Usmani Underscores New and Updated Data Across Myeloma Paradigm

Saad Z. Usmani, MD, MBA, FACP

Although the armamentarium of multiple myeloma is rich with available treatment options, novel triplet regimens, maintenance therapies, and targets beyond BCMA are further expanding the paradigm across the newly diagnosed, early-relapse, and late-relapse disease states.

During the 2021 ASCO Direct Highlights™ webcast in Charlotte, North Carolina, a program developed by Physician’s Education Resource® (PER®), LLC, Saad Z. Usmani, MD, MBA, FACP, discussed key data presented during the 2021 ASCO Annual Meeting in multiple myeloma and the potential clinical implications of these data in the management of this disease. 

Newly Diagnosed, Transplant-Eligible Multiple Myeloma

Currently, triplet-based therapy followed by autologous stem cell transplant (ASCT) and maintenance therapy remains the standard of care for patients with standard- and high-risk, newly diagnosed, transplant-eligible multiple myeloma, said Usmani. 

Findings from the phase 2 Cardamon trial (NCT02315716) demonstrated that 4 cycles of induction carfilzomib (Kyprolis), cyclophosphamide, and dexamethasone (KCd) induced deep responses with a 24.3% minimal residual disease (MRD)–negativity rate in this patient population.¹

Following induction therapy, patients were randomized 1:1 to receive ASCT with high-dose melphalan or 4 cycles of KCd consolidation, both followed by maintenance carfilzomib for 18 cycles.

The results of the randomization showed similar increases in the rates of very good partial responses between arms; however, the rate of MRD negativity was higher in the cohort that underwent ASCT (53.1%) vs those who received consolidation (35.8%). Additionally, the 2-year progression-free survival (PFS) rate for KCd was not noninferior to ASCT, at 70% vs 76%, respectively (difference, -5.8%; 95% CI, -10.4% to -0.3%). Notably, high-risk patients had inferior PFS compared with standard-risk patients.

“This is another study showing that [ASCT] remains the standard of care as it provides better depth of response. [However], in terms of survival outcome data, we only have a short follow-up of 2 years. It is a bit early of a time point given that the overall survival [OS] for this disease is well over 10 years and the median PFS regardless of [transplant-eligibility status] is well beyond 5 years,” said Usmani, clinical professor of medicine, division chief of Plasma Cell Disorders, and director of Clinical Research in Hematologic Malignancies in the Department of Hematologic Oncology and Blood Disorders at the Levine Cancer Institute of Atrium Health.

Findings from part 2 of the phase 3 CASSIOPEIA trial (NCT02541383) demonstrated that reduced-frequency maintenance therapy with daratumumab (Darzalex) given every 8 weeks significantly improved post-ASCT outcomes in patients with multiple myeloma who received bortezomib (Velcade), thalidomide (Thalomid), and dexamethasone (VTd) induction or consolidation.²

Initial results from part 1 of the study supported the regulatory approvals of daratumumab plus VTd (D+VTd) in this patient population based on improved PFS with D+VTd vs VTd alone.³

In part 2 of the study, at a median follow-up of 35.4 months from second randomization, the median PFS from second randomization was not reached with daratumumab maintenance vs 46.7 months with observation (HR, 0.53; 95% CI, 0.42-0.68; P < .0001). Moreover, the benefit with daratumumab maintenance was observed across most prespecified subgroups.

Notably, findings from a prespecified analysis demonstrated that patients who received VTd plus daratumumab maintenance derived a PFS benefit compared with patients who received VTd plus observation. No PFS benefit was reported in patients who received D+VTd plus daratumumab maintenance vs D+VTd plus observation.

“Daratumumab may be a [maintenance] option in the future, but it needs to be compared with lenalidomide [Revlimid] or combined with lenalidomide,” Usmani said.

As such, the ongoing, phase 3 DRAMMATIC (NCT04071457) and AURIGA (NCT03901963) trials are evaluating daratumumab plus lenalidomide as maintenance therapy for patients with newly diagnosed multiple myeloma following ASCT.

Early Relapsed/Refractory Multiple Myeloma

Upon first relapse, treatment selection for patients with multiple myeloma depends largely on whether they are refractory to lenalidomide, said Usmani. Moreover, as daratumumab is being used in the up-front setting, identifying alternative CD38-directed monoclonal antibodies for patients with daratumumab-refractory disease is an ongoing research effort. 

Data from the primary analysis of the phase 3 ICARIA-MM trial (NCT02990338) led to the March 2020 FDA approval of isatuximab-irfc (Sarclisa) in combination with pomalidomide (Pomalyst) and dexamethasone (Isa-Pd) for patients with multiple myeloma who have received at least 2 prior therapies, including lenalidomide and a proteasome inhibitor (PI).⁴ The results of the study demonstrated a significant improvement in PFS with the combination vs Pd alone (11.5 months vs 6.5 months, respectively; HR, 0.596; 95% CI, 0.436-0.814; P = .001).

Updated data from the study, which were presented during the 2021 ASCO Annual Meeting, showed that the median PFS2 was 17.51 months with Isa-Pd vs 12.88 months with Pd alone (HR, 0.759; 95% CI, 0.582-0.989; P = .0202). The median OS was 24.57 months vs 17.71 months, respectively (HR, 0.760; 95% CI, 0.574-1.008; P = .0280).

Notably, responses continued to deepen with Isa-Pd vs Pd alone after an additional 2 years of therapy.

