Heather J. Landau, MD

New Directions in Newly Diagnosed Multiple Myeloma

Question

How has the treatment landscape for newly diagnosed multiple myeloma evolved over the years and what do you feel are the most promising approaches on the horizon in this setting?

Answer

Historically, multiple myeloma (MM) was treated with alkylating agents and corticosteroids. Over the past 2 decades, an explosion of new drugs, particularly the immune modulating agents (IMiDs; thalidomide, lenalidomide, and pomalidomide), proteasome inhibitors (PIs; bortezomib, carfilzomib, and ixazomib) and monoclonal antibodies (mAbs; daratumumab, isatuximab, and elotuzumab) have significantly shifted the therapeutic landscape. The management of newly diagnosed patients has evolved from treatment with doublets (2-drug combinations) to triplets (3-drug combinations) and we are now exploring 4-drug induction regimens.

We are fortunate to have large randomized trials to guide management in the upfront setting. The SWOG S0777 trial (ClinicalTrials.gov Identifier: NCT00644228) randomly assigned over 500 patients to receive bortezomib, lenalidomide, and dexamethasone (VRd) or lenalidomide and dexamethasone (Rd) and demonstrated a progression-free survival (PFS; 43 vs 30 months; hazard ratio [HR], 0.712, 96% CI 0.56-0.906; P =.0018) and overall survival (OS) (75 vs 64 months, HR, 0.709; 95% CI, 0.524-0.959; P =.025) benefit with the 3-drug combination establishing VRd as the standard of care.¹

While the SWOG S0777 study included patients who were not intending on immediate consolidation with high-dose therapy and autologous hematopoietic cell transplant, this combination has also been studied in the context of transplant. The IFM 2009 trial (ClinicalTrials.gov Identifier: NCT01191060) randomized transplant-eligible patients to RVd alone vs RVd followed by transplantation showing deeper responses (59% vs 48% complete responses) and longer PFS (50 vs 36 months; HR, 0.65; P <.001) for patients who underwent transplantation, but 4-year OS was not different between the groups.²

More recently, the second-generation irreversible PIs carfilzomib (K) has been moved to the frontline setting. Carfilzomib, lenalidomide, and dexamethasone (KRd) upfront resulted in even deeper responses including minimal residual (MRD) negative disease in over 50% of patients.

In the FORTE trial (ClinicalTrials.gov Identifier: NCT02203643), where newly diagnosed MM patients were randomized to receive KRd alone vs KRd plus transplantation, sustained MRD negativity at 1 year was seen in 90% of patients who received transplantation vs 78% who received KRd alone, including in patients with high-risk disease (R-ISS II/III).³

Despite the promise of KRd, the results of the ENDURANCE trial (ClinicalTrials.gov Identifier: NCT01863550), which compared induction therapy with VRd versus KRd in over 1000 newly diagnosed MM patients excluding cytogenetically defined high-risk patients, were recently reported at the 2020 American Society of Clinical Oncology Meeting by Shaji Kumar.⁴ Median PFS (95% CI) was 34.4 (30.1 to NE) months for VRd compared with 34.6 (28.8 to 37.8) months for KRd; the HR was 1.04 (95% CI, 0.83-1.31); P =.742. These results suggest that VRd should remain the standard of care for standard- and intermediate-risk newly diagnosed MM, although the implications for high-risk patients remain unknown.

Most recently, the anti-CD38 monoclonal antibodies daratumumab and isatuximab were established as extremely safe and effective as single agents in relapsed/refractory MM. Now, they have been incorporated into frontline therapy as triplets (daratumumab, lenalidomide, and dexamethasone; DRd) in the MAIA study (ClinicalTrials.gov Identifier: NCT02252172) and quadruplets (daratumumab + VRd; daratumumab + KRd, isatuximab + VRd, with and without transplantation).

