ASH 2020 Highlights – Multiple Myeloma (MM)

ASH 2020 Highlights – Multiple Myeloma (MM)

Prescient looks at the critical data presented at the American Society of Hematology (ASH) Annual Meeting and how they might affect the treatment paradigm in MM.

DECEMBER 2020

Prescient Analytics

Jyotsana Chaudhary, MSc, Therapeutic Area Group Manager; Manisha Chugh, PhD Senior Research Manager; Saugata Roy, MSc, Associate Research Manager; Himani Jain, MTech, Senior Research Analyst; Yashleen Kaur, MBA, Research Analyst; and Srishti Prajapati, MSc, Research Analyst

Context

The introduction of new drug classes like proteasome inhibitors, immunomodulators, and anti-CD38 and anti-SLAMF7 monoclonal antibodies have doubled the response rate in MM patients but has also developed relapsed/ resistance to these therapies. This has led to a quest in the discovery of new targeted therapies. BCMA has emerged as a significant target for MM therapy in recent years. BCMA targeting chimeric antigen receptor (CAR)-modified T-cell therapy is upcoming modality with encouraging safety and efficacy profile in RRMM patients. Ciltacabtagene autoleucel (Cilta-cel) in phase 1 LEGEND-2 study in China demonstrated deep and durable responses with a manageable safety profile in RRMM patients. The phase Ib/II CARTITUDE-1 study is evaluating Cilta-cel in 4L+ patient population in the US. 

Study Highlights

The updated safety and efficacy data of pivotal Phase Ib/II study of Cilta-cel at mFU of 8.8 mos (n=97) in 4L+ RRMM patients of which ~83% being triple-refractory and 42% penta-refractory patients are as follows:

Efficacy

N (evaluable) = 97

  • ORR: 96.9%; ≥VGPR: 92.8%; VGPR: 25.8%; sCR: 67%; PR: 4.1%; mDoR: NR
  • mPFS: NR; PFS rate (12 mos): 76.6%
  • mOS: NR; OS rate (12 mos): 88.5%

MRD response data, evaluable (n=57) vs. treated (n=97)

  • Overall MRD-neg (10-5), 93.0% vs. 54.6%
  • MRD-neg with sCR: 57.9% vs. 34.0%
  • MRD-neg with ≥VGPR: 86.0% vs. 50.5%

Safety

  • Grade 3/4: Hematologic AEs: 99% – Neutropenia: 94.8%; Anemia, 68%; Leukopenia: 60.8%; Grade 3/4 infections: 19.6%
  • Grade 3/4 CRS: 4.1%; Grade 3/4 Neurotoxicity: 9.3%; Grade ≥3 ICANS: 2.1%
  • Grade 5 CRS: 1%; Grade 5 Neurotoxicity: 1%
  • Deaths due to AEs: 6.2%

Insights & Implications

  • Cilta-cel is designed to bind to two different epitopes on BCMA and induce selective toxicity in BCMA-expressing tumor cells and clinically it has demonstrated an impressive response with manageable safety
  • Compared to the other CARTs, cilta-cel could potentially be an outpatient treatment because the CRS sets in later, typically after seven days, hence the patients might not need immediate monitoring as is the case with other CAR-Ts
  • While CART-cell therapies provide deep and durable responses, the feasibility of treatment being administered in an outpatient setting with a manageable CRS profile will pave the way for significant adoption of such breakthrough cell therapies
ABSTRACT #130, #129, #134, #133, #1428

High clinical development activity witnessed with multiple BCMA-targeting CARTs under evaluation for RRMM

Context

Following behind idecabtagene vicleucel (Ide-cel, bb2121) and ciltacabtagene autoleucel (Cilta-cel, JNJ-68284528), a number of other BCMA-targeting CART therapies are in clinical development for heavily pretreated RRMM patients, including pivotal Phase I/II trials of P-BCMA-101 and CT-053.

Study Highlights

The following data present the efficacy and safety results of upcoming BCMA CARTs in 4L+ RRMM

bb21217 CRB-402 trial (Abs #130):

Overall Data with original and updated manufacturing process

At all doses, mFU 5.8 mos, n=69

  • ORR: 68% (n=40/59); sCR/CR: 29%; VGPR: 25%; PR: 14%; MRD-neg ≥CR: 100% (n=13)
  • Safety: CRS grade≥3: 4%, 2 deaths due to CRS, Infections (Grade 3/4): 26%; Neurotoxicity grade≥3: 4%, 2 deaths due to CRS

At RP2D (450 x 106), mFU 4 mos, n=43

  • ORR: 73%; sCR/CR: 30%; VGPR: 21%; MRD-neg ≥CR: 100% (n=7)
  • Safety: CRS (Grade 5): 5%, Neurotoxicity: 2%

Expansion Data at RP2D with updated manufacturing process, at mFU 2 mos, n (treated) =29

