Neil Iyengar, 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

The treatment landscape in newly diagnosed myeloma has evolved significantly over the past few years. A major change has been the addition of the CD38 antibodies to frontline regimens in both transplant-eligible and transplant-ineligible patients. For example, in the phase 3 GRIFFIN study (ClinicalTrials.gov Identifier: NCT02874742) transplant-eligible patients were randomized to treatment with either VRd or VRd-daratumumab. The addition of daratumumab to frontline VRd resulted in an increase in complete remission (CR) from 32% to 42% at the end of postautologous stem cell transplant (ASCT) consolidation, which met the primary endpoint of the study.¹

The rate of minimal residual disease (MRD) negativity at 10-5 also favored VRd-dara (51%) vs VRd (20%). In terms of patients without intent to proceed with ASCT, the ongoing phase 3 CEPHEUS (daratumumab; ClinicalTrials.gov Identifier: NCT03652064) and IMROZ (isatuximab; ClinicalTrials.gov Identifier: NCT03319667) studies are comparing the addition of a CD38 antibody to a VRd backbone. The primary endpoint for CEPHEUS is the rate of MRD negativity at 10-5 and for IMROZ, the progression-free survival (PFS). Results are awaited. Furthermore, daratumumab has already shown prolonged PFS in combination with VMP² and lenalidomide³ in transplant-ineligible newly diagnosed myeloma patients compared with standard regimens.

Cell therapy, including chimeric antigen receptor T-cell (CAR-T) therapies, BCMA-targeted antibodies, and bispecific T-cell engagers, may be some of the most promising therapeutics to be added to the frontline treatment of multiple myeloma (MM). Clinical trials are underway to assess some of these therapies as part of the initial therapy for myeloma. The addition of CD38 antibody to the initial treatment of myeloma in the maintenance phase is also promising, and trials are underway to assess potential clinical benefit.

Question

The ANDROMEDA study recently met its primary endpoint⁴ 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 addition of subcutaneous daratumumab to the bortezomib-cyclophosphamide-dexamethasone backbone for frontline treatment of AL amyloidosis has resulted in an impressive increase in the rate of complete hematologic response in these patients (18% compared with 50%). The major advantage of using subcutaneous vs intravenous daratumumab is the convenience to the patient. Additionally, fewer infusion reactions are observed with subcutaneous drug delivery.

Question

Please discuss the results of the DREAMM-9 phase 3 study⁵ 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, in your view?

Answer

The major advantage of adding a BCMA antibody drug conjugate to the VRd backbone in newly diagnosed transplant-ineligible myeloma is the potential for increased treatment efficacy and deeper responses translating into improved clinical outcomes for these patients. A possible disadvantage could be drug therapy interruption due to corneal toxicity. However, the study will evaluate several dosing schedules of belantamab mafodotin, which could result in decreased toxicity. Studies like this one, which are adding new therapies to the frontline treatment of myeloma, should be celebrated.

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).⁶ Do you agree with this assessment? Why or why not?

Answer

I agree that patients who are newly diagnosed with MM and have kidney function impairment due to this should be treated with effective therapy and be considered for treatment for VRd. Additionally, I agree that patients with newly diagnosed myeloma and renal impairment should be considered for inclusion in clinical trials. This is because patients who have renal impairment due to myeloma can recover their kidney function with effective treatment for MM (ie, VRd).

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

The ENDURANCE phase 3 study compared VRd vs KRd in the treatment of newly diagnosed myeloma and these results were recently presented at ASCO20. In this study, upfront ASCT was optional and about 25% of patients underwent upfront ASCT in each arm.⁷ Patients with grade 2 or higher peripheral neuropathy and the following high-risk abnormalities (t[14;20], t[14;16], del17p, LDH greater than 2 upper limit of normal, no plasma cell leukemia) were excluded. The median number of cycles of therapy received was longer for KRd vs VRd (8.9 vs 6.5 months, respectively) and more patients discontinued therapy in the VRd arm due to toxicity when compared with the KRd arm (61.6% vs 43.3%, respectively). The median PFS was similar in both arms around 34 months.

Surprisingly, the PFS in the KRd arm seems much shorter in this study than in other phase 2 studies reported previously of KRd frontline (median PFS without ASCT of 67 months, 36-month PFS of 86% with ASCT, and 2-year PFS of 91% with ASCT).^8,9,10 In my opinion, based on these preliminary data in abstract format, both options are suitable frontline therapies for newly diagnosed myeloma, and choice of therapy should be guided by specific patients’ comorbities and toxicity profiles.