Costa Breaks Down Treatment Options for Patients With Multiple Myeloma

Luciano J. Costa, MD, PhD

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 Oncology^TM: 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 [100] 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.

_REFERENCES:

_{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}