In the MAIA trial, DRd was compared to Rd and showed a 44% reduction (HR, 0.56; 95% CI, 0.43-0.73; P =.0001) in the risk of progression or death in transplant-ineligible patients receiving DRd compared with Rd.5 There was a 3-fold higher rate of MRD negativity with DRd, however, data are immature at 28 months of follow-up to assess the impact on OS. How DRd compares with our current standard, VRd, was not addressed in this study. However, with minimal toxicity this combination is likely to emerge as another standard in patients at risk for toxicity from VRd. The most informative trials in transplant-eligible newly diagnosed patients with MM moving forward include the phase 2 GRIFFIN study (ClinicalTrials.gov Identifier: NCT02874742) comparing D-VRd vs VRd as induction and consolidation before and after transplantation.6 It has been fully accrued.

The innovatively designed MASTER trial (ClinicalTrials.gov Identifier: NCT03224507) using D-KRd induction, autologous transplantation and then an MRD-based response adapted D-KRd consolidation strategy, is continuing to enroll. Lastly, the anti-CD38 antibody isatuximab is being studied in combination with KRd in newly diagnosed high-risk (del17p, t(4;14), t(14;16), excess 1q and R-ISS II/III) in both transplant eligible and ineligible MM patients in the GMMG-CONCEPT trial (ClinicalTrials.gov Identifier: NCT03104842), which is a patient population with an unmet medical need.

Question

The ANDROMEDA study recently met its primary endpoint of more than 50% of patients with hematologic complete response to subcutaneous daratumumab in newly diagnosed amyloid light-chain (AL) amyloidosis. In your view, what could be the biggest advantages of subcutaneous drug delivery over other methods?

Answer

The ANDROMEDA study (ClinicalTrials.gov Identifier: NCT03201965) is very exciting for a multitude of reasons, with only 1 being the establishment of the safety of using subcutaneous daratumumab in patients with AL amyloidosis.⁷ In truth, the recent approval by the US Food and Drug Administration (FDA) of the subcutaneous formulation of daratumumab comes from the phase 3 COLUMBIA trial (ClinicalTrials.gov Identifier: NCT03277105), which demonstrated noninferiority in terms of efficacy compared with the IV formulation in over 500 relapsed refractory MM patients.⁸

In this trial, the objective response rate (ORR) was 41.1% with subcutaneous daratumumab compared with 37.1% with the IV formulation (relative risk [RR], 1.11; 95% CI 0.89-1.37; P <.001). The median duration per infusion dropped from over 3 hours per infusion to less than 5 minutes for the injection and there were significantly fewer infusion/injection-related reactions with subcutaneous daratumumab (12.7% vs 34.5%; OR 0.28; 95% CI, 0.18-0.44; P =.0001). These data were also supported by the results from the ongoing phase 2 PLEIADES trial (ClinicalTrials.gov Identifier: NCT03412565), which is investigating the use of subcutaneous daratumumab in both newly diagnosed and relapsed MM patients in combination with commonly used regimens (D-VRd, D-VMP, D-Rd).

The reduction of treatment time from hours to minutes while maintaining the original formulation’s efficacy and improving tolerability are among the biggest advantages of the drug from a patient and provider perspective. In addition, from a resource utilization standpoint, the dramatic reduction in duration of therapy significantly reduces the burden of this therapy on infusion centers.

The ANDROMEDA trial is evaluating subcutaneous daratumumab-CyBorD vs CyBorD in newly diagnosed AL amyloidosis and it has already completed accrual of over 360 patients. Should the trial meet its primary endpoint of complete hematologic response rate, it has the potential to lead to the first drug and/or drug combination to have regulatory approval in this disease.

Question

Please discuss the results of the DREAMM-9 phase 3 study examining the addition of belantamab mafodotin to bortezomib, lenalidomide, and dexamethasone (VRd) compared with VRd alone in transplant-ineligible newly diagnosed multiple myeloma. What would be some likely pros and cons of treatment with this antibody-drug conjugate (ADC), in your view?

Answer

The DREAMM-9 study (ClinicalTrials.gov Identifier: NCT04091126) is a randomized trial to determine efficacy and safety of single-agent belantamab mafodotin (belamaf) with VRd vs VRd alone in patients with transplant ineligible newly diagnosed MM.⁹ Belamaf is a first-in-class anti-BCMA antibody-drug conjugate, which has shown deep and durable responses as a single agent in heavily pretreated patients with relapsed/refractory multiple myeloma in the phase 2 DREAMM-2 study (ClinicalTrials.gov Identifier: NCT03525678). It is a 2-part study initially evaluating the safety and tolerability of different doses of belamaf in combination with VRd in order to select the recommended phase 3 dose for the randomized portion of the study.