  • ORR: 84% (n=16/19); sCR/CR: 32%; VGPR: 21%; PR: 32

ALLO-715, Universal Trial (Abs #129)

Efficacy: At mFU: 3.2 mos of ALLO-715 at 320M cell dose (Dose Level 3) at which encouraging data reported)

  • mTTR: 16 days
  • With low and high dose ALLO-647: ORR: 60% n=10: VGPR: 40%, MRD-neg ≥VGPR: 83.3% (n=6 tested)
  • High ALLO-647, n=4: ORR: 75%; VGPR: 25%
  • Low ALLO-647, n=6 (DL3): ORR: 50%; VGPR: 50%

Safety: (n=31)

  • Serious AEs: 19%, All grade CRS: 45%; Grade 5 infections: 3%, Grade 3 infections: 13%


CT053, LUMMICAR-2 (Abs #133)

Efficacy

  • Dose: 1.5-3.0 ×108 CAR+ T cells, at mFU: 6 mos, n=18
  • ORR: 94%; VGPR: 27.7%; sCR/CR: 27.7%; MRD-neg: 91.6% (n=12, mFU: 4.5 mos)

Safety

  • Dose: 1.5-3.0 ×108 CAR+ T cells, n=20
  • SAEs: 25%; Grade ≥3 AEs: CRS/ICANS: 0%
  • Grade ≥3 hematological toxicity and infections and infestations: 10%

P-BCMA-101/P-BCMA-101 + Rituxan + Revlimid, PRIME (Abs #134)

Efficacy:

  • Original manufacturing process: At mFU: 2.0-8.5 mos; n=2-9 across dosing cohorts, dose ranging between 51 x106 – 1,178 x106 dose
  • ORR: 50%-75%
  • Updated manufacturing process (Nanoplasmid): n=6, at 0.75 x106 dose
  • ORR: 66.7%; VGPR + sCR: 50%

Safety:

  • Data for overall population (n=53)
  • Grade 3 CRS: 0%; Grade ≥3 AE: Neurotoxicity: 3.8%; neutropenia: 75.5% thrombocytopenia: 30.2%; anemia: 30.2%; deaths: none
  • Updated manufacturing process (Nanoplasmid): n=5, DL1: 51 x106, CRS (all grade): 20%

Insights & Implications

The prospective BCMA-targeting CARTs have evidently proven to be very effective for patients in the later course of the disease. Each BCMA CART is designed in a unique way to increase the display of T-cells over tumor cells and enhance the antitumor efficacy
Combating complex CART manufacturing and administration processes, followed by hospitalization requirements to closely monitor CRS and neurotoxic AEs, will be key in driving adoption

Recent data with BCMA-CARTs bb21217 and P-BCMA-101 emphasize implementation of manufacturing process change in order to achieve higher response rates while maintaining a tolerable safety profile; however, combating complex CART manufacturing and administration processes followed by hospitalization requirements to closely monitor CRS and neurotoxic AEs is likely to remain inevitable for driving adoption

Off-the-shelf allogeneic CARTs, such as ALLO-715, are explored with the intent to overcome the manufacturing challenges imposed by autologous CARTs

Recently approved or upcoming modalities such as ADC and bispecifics have evaluated or are evaluating BCMA as potential target, which will eventually warrant exploration of the optimal sequencing of CARTs in the MM treatment continuum

Although the current focus of BCMA-targeting CARTs is directed towards heavily pre-treated RRMM patients (including patients with median of 7 prior lines of therapy), evaluation in early relapse settings is warranted owing to their potential for deeper and longer-duration responses with a manageable safety profile

With more than one expected potential approval, BCMA-CARTs will face significant in-class competition.

ABSTRACT #181, #291, #293, #180

Novel Anti-BCMA x Anti-CD3-targeting Bispecifics in Multiple Myeloma

Context

BCMA-targeting bispecific antibodies are designed to redirect T-cells to BCMA-expressing MM cells. Since BCMA plays an important role in MM pathophysiology, bispecifics allow an effective T-cell-mediated killing through the direct engagement of BCMA-expressing neoplastic plasma cells and effector cells. Hence, BCMA bispecifics are being evaluated to obtain an effective treatment option for heavily pre-treated RRMM patients and would be interesting to explore in the studies given below.

Study Highlights

AMG 701, ParadigMM-1B (Abs #181)

Efficacy: at mFU of 1.7 mos (n=82)

  • Overall ORR: 26%; ≥VGPR: 17%
  • Most recent cohort (n=6) (4/5 responders triple-class refractory): ORR: 83%; ≥VGPR: 50%

Safety: (n=85): Grade >3 CRS: 9%; SAE: 38%; discontinued treatment due to PD: 60%; discontinued treatment due to AEs: 6%

REGN-5458, R5458-ONC-1826 (Abs #291)

Efficacy (mFU: 2.6m)

