Upfront Multidrug Regimens Prove Beneficial in Myeloma

Marc J. Braunstein, MD, PhD

Pivotal data from the MAIA, ALCYONE, and GRIFFIN trials have showcased encouraging clinical activity, as well as tolerably safety profiles, with triplet and quadruplet regimens for patients with newly diagnosed multiple myeloma and continue to transform the paradigm, explained Marc J. Braunstein, MD, PhD.

“Now that we have more targeted therapies and monoclonal antibodies, we are able to consider quadruplet therapies for more patients, because these drugs are targeted therapies and are better tolerated,” said Braunstein.

For example, in the phase III MAIA trial, the combination of daratumumab (Darzalex) with lenalidomide (Revlimid) and dexamethasone (DRd) led to a 44% reduction in the risk of disease progression or death versus lenalidomide/dexamethasone alone (Rd) in newly diagnosed, transplant-ineligible patients with myeloma (HR, 0.56; 95% CI, 0.43-0.73; P <.001).¹ In June 2019, the FDA approved DRd for the treatment of patients with newly diagnosed myeloma who are ineligible for autologous stem cell transplantation (ASCT), based on the MAIA findings.

In the phase II GRIFFIN trial, researchers looked at the combination of daratumumab with bortezomib (Velcade) and Rd (D-RVd) in transplant-eligible patients with newly diagnosed disease. At a median follow-up of 22.1 months, results showed that the stringent complete response (sCR) rate was 62.6% with D-RVd versus 45.4% with RVd alone (odds ratio, 1.98; 95% CI, 1.12-3.49; P = .0177).²

In the randomized phase III ALCYONE study, the addition of daratumumab to bortezomib, melphalan, and prednisone (VMP) in transplant-ineligible patients with myeloma was evaluated. At a median follow-up of 40.1 months, updated findings showed that the median progression-free survival (PFS) with D-VMP was 36.4 months versus 19.3 months with VMP alone (HR, 0.42; 95% CI, 0.34-0.51; P <.0001).³ In May 2018, the FDA approved daratumumab plus VMP for the treatment of patients with newly diagnosed myeloma who are ineligible for ASCT, based on earlier ALCYONE findings.

In an interview during the 2020 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Braunstein, clinical assistant professor, Department of Medicine, co-director, Autologous Stem Cell Transplant Program, NYU Winthrop Hospital, NYU Langone Health’s Perlmutter Cancer Center, expanded on the 3- and 4-drug regimens that are showing promise in the multiple myeloma paradigm.

OncLive: What are the differences between the treatment options for transplant-eligible and -ineligible patients?

Braunstein: Historically, when we first approached a patient with multiple myeloma, the key decision has been whether a patient is fit enough for high-dose chemotherapy followed by ASCT. That was the key therapy in absence of effective targeted therapies designed specifically for the biology of multiple myeloma.

Now, we tend to focus on the general fitness for intensive or less-intensive upfront therapy, but it is still important to consider the trajectory of the patient—whether or not they are eventually going to go for consolidation with high-dose chemotherapy and ASCT.

For a transplant-ineligible patient, we typically treat them with a doublet or triplet regimen and then, perhaps, continuous therapy thereafter. For a patient who is eligible for ASCT, the process would typically involve a triplet or quadruplet induction regimen followed by consolidation with ASCT.

How is minimal residual disease (MRD) currently being assessed in multiple myeloma?

This is becoming an important surrogate marker for both PFS and overall survival (OS). It is being used in the context of clinical trials as a regulatory endpoint to determine whether patients will have long-term efficacy of that therapy, should they arrive at the absence of MRD.

How is maintenance therapy utilized in multiple myeloma?

Maintenance therapy has been shown in both prospective studies as well as meta-analyses to have an OS benefit in patients with multiple myeloma, particularly after ASCT. The idea behind maintenance therapy is to target the multiple myeloma clone over time with therapies that are somewhat reduced in dose, but are still tolerable. Surveillance is persisted should any resisting clones start to arrive.

Multiple myeloma is still concluded to be incurable because when patients are first diagnosed, they have multiple non-identical plasma cell clones, many of which are destroyed by induction chemotherapy. Some of these clones will persist in the bone marrow microenvironment following ASCT.

Regarding transplant-ineligible patients, could you discuss the results of the MAIA study?

MAIA was a randomized, phase III trial on transplant-ineligible patients with newly diagnosed multiple myeloma. Researchers looked at DRd compared with Rd.

The primary endpoint was PFS; a secondary endpoint was MRD negativity. At a median follow-up of 20 months, results showed a significant improvement in PFS with the triplet regimen compared with the doublet. Overall, it was well tolerated; there was some increase in myelosuppression and infections.

In addition, more patients achieved an absence of MRD with the triplet regimen compared with the doublet regimen. This study demonstrated that for transplant-ineligible patients, DRd is a good regimen.

Also for transplant-ineligible patients, could you share updates of the ALCYONE trial?

The ALCYONE trial was the first randomized, phase III study that looked at including daratumumab upfront for multiple myeloma. Researchers looked at a quadruplet regimen of D-VMP versus the triplet regimen of VMP for transplant-ineligible patients.

The recent update showed an OS benefit [in the D-VMP arm]. This is an impressive outcome for upfront, newly diagnosed patients who are ineligible for stem cell transplant. The backbone of that regimen is not as commonly used in the United States, but it still proves the principle that when you add a monoclonal antibody to that triplet backbone, you allow for an OS benefit, which is very encouraging.

There was also an update with the GRIFFIN study. Could you discuss those data?

The GRIFFIN study is a highly-anticipated phase II trial of D-RVd versus the standard triplet regimen of RVd for transplant-eligible patients. Data showed a PFS benefit; however, the primary endpoint was sCR. At every point of the study, there was an increase in sCR in the quadruplet arm compared with the triplet arm.

This may become the new standard of care for transplant-eligible patients; however, we still require more long-term readout of the data in order to see which type of patient benefits most.

What else is coming down the pipeline in terms of first-line therapy?

There are more monoclonal antibody studies, beyond daratumumab, that are looking at whether they can be combined with a standard triplet.

For example, a phase III study [is looking at the] combination of elotuzumab (Empliciti) with lenalidomide and dexamethasone for upfront therapy. In addition, while we have not gotten approval for CAR T-cell therapy in multiple myeloma, there are trials being proposed to include CAR T-cells upfront for patients who have not achieved a CR following stem cell transplant.

References

1. Facon T, Kumar S, Plesner T, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380(22):2104-2115. doi: 10.1056/NEJMoa1817249
2. Voorhees PM, Kaufman JL, Laubach, JP, et al. Depth of response to daratumumab (DARA), lenalidomide, bortezomib, and dexamethasone (RVd) improves over time in patients (pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): Griffin study update. Blood. 2019;134(suppl 1;abstr 691). doi: 10.1182/blood-2019-123456
3. 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