Optimal Strategies for Treatment of Multiple Myeloma in Newly Diagnosed Patients

Shaji K. Kumar, MD

The multiple myeloma treatment paradigm has seen an assortment of therapeutic advances in recent years with agents that have demonstrated the ability to extend survival in patients and improving disease outcomes. However, the severity of the disease continues to linger without a cure, calling for oncologists to take new approaches to ensure that patients do not lose benefit while on treatment.

During a presentation at the National Comprehensive Cancer Institute (NCCN) 2020 Virtual Congress: Hematologic Malignancies, Shaji K. Kumar, MD, explained that each case of multiple myeloma requires a long-term strategy that starts with a strong approach in the frontline setting.¹

Treatment Options in the Myeloma Paradigm

Once patients are diagnosed and stratified for risk, those who are eligible for stem cell transplantation (SCT) are eligible for consideration of induction, consolidation, and maintenance therapy cycles, said Kumar, who is medical director of the Clinical Research Office at the Mayo Clinic Cancer Center in Rochester, Minnesota. Patients who are ineligible for SCT, however, can only receive induction therapy followed by continuous systemic treatment. In addition, options vary for patients at their first through fourth relapse and beyond with all therapeutic options selected based on patient’s tumor burden.

Triplet Therapy for Transplant-Ineligible Newly Diagnosed Multiple Myeloma​

The phase 3 SWOG S0777 [NCT00644228] trial demonstrated results that have informed decision making for frontline triplet therapy using a proteasome inhibitor plus an immunomodulatory drug. The study showed that the addition of bortezomib (Velcade) to lenalidomide (Revlimid) and dexamethasone (VRd) can significantly improve overall survival (OS) and progression-free survival (PFS) in patients with newly diagnosed myeloma who were not planned for immediate SCT with acceptable toxicity.²

The VRd regimen was compared with that of lenalidomide and dexamethasone alone (Rd). The trials primary end point was PFS using a prespecified one-sided stratified log rank test. Other end points explored in the study were OS, overall response rate (ORR), and safety.

The median PFS observed with the VRd regimen was 43 months versus 30 months with the Rd regimen. The stratified HR for the difference between the 2 arms was HR, 0.712; 96% CI, 0.56–0.906; one-sided P = .0018). The median OS was 75 months in the VRd arm compared with 64 months in the Rd arm (HR, 0.709; 95% CI, 0.524-0.959; two-side P = .025).

The superiority of VRd was significant and remained so, even when tested against other regimens. For example, the combination of carfilzomib (Kyprolis) plus Rd (KRd), as observed in the phase 3 ENDURANCE (E1A11) trial (NCT01863550). In the study, KRd did not improve survival over VRd with a median PFS of 34.6 months (95% CI, 28.8-37.8) versus 34.4 months (95% CI, 30.1 to not evaluable [NE]), respectively (HR, 1.04; 95% CI, 0.83-1.31; P =.742), according to results from the second interim analysis presented at the 2020 American Society of Oncology Virtual Annual Meeting and simultaneously published in the Lancet Oncology.³

It was notable that VRd appeared to be a less toxic regimen compared with KRd. Non-hematologic treatment-related adverse events (TRAEs) of grade 3 occurred in 40.1% of the KRd arm versus 37.4% of the VRd arm; grade-4 events were observed in 6.8% versus 3.8%. respectively. The most common nonhematologic TRAEs observed in the study were peripheral neuropathy, dyspnea, hyperglycemia, fatigue, and rash.

Also in 2019, results from the phase 3 MAIA trial (NCT02252172) of daratumumab (Darzalex) in combination with Rd (DRd) compared with Rd alone were published in the New England Journal of Medicine and showed that in newly diagnosed patients who are ineligible for autologous stem-cell transplantation (ASCT), DRd can significantly lower the risk of disease progression or death. However, this boost in efficacy comes with more cytopenic toxicity.⁴

In 737 patients, the median PFS was not reached in the DRd arm compared with 31.9 months in the Rd arm (HR, 0.56; 95% CI, 0.43-0.73; P <.001). In terms of response, the ORR was higher with DRd at 92.9% with a CR or better rate of 47.6% versus 81.3% and 24.9%, respectively, with Rd.