  • ORR: 39.5% (all dose levels, 3-96 mg, n=49); ≥VGPR: 95%, sCR/CR (in responders): 42%; MRD-neg (10-5): 57%
  • ORR: 62.5% (96 mg, n=8), sCR/CR: 0%
  • ORR: 41.2% (24/48 mg, n=17), sCR/CR: 17.7%
  • ORR: 29.2% (2/6/12 mg, n=24), sCR/CR: 10.9%•mDoR: 6m

Safety: No ≥3 CRS or neurotoxicity; CRS (all grades): 39%

TNB-383B, TNB383B.0001 (Abs #293)

Efficacy: (n=58) Overall ORR: 52%; VGPR: 13%
Safety: (n=58), Grade ≥3 TEAE: 57%; SAE: 33%; TRAE: 62%; Grade ≥3 AEs, anemia: 17%; neutropenia: 16%; thrombocytopenia: 14%; infection: 14%; discontinued treatment due to DLTs: 3%

Teclistamab, 64007957MMY1001 (IV & SC, Abs #180)

Efficacy

  • At RP2D (1,500 µg/kg SC, (n=22): ORR: 73%; VGPR: 31.8%
  • For both IV and SC formulations across all doses: MRD-neg CR (10-6): 72.7%; MRD-neg CR (10-5): 4.5%
  • MTD not reached

Safety

  • Overall (n=149), Grade ≥3 AEs: 39%; across all doses Grade >3 neurotoxicity: 5%; Grade ≥3 infections: 15%
  • At RP2D (n=33), Grade ≥3 neurotoxicity: 3%; Grade ≥3 infections: 6%
  • No Grade 3 CRS reported in both overall and RP2D patients

Insights & Implications

BCMA has emerged as a breakthrough therapeutic target in multiple myeloma; yet another novel approach evaluating this target as part of BCMA-bispecific-Ab or BCMA-targeting bispecific T-cell engager has led to the initiation of several trials set to tap the RRMM space, which is in need of an alternative class of drugs and modalities to cater to personalized patient needs

Compared to CARTs, a BCMA x CD3 bispecific antibody approach offers an off-the-shelf option requiring less manufacturing time, reducing the need for bridging therapy, the role of which is still under debate

Phase I data presented for multiple BCMA x CD3 bispecific antibodies have demonstrated CRS was restricted to grade 1-2 (REGN-5458, TNB-383B, Teclistamab) or was reversible if grade 3 within a median duration of 2 days (AMG-701), which drives the BCMA-bispecifics towards having a better safety profile compared to CARTs; however, additional and long-term follow-ups are required to establish this clear advantage

Fewer CRS and neurologic events compared to CART therapy will tend to make it a preferable option in patients with a lower tolerability such as the elderly/frail

MRD-negativity is also increasingly being evaluated with these novel modalities, which may eventually lead to optimal sequencing of the myeloma therapies, which at present is not very well defined

Context

The therapeutic potential of BCMA is being therapeutically evaluated as part of various modalities, including BCMA-CART, BCMA-bispecific and now BCMA-ADC. The recently approved belantamab mafodotin (Blenrep) is the first BCMA-ADC for RRMM settings and has set the pace for other BCMA-ADCs being evaluated in this space. MEDI-2228 is a novel pyrrolobenzodiazepine ADC with potential to synergize with the anti-CD38 or bortezomib (Velcade). It is being evaluated as a single agent in 3L+ RRMM patients who have progressed on therapy including PIs, IMiDs, and monoclonal antibodies.

Study Highlights

Dose-expansion and escalation data evaluating MEDI2228 (n=82) in triple-class refractory RRMM (3L+) patients were as follows:

Efficacy

  • ORR at 0.14 mg/kg (MTD) (n=41): 65.9%; CR/sCR: 2.4%; VGPR: 24.4%; PR: 39%; MR: 4.9%
  • SD: 12.2%, PD: 14.6%
  • mDOR: 5.9 mos, mTTR: 2.1 mos

Safety

  • SAEs in 0.14 mg/kg group: 32.93%
  • Overall: Photophobia (58.5%), thrombocytopenia (31.7%), rash (29.3%), increased gamma-glutamyltransferase (24.4%), dry eye (19.5%), and pleural effusion (24.4%)
  • Grade ¾: Photophobia (17.1%), thrombocytopenia (24.4%), rash (0%) and pleural effusion (2.4%); GGT increased: 19.5%
  • No keratopathy or visual acuity loss were reported
  • Patients discontinued treatment: 50%
  • Death: 1.22%

Insights & Implications

MEDI-2228 is a BCMA-targeting ADC like belantamab mafodotin but carries a PDC payload that acts by damaging DNA, unlike the microtubule-targeting MMAF payload in belantamab

MEDI-2228 has exhibited promising clinical efficacy and a manageable toxicity profile in 3L+ pre-treated triple-class refractory multiple myeloma patients, reinforcing the role of BCMA-ADC as a safe and effective therapeutic option in RRMM

