This past year has been a busy one for treatment approvals in multiple myeloma (MM). Three randomized, phase 3 studies led to new approvals from the US Food and Drug Administration (FDA): the combinations of selinexor, bortezomib, and dexamethasone from the BOSTON study (ClinicalTrials.gov Identifier: NCT03110562); isatuximab, pomalidomide, and dexamethasone from the ICARIA-MM study (ClinicalTrials.gov Identifier: NCT02990338); and daratumumab, carfilzomib, dexamethasone from the CANDOR study (ClinicalTrials.gov Identifier: NCT03158688). In addition, the antibody-conjugate therapy belantamab mafodotin and the combination of daratumumab and hyaluronidase-fihj also received FDA approval.
Ajai Chari, MD, professor of medicine at Icahn School of Medicine at Mount Sinai, director of clinical research in the Multiple Myeloma Program, and associate director of clinical research at the Mount Sinai Cancer Clinical Trials Office provides his perspective on the current treatment landscape in multiple myeloma and what to look forward to in 2021.
The FDA approved several new regimens for the treatment of patients with multiple myeloma in 2020. How will this series of indications change myeloma care in 2021?
On approvals gained after the BOSTON, ICARIA-MM, and CANDOR studies
Dr Chari: The phase 3 studies resulted in additional indications for selinexor and daratumumab/carfilzomib, and it was the first approval for isatuximab. Selinexor is showing a progression-free survival (PFS) benefit and a particularly encouraging benefit in del(17p) disease. Isatuximab/pomalidomide/dexamethasone and daratumumab/carfilzomib/dexamethasone also showed added value over their comparator arm. I think the latter is particularly interesting, as unlike some other phase 3 studies where they use a historical doublet, here they use carfilzomib/dexamethasone at 56 mg/m2 twice weekly, which was shown to be superior to bortezomib/dexamethasone. The addition of daratumumab is on top of an already very effective backbone and, despite this, it showed added value. That’s an important message here, considering that PFS for the triplet arm is not even reached yet.
The unifying thing about all 3 of these regimens is that lenalidomide refractoriness is an increasing problem in early relapse because people are using either daratumumab/lenalidomide/dexamethasone for frontline transplant-ineligible patients or induction/transplant/lenalidomide maintenance for those who went to transplant. So, the vast majority of patients are ending up refractory to lenalidomide at the time of relapse. It is nice to have these phase 3 regimens, all of which would have allowed a lenalidomide-refractory patient to participate, reflecting a real-world need.
On belantamab mafodotin
Dr Chari: Belantamab mafodotin is the first antibody conjugate targeting B-cell maturation antigen (BCMA) to be approved by the FDA for MM. It demonstrates response rates of 20% to 30% in patients who are heavily treated, triple-class exposed, and refractory. There are some toxicities, such as corneal and platelet issues, but it is a very convenient drug that can be administered intravenously (IV) every 3 weeks. There is also no cytokine release syndrome associated with it. It can be given in the community as long as people are familiar with its Risk Evaluation and Mitigation Strategy (REMS) program.
On daratumumab and hyaluronidase-fihj
Dr Chari: The IV formulation of the anti-CD38 monoclonal antibody daratumumab was approved in 2015. Since then, given its efficacy, tolerability, and ability to combine with many other antimyeloma agents, it has received several additional approvals both in the newly diagnosed and relapsed settings. One of the main barriers to its uptake, particularly in the community setting, was the risk of infusion-related reactions (IRRs) of approximately 50%. Although the IRRs are typically of low grade, IV daratumumab requires a stepwise increase in the infusion rate, resulting in a median first dose infusion time of 6 to 8 hours. Subsequent infusions can eventually be done in 3 to 4 hours or with recent rapid infusion protocols in 90 minutes. On the basis of the COLUMBA study (ClinicalTrials.gov Identifier: NCT03277105), which compared the IV and subcutaneous formulations and demonstrated comparable efficacy, safety, and pharmacokinetics but with a risk of IRRs of less than 10% and an infusion time of 3 to 5 minutes, subcutaneous daratumumab was approved in 2020. This is a win for pharmacists, nurses, and most of all patients, particularly in the era of COVID-19, with a decrease in infusion chair time.
What trial data are awaited this year that could potentially answer optimal treatment sequencing questions introduced by the wave of new approvals in this space?
Dr Chari: The nature of drug approvals is that you get your arm A vs arm B comparison, but you are not told how to sequence the drugs. So, we have been left with a bit of a conundrum in MM because we keep getting lots of approvals, but the sequencing is being left up in the air.
I would highlight that lenalidomide refractory disease is a big problem. Some of the original phase 3 studies (OPTIMISMM [ClinicalTrials.gov Identifier: NCT01734928], CASTOR [ClinicalTrials.gov Identifier; NCT02136134), ENDEAVOR [ClinicalTrials.gov Identifier: NCT01568866]) that included individuals with lenalidomide-refractory disease had poorer outcomes. The PFS for all patients ranged from 11 to 19 months but for lenalidomide-refractory patients it was 8 to 9.5 months. This really has an impact on the outcomes of salvage therapy even if you aren’t using a lenalidomide-based salvage regimen. I think now when we look at the ability to salvage that, usually if someone is naive to treatment with a CD38 inhibitor at first relapse, we have seen really impressive results, whether you’re using daratumumab or isatuximab. Although the addition of a CD38 inhibitor to pomalidomide/dexamethasone was significantly better than pomalidomide/dexamethasone alone, the PFS of only 11 to 12 months was unexpectedly short. The PFS for CD38 inhibition with carfilzomib and dexamethasone was unreached and will be more than 20 months.
We should avoid cross-study comparisons as there were more lenalidomide-refractory patients in the pomalidomide/dexamethasone studies. To potentially overcome lenalidomide refractoriness, if you’re going to use pomalidomide-based regimens, you might also want to consider using cyclophosphamide as well. A study from Canada presented at the 2020 ASH Annual Meeting1 that used daratumumab, cyclophosphamide, dexamethasone, and pomalidomide reported a very compelling PFS of more than 20 months. Another alternative to overcoming lenalidomide refractoriness is to add a CD38 inhibitor to a carfilzomib and dexamethasone backbone, which is highly efficacious. It is exciting to finally see the results of these studies on next-generation immunomodulatory imide drugs and proteasome inhibitors, which allow an evidence-based approach to move then into the management of early relapsed MM.
The other thing to say about sequencing is that because of the excitement about T-cell redirection therapies – CAR T-cell therapies and bispecific antibodies — there is a lot of interest in those moving up earlier, as well.