with the IFM 2009 trial], the FORTE trial [NCT02203643] used KRd instead of VRd. There were 3 arms in this study. The first arm [consisted of] 12 cycles of KRd. In the second arm, patients received 4 cycles of KRd, a single stem cell transplant, and then 4 more cycles of KRd. The third arm [was structured like the second], but patients received carfilzomib, cyclophosphamide, and dexamethasone [KCd] instead of KRd. Finally, there was a second randomization after which patients received either lenalidomide or carfilzomib plus lenalidomide [KR] for maintenance.^5,6

The results suggest that the best outcomes are obtained with a regimen of KRd, stem cell transplant, plus additional KRd; the worst outcomes were seen when KRd was replaced by KCd. This is 1 more study that suggests that cyclophosphamide is [going to be used less often as] front-line treatment. Furthermore, the percentage of patients demonstrating PFS at 3 years was 78% for the KRd plus transplant group, 66% for the KRd-only group, and 58% for the KCd plus transplant group [KRd plus transplant vs KRd alone, HR, 0.64; 95% CI, 0.44-0.94; P = .023]. In almost all the subgroups they examined [as defined by ISS stage, FISH, and LDH level], KRd plus transplant was favored over KRd alone.6 This seems to point to the contribution of transplant in early treatment. I will note that, in my opinion, 2 things are missing [from this study]: better MRD determination and [consideration of whether] any other treatment that is able to similarly induce MRD negativity might [perform similarly].

How did the choice of maintenance therapy affect PFS?

PFS was analyzed following the second randomization to R vs KR maintenance therapy. [After 3 years], the percentage of patients exhibiting PFS was statistically significantly greater with KR than with R [75% vs 66%, respectively; HR, 0.63; P = .026], and this result was consistent throughout subgroup analyses.⁶ This tells me that in multiple myeloma, more treatment of any kind [as long as it is a good treatment], results in better outcomes. [In this case] there’s nothing intrinsically magical about 4 cycles of induction and transplant, it’s just [a means to achieving] the best possible response, and the data suggest that more treatment after transplant could be beneficial. These are early results, but very intriguing.

What data support the addition of daratumumab to the bortezomib, thalidomide (Thalomid), and dexamethasone combination (VTd)?

The CASSIOPEIA study [NCT02541383] was a global study that compared triplet vs quadruplet therapies: VTd vs D-VTd.⁷ Admittedly, we don’t use thalidomide much in the United States, but this trial does allow you to isolate the effect of daratumumab, so this study is a good test of the principle [that more good therapies are better than fewer].

In this study, patients received 4 cycles of induction with either VTd or D-VTd, followed by stem cell mobilization and transplant, and then they received 2 more cycles of their assigned induction therapy. Like the FORTE study, this study had a second randomization, after which patients either received daratumumab every 8 weeks until progression or were simply observed until progression.⁷

The depth of response was greater with the quadruplet regimen than with the triplet regimen. The percentage of patients who achieved stringent complete response [CR] was 29% vs 20%, respectively [P = .0010]. The percentage of patients who achieved MRD negativity [using a threshold of 10-5], was 64% among those who received D-VTd vs 44% among those who received VTd [P < .0001]. The percentage of patients who exhibited PFS [about 31 months after randomization] was over 80% in the quad group [HR, 0.47; 95% CI, 0.33-0.67; P < .0001].⁷ [This supports the idea that] better, high-activity regimens control disease better, and this control seems to stem from an earlier, better response.

Again, we don’t use thalidomide in the United States but this [study serves] a proof of principle. [In contrast], the GRIFFIN study [NCT02874742] does not have [data that are as strong as those produced by the CASSIOPEIA study], but the GRIFFIN study used regimens that we use in the United States.^8,9

What regimens did the GRIFFIN study examine and what results did they produce?

The GRIFFIN study was a randomized phase 2 study that compared D-VRd vs VRd among transplant-eligible, newly diagnosed patients with multiple myeloma who ranged in age from 18 to 70 years old [and] who had good renal function and ECOG performance scores that ranged from 0 to 2. Following induction with D-VRd or VRd, patients received a stem cell mobilization regimen and transplant and then 2 cycles of consolidation with the same regimen that they had received for induction. Finally, for cycles 7 through 32, patients were placed on maintenance therapy; the quadruplet arm received D-R and the triplet arm received R only. The primary end point was stringent CR by the end of consolidation (1-sided α, 0.10). The secondary end points were MRD negativity, CR, very good partial response [VGPR], and overall response rate.⁹

The percentage of patients who achieved CR or better was [about] 81% in the quadruplet arm vs 60% in the triplet arm [P = .0014] at 12 months of maintenance.¹⁰ These data, again, support the idea that better treatment gives a better depth of response.

What did subgroup analyses reveal in this study?