The early response rates demonstrated by MEDI-2228 are comparable to those of belantamab and, with this early evidence of clinical activity, AstraZeneca is planning to initiate a Phase II trial in 2021 to further advance the development of MEDI-2228

Given the median age of onset for MM is 65-70 years, ocular toxicity in general will be a challenge to mitigate for smoother adoption of these transformational treatment options

Context

There remains an unmet need for novel therapies to improve outcomes and reduce the adverse effects of RRMM patients with high-risk cytogenetics. Bortezomib (Velcade), a proteasome inhibitor has a profound role in second- and third-line myeloma patients, but its chief tolerability issue of peripheral neuropathy has always been a challenge for its adoption. In the Phase IIb STORM study, the first-in-class XPO1 inhibitor selinexor (Xpovio) and dexamethasone (Sd) combination showed clinical benefit across high-risk cytogenetics, making it eligible for further evaluation. The Phase III BOSTON trial compared weekly Sd with bortezomib (SVd), against standard twice weekly bortezomib-dex (Vd) in patients with MM who had received 1-3 prior therapies. SVd significantly improved PFS, ORR and depth of response. Subgroup analyses was then undertaken based on high-risk cytogenetics.

Study Highlights

The results of pre-specified subgroup analyses, evaluating the combination of weekly sel-dex with the proteasome inhibitor (PI) bortezomib (SVd) against standard twice weekly bortezomib-dex (Vd) in patients with MM who had received 1-3 prior therapies (2L-4L), are as follows:

Efficacy

Overall [SVd vs. Vd]

  • mPFS: 13.93 mos vs. 9.46 mos (HR-0.70, p=0.0075)
  • ORR: 76.6% vs. 62.3%
  • ≥VGPR: 44.6% vs. 32.4%
  • DoR: 20.3 mos vs. 12.9 mos

High Risk patients [SVd (n=70) vs. Vd (n=71)]

  • ORR: 78.6% vs. 57.7% (p=0.004); VGPR: 42.3% vs. 24.2% (p=0.0041)
  • PFS: 12.91 vs. 8.61 mos (HR: 0.73; p=0.008)
  • OS: NR vs. 23.5 mos

Standard risk patients [SVd (n=125) vs. Vd (n=136)]

  • ORR: 75.2% vs. 64.7% (p=0.03); VGPR: 49.6% vs. 39.3% (p=0.13)
  • PFS: 16.62 vs. 9.46 mos (HR: 0.61; p=0.004)
  • OS: NR vs. NR

Patients with Del (17p) [SVd (n=21) vs. Vd (n=16)]

  • ORR: 76.2% vs. 37.5% (OR 5.3, p=0.0096)
  • PFS: 12.22 mos vs. 5.91 mos (HR 0.38, p=0.008)
Patients with t(4;14) abnormality [SVd (n=22) vs. Vd (n=27)]

  • ORR: 90.9% vs. 74.1% (OR 4.0, p=0.007)
  • PFS: 13.24 mos vs. 8.33 mos (HR 0.70, p=0.18)

Patients with cytogenetics abnormality [Svd vs Vd]

  • 1 abnormality: PFS 10.2 mos vs. 8.6 mos (HR 0.69, 0.41-1.15); p=0.08
  • ≥2 abnormalities: PFS 15.5 mos vs. 5.9 mos (HR 0.54, 0.22-1.33); p=0.09

Insights & Implications

SVd significantly improved ORR in the high-risk group and numerically in the standard-risk group over Vd, with comparable response rates in both risk groups

SVd demonstrated reduced peripheral neuropathy vs. Vd, which is likely to significantly drive its adoption in RRMM patients, including high-risk cytogenetics

The PFS benefit was statistically significant in patients with del(17p) and amp(1q21) abnormalities. Although response rates were higher with SVd, PFS benefit was not seen in the t(14;16) subgroup

Encouraging clinical data with SVd triplet indicate it offers a safe, IMiD-free treatment option in early relapsed patients with a reduced dose of bortezomib and dexamethasone prompting its positive uptake

Whether the SVd triplet will be able to carve out a niche for itself in MM patients with high-risk cytogenetics may eventually depend on a head-to-head comparison with the established triplet combinations, especially in earlier line of therapies, before it gains traction with oncologists

Its potential approval in Q1 2021 will further strengthen selinexor’s position in the MM market

Context

Daratumumab (Darzalex) IV is approved across multiple lines of therapy for multiple myeloma. Daratumumab SC was recently approved leading to the availability of the preferred CD38 inhibitor combinations with shorter administration time and lesser infusion-related reactions. The PLEIADES study was one of the studies based on which daratumumab SC was approved in transplant-ineligible NDMM and RRMM. The study is evaluating three cohorts based on different daratumumab combinations in different patient settings. Primary analysis of carfilzomib (Kyprolis)/dexamethasone (D-Kd), and updated data for the daratumumab SC in combination with lenalidomide (Revlimid)/dexamethasone(D-Rd) and daratumumab SC in combination with bortezomib/Melphalan/prednisone (D-VMP) are presented here.