While the study is ongoing and the results are not yet available for the DREAMM-9 study, Dr. Ajay Nooka presented the preliminary results of the DREAMM-6 study evaluating belamaf plus bortezomib and dexamethasone or lenalidomide and dexamethasone in relapsed or refractory MM patients. Among 18 patients evaluable for response, the ORR was 78% with 50% achieving [very good partial response]. Similar to what has been seen in the DREAMM-2 study, the most common side effects were corneal events (keratopathy) and thrombocytopenia, with grade 3/4 adverse events seen in 89% of patients. Of note, keratopathy and thrombocytopenia lead to dose interruptions/delays in 83% and 39% of patients, respectively.

It was noted that the data were not sufficiently mature to report on resolution of the events at the time of the ASCO presentation. However, it was noted that when similar toxicity was seen in the DREAM-2 study, at limited follow-up in 81% (65/85) of patients, vision had returned to baseline or near baseline. While response rates in this small study appear promising, the toxicity profile of this drug concerns me when considering it in the context of upfront therapy (ie, DREAMM-9) where if the belamaf-VRd arm is deemed superior, this quadruplet will have to compete with other 3- and 4-drug combinations, which have more favorable side-effect profiles. It is my opinion that this drug is likely going to have a role in patients who require salvage therapy.

Question

According to research presented during the ASCO20 Virtual Scientific Program (and based on real-world results from a study on patients with newly diagnosed disease who were in the Connect MM Registry), patients with renal impairment should now be considered for inclusion in clinical trials, as well as for treatment with lenalidomide-bortezomib-dexamethasone (RVd). Do you agree with this assessment? Why or why not?

Answer

The data that were presented at ASCO20 on behalf of Connect MM Registry investigators, which included transplant-eligible and -ineligible newly diagnosed MM patients, indicate that patients with even moderate (creatinine clearance [CrCl] 30-50 ml/min) or severe renal impairment (<30 ml/min) who receive RVd for 3 or more cycles have the potential to improve renal function with over 50% of patients with moderate impairment (86 individuals) and 20% to 30% of patients with severe impairment (36 individuals) improving. When the entire patient population was analyzed and the overall PFS with RVd induction was similar, regardless of baseline renal function (60 ml/min or less or more than 60 ml/min) or transplant eligibility.¹⁰

I agree with the authors that these data support exploring the use of RVd in patients with renal impairment, since a rapid response with the 3-drug combination is closely associated with renal improvement and the combination has demonstrated an OS benefit. However, a formal study is warranted comparing this regimen to other commonly used practices (ie, CyBorD x 1 followed by RVd) in order to determine the optimal strategy for this often fragile patient population. In addition, the timely access to lenalidomide in a newly diagnosed patient who requires urgent therapy is often an issue in a real-world situation and treatment should not necessarily be delayed in order to offer this combination.

On the other hand, liberalizing the inclusion criteria of clinical trials to include patients with modest renal impairment would be a welcome change, especially as newer regimens that include monoclonal antibodies are likely to lead to even quicker responses without significant risk of nephrotoxicity.

Question

Are there any other recent study results or data that you feel are of particular interest in the setting of newly diagnosed multiple myeloma?

Answer

With the demonstrated efficacy of the KRd regimen in terms of depth of response, and the unexpected interim results of the ENDURANCE trial, Ola Landgren, MD, PhD, of the Memorial Sloan Kettering Cancer Center is leading a randomized trial of KRd versus D-KRd versus VRd (ClinicalTrials.gov Identifier: NCT04268498) in order to determine in all-comers (inclusive of high-risk patients) if a carfilzomib-containing regimen with carfilzomib given weekly may be safer and more effective than RVd. This trial intends to enroll 462 patients in order to determine the primary endpoint, which is the difference in measurable residual disease/minimal residual disease negativity between the arms.