In the analyses of subgroups that were defined according to sex, age, ISS disease stage, ECOG performance score, and multiple myeloma type (IgG vs non-IgG), the data for stringent CR and MRD negativity favored the 4-drug combination in all subgroups. Subgroup analysis of cytogenetic risk groups [showed effectiveness for the standard-risk group but not for the high-risk group].¹⁰ A recent meta-analysis suggests that daratumumab might be just as effective for high-risk disease [as for standard-risk disease when added to various backbone regimens],¹¹ but this particular analysis [did not demonstrate that].

At 24 months of follow-up, about 95% of the patients in the D-VRd group exhibited PFS [vs about 91% of patients in the VRd group]; these are outstanding results. OS rate at 24 months [was outstanding as well: about 95% vs 93%, respectively].¹⁰ We have to wait for these data to mature but [so far, they] favor the 4-drug combination. In our practice, we still use both 3-drug and 4-drug combinations. I think this is one of the most pressing questions we have in the multiple myeloma community today.

When using 4-drug combinations, what should physicians keep in mind regarding adverse events (AEs), as demonstrated by this study?

Some AEs, myelosuppression in particular, may be more common with 4-drug combinations. Neutropenia of any grade occurred in 57.6% of the D-VRd group vs 35.3% of the VRd group; neutropenia of grades 3 and 4 occurred in 41.4% vs 21.6%, respectively. [Similar trends were observed for] thrombocytopenia and leukopenia.9,10 In general, the combination of monoclonal antibodies and immunomodulatory drugs can cause myelosuppression. It’s not [catastrophic] but it’s something one has to be mindful of; [consider] dose adjustment when you use these combinations.

Most of the nonhematologic toxicities were similar between the study arms. However, notably, upper respiratory tract infection of any grade was more common with the 4-drug combination [62.6%] than with the 3-drug combination [44.1%].^9,10 We have to be mindful of the potential for immunosuppression with the use of a powerful anti-CD38 [therapy like daratumumab]¹² and the effects this immunosuppression may have on humoral immunity. Finally, there were no infusion reactions in patients who did not receive daratumumab, of course.^9,10

What can we conclude from these 4 studies?

In summary, if you consider postconsolidation VGPR as a marker—we have to wait for PFS and OS data as they mature—it seems that we’ve [achieved results superior to those achieved with VRd alone].

Some people might ask about the ENDEAVOR clinical trial [NCT01568866]¹³; that’s an important consideration because that trial showed that carfilzomib combinations were not superior to bortezomib combinations for front-line therapy. Based on that study and those described here, a couple of conclusions can be reached. I think it’s reasonable to use either VRd or KRd in clinical practice. I also think it’s reasonable to use either combination as the backbone of future clinical trials. In fact, the MASTER trial [NCT03224507] uses KRd plus daratumumab [with and without transplant] and the MANHATTAN trial uses KRd plus daratumumab without transplant.

The caveat is that there are trade-offs with toxicity. With bortezomib, [patients can] have peripheral neuropathy, which is perhaps less serious and something that improves over time, though it can cause quite a decrement of quality of life for patients.¹⁴ In comparison, carfilzomib can cause cardiorenal toxicity, which is admittedly more serious,¹⁵ though most of [it] seems to be reversible. I don’t see a lot of people with chronic heart problems in the clinic, but my clinic is full of patients with peripheral neuropathy. I treat most of my patients [with the regimen described in] the FORTE study: KRd, followed by stem cell transplant, then additional treatment plus transplant if the patient is MRD positive.

_REFERENCES:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 1.2022. Accessed September 23, 2021. https://bit.ly/3m69slp}

_{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 September 25, 2021. https://bit.ly/3um8XaT}

_{9. Voorhees PM, Kaufman JL, Laubach J, et al; GRIFFIN Trial Investigators. 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}

_{10. 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}

_{11. Giri S, Grimshaw A, Bal S, et al. Efficacy of daratumumab in the treatment of multiple myeloma with high-risk cytogenetics: meta-analysis of randomized phase III trials. J Clin Oncol. 2020;38(suppl 15):8540. doi:10.1200/JCO.2020.38.15_suppl.8540}

_{12. Darzalex. Prescribing information. Janssen Biotech Inc; 2021. Accessed September 25, 2021. https://bit.ly/3CRScHu}

_{13. Orlowski RZ, Moreau P, Niesvizky R, et al. Carfilzomib-dexamethasone vs bortezomib-dexamethasone in relapsed or refractory multiple myeloma: updated overall survival, safety, and subgroups. Clin Lymphoma Myeloma Leuk. 2019;19(8):522-530. e1. doi:10.1016/j.clml.2019.04.018}

_{14. Velcade. Prescribing information. Millennium Pharmaceuticals Inc; 2019. Accessed September 25, 2021. https://bit.ly/3urSTnR}

_{15. Kyprolis. Prescribing information. Amgen Inc; 2021. Accessed September 25, 2021. https://bit.ly/3AS9J1w}