Study Highlights

Primary results of the trial of daratumumab SC in combination with carfilzomib (Kyprolis)/dexamethasone (D-Kd), and updated data for the daratumumab SC in combination with lenalidomide (Revlimid)/dexamethasone(D-Rd) and daratumumab SC in combination with bortezomib/Melphalan/prednisone(D-VMP) cohorts are as follows:

Efficacy:

D-Kd (SC) vs. D-Kd (IV): PLEIADES (at mFU: 9.2 mos; n=66) vs. CANDOR- (at mFU: 17 mos; n=312)

  • ORR: 84.8% vs. 84.3%; VGPR: 39.4% vs. 40.7%; sCR: 16.7% vs. No value
  • MRD-NEGve (10-5); n=66: 24.2%; MRD-NEGve (10-5) ≥CR: 21.2%

D-Rd (SC) vs. D-Rd (IV): PLEIADES (at mFU: 25.7 mos; n=65) vs. POLLUX (at mFU: 54.8 mos; n=281)

  • ORR: 93.8% vs. 92.9%; VGPR: 30.8% vs. 23.5%; sCR: 23.1% vs. 29.5%
  • MRD-neg (10-5); n=65: 20%; MRD-neg (10-5) >≥CR: 20%

D-VMP (SC) vs. D-VMP (IV): PLEIADES (at mFU: 25.2 mos; n=67) vs. ACYCLONE (at mFU: 40.1 mos; n=350)

  • ORR: 89.6% vs. 90.9%; VGPR: 22.4% vs. 27.1%; sCR: 31.3% vs. 23.1%
  • MRD-neg (10-5); n=67: 25.4%; MRD-neg (10-5) ≥CR: 25.4%
Safety:

  • D-Kd (SC):
    • Grade 3/4 SAE: 71%; Hypertension: 21%; Neutropenia: 11%; Thrombocytopenia: 20%
    • Serious AEs: 27%
  • D-Rd (SC):
    • Grade 3/4 SAE: 94%; Hypertension: 12%; Neutropenia: 55%; Thrombocytopenia: 14%
    • Serious AEs: 55%
  • D-VMP (SC):
    • Grade 3/4 SAE: 78%; Hypertension: 9%; Neutropenia: 37%; Thrombocytopenia: 45%
    • Serious AEs: 45%

Insights & Implications

The updated PLEIADES data compared with data for the IV formulation evaluated in various trials, such as CANDOR, POLLUX and ACYCLONE, reinforce the use of daratumumab SC in combination with standard combinations across multiple lines of therapy

Daratumumab SC has emerged as an effective and potentially preferable formulation owing to its clinical data being consistent with that of the IV formulations of the drug

Reduced administration time (3-5 mins) and lesser infusion-related reactions are considered to be driving factors for quick adoption among treating physicians and is expected to significantly increase patient compliance

ABSTRACT #1417

Phase II DREAMM 2 Trial-Subgroup analysis by number of prior therapies

Context

Belantamab mafodotin (Blenrep) is the first anti-BCMA agent approved in multiple myeloma. Single-agent Belantamab had shown clinically meaningful sustained responses and a manageable safety profile in heavily pretreated (4L+) RRMM patients at a 13-month follow-up. There is, however, a need for therapies with longer response durations in RRMM, given that response and duration decrease with every subsequent progression. A subgroup analysis by number of prior therapies after 13-months’ follow-up is presented to assess Belantamab’s potential to cater to this unmet need.

Study Highlights

At a mFU of 12.4 months, the results of the post-hoc analysis evaluating single-agent Belantamab mafodotin (Blenrep) in patients with 3-6 prior therapies (n=47) vs. ≥7 prior therapies (n=52) are as follows:

Efficacy

  • ORR: 34% vs. 30%; VGPR: 17% vs. 20%; mDoR: 11 mos vs. 13.1 mos
  • mPFS: 2.9 mos vs. 2.2 mos
  • PFS at 6 mos: 35% vs. 30%

Safety

  • Keratopathy: 33% vs. 27%; thrombocytopenia: 17% vs. 20%; anemia: 11% vs. 31%; decreased lymphocyte count: 11% vs. 14%; discontinuation due to AEs: 7% vs. 8%

Insights & Implications

The single-agent drug induces stabilization of quality of life with clinically meaningful responses and a well-tolerable safety profile, irrespective of the number of prior lines of therapy.

Although reduction in ocular toxicity levels was observed at longer FU, the need for regular visits to an ophthalmologist is going to be a barrier to utilization of the ADC.

In comparison to CART, BCMA-ADC could be positioned as an off-the-shelf therapy product. Moreover, its property of targeting chemotherapy directly to myeloma cells as opposed to systemic therapy would eventually result in increased usage among patients with aggressive disease and low tolerability issues.

