Myeloma Treatment Continues to Evolve, Addressing the Heterogeneity of the Disease

Paul G. Richardson, MD

The biology of multiple myeloma (MM) has evolved over time, and the therapy of choice impacts the patient’s status and ability to continue on treatment, according to a presentation given by Paul G. Richardson, MD, during the 3rd Summit of Americas on Immunotherapies for Hematologic Malignancies.¹

As the understanding of the changes that can occur in MM has grown, the treatment landscape continues to advance in identifying the therapies that can lead to the best outcomes for patients and overcome the numerous mechanisms of resistance associated with MM treatment.

Of late, Richardson explained that there has been a shift from triplet combination therapies toward quadruplet combinations for the treatment of newly diagnosed MM (NDMM) and relapsed or refractory MM (RRMM).

Effective Quadruplets in Multiple Myeloma

The use of 4-drug regimens and specifically those containing daratumumab (Darzalex) have been effective and well-tolerated in MM, according to multiple phase 2 and 3 clinical trials. Moreover, responses to these quadruplet combinations appear to be more robust in patients who test negative for mismatch repair deficiency.²

CASSIOPEIA

The phase 3 CASSIOPEIA study (NCT02541383) of bortezomib (Velcade), thalidomide, and dexamethasone (VTd) with daratumumab (D-VTd) administered before or after autologous stem cell transplantation (ASCT) in patients with NDMM showed improvements in depth of response and progression-free survival (PFS) compared with VTd alone.³

The study included 1085 patients at 111 study sites in Europe. Randomized 1:1, 543 patients were assigned to the D-VTd arm and 542 were assigned to the VTd-only arm. Stringent complete response (CRs) were observed in 29% of the D-VTd arm compared with 20% of the VTd arm at day 100 following transplant (odds ratio [OR], 1.60; 95% CI, 1.21-2.12; P = .0010).

Achievement of a CR or better occurred in 39% of the D-VTd group vs 26% of the VTd group, and MRD negativity in patients MRD positive at baseline was achieved in 64% of the D-VTd arm compared with 44% of the VTd arm.

The median PFS from randomization was not reached in either treatment arm (hazard ratio [HR], 0.47; 95% CI, 0.33-0.67; P <. 0001). Overall, 14 patients in the D-VTd arm died vs 32 in the VTd-only group (95% CI, 0.23-0.80).

CASSIOPEIA was the first study to demonstrate clinical benefit of daratumumab in combination with standard of care in patients who were eligible for transplant, paving the way for other phase 3 clinical trials in MM.

ALCYONE

Treatment with daratumumab, bortezomib, melphalan flufenamide (Melflufen), and prednisone (D-VMP) in NDMM was shown to prolong overall survival (OS) in comparison with VMP alone, according to results from the phase 3 ALCYONE clinical trial (NCT02195479). With 3-year of follow-up, the study also demonstrated improvement in PFS with D-VMP over VMP only, with no new safety signals.⁴

There were 760 patients included in ALCYONE who were randomly assigned 1:1 to receive wither D-VMP or VMP. At 36-months, the D-VMP arm showed an OS rate of 78.0% (95% CI, 73.2%-82.0%) vs 67.9% (95% CI, 62.6%-72.6%) in the VMP arm (HR, 0.60; 95% CI, 0.46-0.80; P = .0003). PFS after 3 years was also prolonged with D-VMP vs VMP (HR, 0.42; 95% CI, 0.34-0.51; P < .0001).

According to the investigators of ALCYONE, the study showed continued support of using daratumumab-based regimens for the upfront treatment of patients with NDMM, but this time, in the transplant ineligible population.

GRIFFIN

In transplant-eligible patients with NDMM, the combination of lenalidomide (Revlimid), bortezomib, and dexamethasone (RVd) followed by ASCT was evaluated in the phase 3 GRIFFIN study of 207 patients (NCT02874742). D-RVd as induction and consolidation therapy showed an improvement in depth of response vs RVd alone.⁵

Patients treated with D-RVd in the study had a stringent CR of 42.9% compared with 32.0% in the RVd-only group (OR, 1.57; 95% CI, 0.87-2.82; 2-sided P = .068). Further, MRD negativity rates were better with D-RVd at 62.6% vs 45.4% with RVd (P = .0177). Only 4 patients in the D-RVd arm showed progressive disease vs 7 in the RVd arm.

Even with efficacious quadruplet regimens for the upfront treatment of MM, more options are need in later line, according to Richardson. “Drug systems may drive a relapse in myeloma and obviously novel mechanisms of action are critical with relapse,” Richardson stated during his presentation.¹

The Next Wave of Myeloma Treatment

The updated guidelines for the National Comprehensive Cancer Network list multiple 2- and 3-drug regimens for patients who are in their first relapsed. As additional options, the NCCN recommends FDA approves combinations containing isatuximab-irfc (Sarclisa), selinexor (Xpovio), VTd in combination with cisplatin, cyclophosphamide, dexamethasone, and doxorubicin (PACE), and others.

Investigational options available for patients with RRMM in the clinical trial setting include BCMA-targeted therapies, Melphalan flufenamide (Melflufen), and venetoclax (Venclexta). According to Richardson, these options are being investigated in studies like STORM (NCT02336815), DREAMM-6 (NCT03544281), and OCEAN (NCT03151811).

“The really good news is that we’re making an impact for the second- and third- relapse space. Second-, third-, fourth-, and fifth- line really still remains a huge challenge, but nonetheless is improving, explained Richardson. “And in that context, we used to think about double refractory patients as our biggest challenge, but now we’re dealing with penta-refractory or triple-class refractory,” he added.

_REFRENCES:

_{1. Treatment approach for high-risk acute myeloid leukemia in 2022. Presented at: 3rd Summit of the Americas on Immunotherapies for Hematologic Malignancies; April 8-9, 2022; Miami, FL.}

_{2. Ali S, Selene I, Tayyeb M, et al. Efficacy of four drug regimens in multiple myeloma: a systemic review. Blood. 2020;136 (suppl 1: 21-22. doi: 10.1182/blood-2020-142008}

_{3. 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}

_{4. 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. doi: 10.1016/S0140-6736(19)32956-3}

_{5. Voorhees PM, Kaufman JL, Laubah 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}