Quadruplet Therapies for Newly Diagnosed Multiple Myeloma

Of late, clinical trial data have explored quadruplet regimens in patients with newly diagnosed disease.

The phase 2 CASSIOPEIA trial (NCT02541383) that was published in the Lancet in 2019 showed the combination of daratumumab plus bortezomib, thalidomide (Thalomid), and dexamethasone (D-VTd) could improve the depth of responses and PFS in patients receiving pre-transplant induction and consolidation therapy with acceptable toxicity compared with VTd alone.⁵

The sCR rate 100 days post-transplant, 1 of the primary end points, was 29.8% in the D-VTd arm versus 20.3% in the VTd arm. The hazard ratio for the risk of disease progression or death observed in this study was 0.47 (95% CI, 0.33-0.67).

Others studies that Kumar highlighted during his presentation confirmed the benefit quadruplet therapies with daratumumab. Starting with the phase 2 GRIFFIN study (NCT02874742), Kumar explained how the benefit of daratumumab plus VRd (D-VRd) as induction and consolidation compared with VRd alone was confirmed based a difference in the sCR rate in patients with transplant-eligible disease (odds ratio, 1.57; 95% CI, 0.87‐2.82; 1‐sided P = 0.068).⁶

In the ongoing MASTER trial (NCT03224507), Kumar noted how daratumumab added to KRd was shown to be feasible as induction therapy with SCT and as consolidation therapy in this patient population, according to early result presented during the 2019 American Society of Hematology (ASH) Annual Meeting.⁷

Finally, Kumar highlight results from the phase 3 randomized ALCYONE trial (NCT02195479), which explored daratumumab, bortezomib, melphalan, and prednisone (D-VMP) in newly diagnosed patients with multiple myeloma who were ineligible for SCT. Based on the published results, the regimen significantly improved PFS after 3 years of follow-up.⁸

Interpreting the Data

Based on all the clinical trials reviewed in the newly diagnosed setting, Kumar explained that oncologist should approach treatment of patients based on their risk level.

For patients eligible for transplant, standard-risk treatment should include 4 cycles of VRd upfront, followed by SCT and another 4 cycles of VRd. After that, patients can receive lenalidomide maintenance. High-risk patients in this group should receive 4 cycles of D-VRd upfront, followed by SCT and maintenance with bortezomib and lenalidomide until disease progression.¹

For patients who are not eligible for transplant, Kumar stated that standard-risk patients should receive VRd for 12 months followed by lenalidomide maintenance; alternatively, patients can be treated with DRd for 12 months followed by maintenance with daratumumab and lenolidomide. High-risk patients should be given VRd upfront followed by bortezomib plus lenalidomide until disease progression.

_References:

_{1. Kumar S. Bonanza of new treatment regimens for multiple myeloma: what is right for my patient? Presented at: National Comprehensive Cancer Network Virtual Congress: Hematologic Malignancies; October 9-10, 2020; Virtual.}

_{2. Durie BGM, Hoering A, Abidi MH, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017;389(10068):519–527. doi:10.1016/S0140-6736(16)31594-X}

_{3. Kumar S, Jacobus SJ, Cohen AD, et al. Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2020; 21(10): 1317-1330. doi:10.1016/S1470-2045(20)30452-6}

_{4. Facon T, Sumar S, Plesner T, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med.2019;380(22):2104-15. doi: 10.1056/NEJMoa1817249}

_{5. 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; 304(10192): 29-38. doi: 10.1016/S0140-6736(19)31240-1}

_{6. 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}

_{7. Costa L, Chhabra S, Godby K, et al. Daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd) induction, autologous transplantation and post-transplant, response-adapted, measurable residual disease (MRD)-based Dara-Krd consolidation in patients with newly diagnosed multiple myeloma (NDMM). Blood. 2019;134(suppl 1):860. doi:10.1182/blood-2019-123170}

_{8. Mateos MV, Cavo M, Blade J, et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet. 2020; 395(10218):132-141. oi: 10.1016/S0140-6736(19)32956-3}