Competitive positioning would make BCMA-ADC prominent among other approved and upcoming 4L+ therapies, leading to its increased acceptance in the MM market

Context

The IV formulation of daratumumab (Darzalex) is approved across all patients segments in MM and is now an established regimen in the MM treatment landscape. It, however, must be given over 7 hours and produces severe infusion-related reactions (IRRs). Janssen launched the SC formulation to overcome these shortcomings with the IV formulation. The SC formulation is now being evaluated with the SoC across all patient segments in MM. Daratumumab IV + pomalidomide (P) + dexamethasone (d) has been approved for the treatment of RRMM patients (3L+). The Phase III APOLLO trial is designed to evaluate daratumumab SC in combination with Pd (D-Pd) for its potential to treat RRMM patients who have failed at least one line of prior therapy including a PI and IMiD.

Study Highlights

At median follow-up of 16.9 months, primary analysis data comparing D-Pd (n=151) vs. Pd (n=153) in 2L+ double-refractory MM patients who progressed on a PI and IMiD were as follows:

Efficacy: D-Pd (n=151) vs. Pd (n=153)

  • ORR: 69% vs. 46%
    • sCR: 9% vs. 1%; ≥CR: 25% vs. 4%; ≥VGPR: 51.0% vs. 20%; VGPR: 26% vs. 16%; 
PR: 18% vs. 27%
  • MRD-negativity rate: 9% vs. 2% (p = 0.0102)
  • mPFS (at median follow-up of 16.9 months): 12.4 months vs. 6.9 months
    • mPFS lenalidomide refractory: 9.9 months vs. 6.5 months
  • PFS rate pre-specified subgroups:
    • Lenalidomide refractory: 63.3% vs. 72.9%; lenalidomide non-refractory: 25.8% vs. 54.8%
    • High risk: 71.7% vs. 74.2%; standard risk: 46.8% vs. 68.4%

Safety: D-Pd (n=149) vs. Pd (n=150)

  • Grade ≥3 AEs — Neutropenia: 68% vs. 51%; leukopenia: 17% vs. 5%; thrombocytopenia: 17% vs. 18%; lymphopenia: 12% vs. 3%; febrile neutropenia: 9% vs. 3%
  • Patient discontinuations due to PD (n=149 vs. 150): 44% vs. 58%; patient discontinuations due to AEs: 2% vs. 3%
  • Deaths due to AEs: 7% vs. 7%

Insights & Implications

  • The APOLLO study met its primary endpoint of improved PFS earlier this year. Full analysis from the trial demonstrates the efficacy of daratumumab SC-based triplet with manageable toxicities in RRMM patients.
  • The SC formulation is likely to differentiate Janssen’s daratumumab from other in-class competitors. Shorter administration time and low IRR rate can increase patient convenience and adoption

Context

The IKEMA trial is evaluating isatuximab (Sarclisa) in combination with carfilzomib (Kyprolis) and dexamethasone (Isa-Kd) in patients with RRMM who received 1-3 lines of prior therapy. Previous results from the data had demonstrated that addition of isatuximab to carfilzomib and dexamethasone reduced the risk of disease progression. As MRD negativity (MRD-neg) is associated with improved PFS outcomes, depth of response was assessed by analyzing MRD-neg achieved by patients and long-term outcomes following treatment.

Study Highlights

MRD-neg and long-term response rates

At median follow-up of 20.7 months, data from interim analysis comparing Isa-Kd (n=179) vs. Kd (n=123) in RRMM patients previously treated with 1-3 prior lines of therapy were as follows:

Efficacy: Isa-Kd (n=179) vs. Kd (n=123)

  • Best overall response — ORR: 86.6% vs. 82.9% (p=0.19); ≥VGPR: 72.6% vs. 56.1% (p=0.0011); ≥CR: 39.7% vs. 27.6%
  • MRD-neg (10-5, ITT population): 29.6% vs. 13.0% (p=0.0004); MRD-neg (10-5, ≥VGPR population): 41.1% vs. 22.9%
  • CR (no adjustment for M-protein interference): 39.7% vs. 27.6%; CR (with adjusted M-protein): 45.8% vs. 27.6%
  • MRD-neg CR (no adjustment for M-protein interference): 20.1% vs. 10.6%; MRD-neg CR (with adjusted M-protein): 24.0% vs. 10.6%

Safety: Data not reported

Insights & Implications

  • MRD-neg is found to be associated with a longer PFS and addition of isatuximab to Kd led to a higher and promising proportion of patients achieving MRD-neg status
  • MRD-neg is now being increasingly used as a surrogate biomarker to predict patient prognosis in clinical trials and MRD-neg status in MM is associated with improved PFS and OS. The interim data analysis of the IKEMA trial supports the use of MRD-neg as a prognostic biomarker in RRMM patients
  • The IKEMA trial results demonstrated enhanced MRD-negative rate (more than double) in patients receiving Isa-Kd, thereby demonstrating the relevance of MRD-negativity as an endpoint to measure the depth of response of the test drug
  • Potential to reach MRD-neg in lenalidomide-refractory patients with a clear PFS benefit in a larger patient population may help Isa-Kd establish itself as a promising treatment regimen for RRMM
  • Isatuximab’s efficacy in daratumumab-refractory patients is a space to watch out, as it will give insight into CD38-rechallenge in subsequent relapse

Context

Based on the efficacy of melflufen + dexamethasone in RRMM patients, the ANCHOR trial was designed to evaluate the triplet combination of melflufen + dexamethasone + daratumumab (D)/bortezomib in RRMM (2L+) patients with an intent to combine agents with different MoAs to overcome treatment resistance seen in heavily pre-treated RRMM patients.