“We’ve already incorporated the [Isa-Pd] regimen into clinical practice,” said Usmani. “[However], we need more data to see how to sequence different anti–CD38 [antibodies]. So far, the data with isatuximab in patients with prior daratumumab refractoriness are not very encouraging.”

Late Relapsed/Refractory Multiple Myeloma

Although treating patients with multiply refractory multiple myeloma remains challenging, a wealth of novel options, including selinexor (Xpovio), belantamab mafodotin-blmf (Blenrep), and melflufen flufenamide (Pepaxto), as well as multiple combination strategies, have allowed for personalized treatment in this setting, explained Usmani.

“This is where therapies become a bit more challenging. We are doing a lot of individualized therapy based on prior drug exposures and patient preferences, as well as the [adverse] effects patients have,” said Usmani. “Since myeloma is a disease of older age, we have to take into account comorbidities, socioeconomic considerations, and whether patients prefer an oral vs parenteral route of administration for a regimen,” added Usmani.

BCMA-directed CAR T-cell therapy has been an important addition to the late-relapse landscape following the March 2021 FDA approval of idecabtagene vicleucel (Abecma) in patients with relapsed/refractory multiple myeloma who received 4 prior lines of therapy, including an immunomodulatory agent, PI, and CD38-directed monoclonal antibody.⁵

Another BCMA-directed CAR T-product, ciltacabtagene autoleucel (cilta-cel), has demonstrated efficacy in this patient population. Updated results from the phase 1b/2 CARTITUDE-1 trial (NCT03548207) demonstrated that at a median follow-up of 18 months, the overall response rate (ORR) was 97.9% with a single dose of cilta-cel in patients with heavily pretreated multiple myeloma.⁶ Moreover, 80.4% of patients achieved stringent complete responses (sCRs) and 91.8% had MRD negativity.

The 18-month PFS rate was 66%, and the 18-month OS rate was 80.9%; no new safety signals were observed with longer follow-up.

“Cilta-cel is quite active. There is a PDUFA date at the end of November [2021], so we are hoping this will be approved by the regulatory authorities. It will be a welcome option,” said Usmani. “Clinical trials [are evaluating cilta-cel] in earlier line settings [in patients who received] 1 to 3 prior lines [of therapy], as well as newly diagnosed studies in high-risk patients. We are looking forward to moving this therapy to those patients.”

Beyond BCMA, GPRC5D is a promising target for therapies in heavily pretreated multiple myeloma, explained Usmani.

Updated findings from the first-in-human, phase 1 MonumenTAL-1 trial (NCT03399799) of the off-the-shelf, T-cell redirecting agent talquetamab demonstrated a 70% ORR in patients with relapsed/refractory disease.⁷ Moreover, ORRs of 65.2% and 83.3% were achieved in patients with triple-class refractory and penta-class refractory multiple myeloma, respectively.

Notably, 4 of 6 evaluable patients achieved MRD-negative CRs or sCRs, including 1 patient who received the recommended phase 2 dose of 405 µg/kg of talquetamab.

The phase 2 expansion study (NCT04634552) is currently enrolling.

References

1. Yong K, Camilleri M, Wilson W, et al. Upfront autologous stem cell transplantation (ASCT) versus carfilzomib-cyclophosphamide-dexamethasone (KCd) consolidation with K maintenance in transplant-eligible, newly diagnosed (NDTE) multiple myeloma (MM). J Clin Oncol. 2021;39(suppl 15):8000. doi:10.1200/JCO.2021.39.15_suppl.8000
2. Moreau P, Sonneveld P. Daratumumab (DARA) maintenance or observation (OBS) after treatment with bortezomib, thalidomide and dexamethasone (VTd) with or without DARA and autologous stem cell transplant (ASCT) in patients (pts) with newly diagnosed multiple myeloma (NDMM): CASSIOPEIA Part 2. J Clin Oncol. 2021;39(suppl 15):8004. doi:10.1200/JCO.2021.39.15_suppl.8004
3. FDA approves daratumumab for transplant-eligible multiple myeloma. News release. FDA. September 26, 2019. Accessed July 7, 2021. https://bit.ly/3jUeGRU.
4. Richardson PG, Perrot A, San-Miguel JF, et al. Updates from ICARIA-MM, a phase 3 study of isatuximab (Isa) plus pomalidomide and low-dose dexamethasone (Pd) versus Pd in relapsed and refractory multiple myeloma (RRMM). J Clin Oncol. 2021;39(suppl 15):8017. doi:10.1200/JCO.2021.39.15_suppl.8017
5. FDA approves idecabtagene vicleucel for multiple myeloma. News release. FDA. March 26, 2021. Accessed July 7, 2021. https://bit.ly/3hjpUxz.
6. Usmani SZ, Berdeja JG, Madduri D, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR-T) therapy, in relapsed/refractory multiple myeloma (R/R MM): updated results from CARTITUDE-1. J Clin Oncol. 2021;39(suppl 15):8005. doi:10.1200/JCO.2021.39.15_suppl.8005
7. Berdeja JG, Krishnan AY, Oriol A, et al. Updated results of a phase 1, first-in-human study of talquetamab, a G protein-coupled receptor family C group 5 member D (GPRC5D) × CD3 bispecific antibody, in relapsed/refractory multiple myeloma (MM). J Clin Oncol. 2021;39(suppl 15):8008. doi:10.1200/JCO.2021.39.15_suppl.8008