Study Highlights

Updated efficacy and safety data for melflufen + dexamethasone + daratumumab (n=33) and melflufen + dexamethasone + bortezomib (n=13) in RRMM patients previously treated with 1-4 prior therapies were as follows:

Efficacy
Melflufen + dexamethasone + daratumumab

  • Melflufen (all) — n=33; ORR: 73%; CBR: 76%
  • Melflufen 30 mg, n=6: —ORR: 83%; CBR: 83%; VGPR: 66.6%
  • Melflufen 40 mg, n=27: — ORR: 70%; CBR: 74%; VGPR: 22.2%
  • mPFS at median follow-up of 18.9 months, n=33 — 12.9 months (95% CI, 7.7-15.4)
  • mDoR, n=33: 12.6 months (95%CI, 7.6-24.2)
  • OS: Immature data (at median follow-up of 18.4 months)

Melflufen + dexamethasone + bortezomib

  • Melflufen (all): n=13; ORR: 62%; CBR: 62%
  • Melflufen 30 mg, n=6 — ORR: 50%; CBR: 50%; VGPR: 16.6%
  • Melflufen 40 mg, n=7 — ORR: 71%; CBR: 71%; VGPR: 42.8%
  • mPFS at median follow-up of 12 months: Immature data

Safety
Melflufen + dexamethasone + daratumumab, n=33

  • Overall Grade ≥3 TRAEs: 88% — thrombocytopenia: 73%, neutropenia: 67%, anemia: 24%
  • Melflufen 30 mg, n=6 — Grade ≥3 TRAEs: 83%; thrombocytopenia: 50%, neutropenia: 83%, anemia: 50%
  • Melflufen 40 mg, n=27 — Grade ≥3 TRAEs: 89%; thrombocytopenia: 78%, neutropenia: 63%, anemia: 19%
  • Fatal AEs: Sepsis was observed in 40 mg cohort (possibly related to melflufen)

Melflufen + dexamethasone + bortezomib, n=13

  • Overall Grade ≥3 TRAEs: 92%; thrombocytopenia: 77%; neutropenia: 54%; anemia: 46%
  • Melflufen 30 mg, n=6: Grade ≥3 TRAEs: 83%; thrombocytopenia: 50%, neutropenia: 33%, anemia: 33%
  • Melflufen 40 mg, n=7, Grade ≥3 TRAEs: 100%; thrombocytopenia: 100%, neutropenia: 71%, anemia: 57%
  • Deaths due to AEs: 7.6%

Insights & Implications

  • Melflufen is being evaluated along with the established SoCs with the intent of it becoming a potential combination partner for the development of novel triplet or quadruplet regimens for RRMM
  • Additional follow-up data will be required that will help validate the high response rate observed with both daratumumab- and bortezomib-based triplets in the long term
  • Based on the data from the ANCHOR trial, the 30 mg dose of melflufen appears to be the preferred dosing option for further analysis owing to lower thrombocytopenia occurrence
  • Based on the encouraging data in combination with daratumumab, a pivotal Phase III trial, LIGHTHOUSE, is planned to confirm the efficacy of the triplet using the SC formulation of daratumumab with the intention for it to move up the treatment ladder and receive approval in 2L+ RRMM
  • Melflufen’s positioning in RRMM remains unclear; with a multitude of upcoming treatment options including CARTs, bispecifics and ADCs, it may provide an additional alternative class of treatment for RRMM

Context

Daratumumab (Darzalex) in combination with lenalidomide (Revlimid) and dexamethasone (D-Rd) was approved in 2019 for the treatment of transplant-ineligible newly diagnosed MM (NDMM) (1L) patients based on the data from the Phase III MAIA trial. Data from the long-term follow-up (4 years) were presented now.

Study Highlights

At median follow-up of 47.9 months, data comparing D-Rd (n=368) vs. Rd (n=369) in frontline transplant-ineligible NDMM patients were as follows:

Efficacy: D-Rd (n=368 vs. Rd (n=369XX)

  • ORR: 93% vs. 82% (ORR is consistent with primary analyses at 28 and 36.4 months)
    • sCR: 34% vs. 14%; CR: 17% vs. 15%; VGPR: 30% vs. 27%; PR: 12% vs. 25%
  • MRD-negative rate: 31% vs. 10% (p<0.0001)
  • Sustained MRD-negative rate:
    • ≥6 months sustained: 20% vs. 5% (p<0.0001)
    • ≥12 months sustained: 16% vs. 3% (p<0.0001)
  • mPFS: NR vs. 34.4 months (HR 0.54, p<0.0001); PFS rate at 36 months: 67.4% vs. 48.4%
  • High-risk transplant-ineligible NDMM — D-Rd (n=48) vs. Rd (n=44): 45.3 months vs. 29.6 months
  • Standard-risk transplant-ineligible NDMM — D-Rd (n=271) vs. Rd (n=279): NE vs. 34.4 months
  • mPFS2: NR vs. 51.3 months (p = 0.0005)

Safety: D-Rd (n=364) vs. Rd (n=365)

  • Grade ≥3 hematologic AEs — Neutropenia: 53% vs. 37%; anemia: 16% vs. 21%; lymphopenia: 16% vs. 11%
  • Grade ≥3 non-hematologic AEs — Pneumonia: 18% vs. 11%; hypokalemia: 12% vs. 10%
  • Discontinuations: 48.4% vs. 74.8%
  • Deaths: 29% vs. 35.7%

Insights & Implications

  • Transplant-ineligible NDMM patients represent a population that is historically associated with low survival benefits, with not many treatment options being available for them
  • With a significant PFS2 benefit conferred by D-Rd compared to Rd, long-term follow-up data reinforce the significant PFS benefit observed previously and with no new safety signals. Improved PFS and the benefit were maintained irrespective of age and cytogenetic risk level
  • Deeper and durable responses sustained in the long term, further strengthened by sustained MRD-negative rates, will continue to drive adoption in frontline myeloma
  • D-Rd will continue to be the choice of treatment owing to its OS and PFS benefits and oral RoA, as desired for transplant-ineligible NDMM patients. Additionally, the SC formulation with once-weekly administration is likely to provide an edge to the regimen as most transplant-ineligible NDMM patients are either old (aged >70 years) or frail for whom travelling can be a challenge
ABSTRACT #2325, #2282 and #2287

CANDOR Trial – D-Kd vs. Kd updated data and analysis by MRD-negativity

Context

CANDOR is a pivotal Phase III trial that evaluated the addition of daratumumab (Darzalex) to carfilzomib (Kyprolis) and dexamethasone (D-Kd) in RRMM patients who have received 1-3 prior lines of therapies. D-Kd was approved earlier in 2020 for RRMM based on the initial data from CANDOR; updated data, including sub-group analysis by MRD negativity (MRD-neg) and in patients with early or late relapse in the trial, were presented now.

Early relapse: Relapse in <12 months of initiation of the most recent line of therapy; for patients with prior ASCT: relapse in <12 months of prior transplant.

Late relapse: Relapse in ≥12 months of initiation of the most recent line of therapy; for patients with prior ASCT: relapse in ≥12 months following prior transplant.

Study Highlights

Updated data comparing D-Kd (n=312, median follow-up: 27.8 months) vs. Kd (n=154, median follow-up: 27 months) in 2L-4L RRMM patients were presented (Abstract #2325):

Efficacy: D-Kd (n=312) vs. Kd (n=154)

  • Median treatment duration: 18.3 months vs. 9.3 months
  • OS data: immature
  • mPFS: 28.6 months vs. 15.2 months (median follow-up: 27.8 months vs. 27 months)

Safety: D-Kd (n=308) vs. Kd (n=153)

  • Grade ≥3 AEs: 87.0% vs. 75.8%; fatal AEs: 8.8% vs. 4.6%
  • Grade ≥3 thrombocytopenia: 24.7% vs. 16.3%; hypertension: 21.1% vs. 15.0%; anemia: 17.2% vs. 15.0%

Data were also presented for MRD-neg evaluated in patients treated in the CANDOR study (Abstract #2282):

Efficacy: D-Kd vs. Kd

  • Best overall MRD-negative CR (confirmed CR with MRD-negativity): 13.8% vs. 3.2% (p<0.0001); at 12 months: 12.5% vs. 1.3% (p<0.0001); lenalidomide refractory: 13.1% vs. 0.0%; lenalidomide not refractory: 12.2% vs. 2.0%
  • MRD-negative rate irrespective of overall response status: 22.8% vs. 5.8% (p<0.0001); at 12 months: 17.6% vs. 3.9% (p<0.0001)
  • CR at 12 months: 26.9% vs. 9.7%
  • MRD level at 12 months within CR: MRD-negative CR (>10-4): 36.9% vs. 73.3% (n=31 vs. n=11)
    • MRD-negative CR (10-4 – 10-5): 16.7% vs. 13.3% (n=14 vs. n=2)
    • MRD-negative CR (10-5 – 10-6): 23.8% vs.13.3% (n=20 vs. n=2)
    • MRD-negative CR (<10-6): D-Kd: 22.6% (n=19)
    • At a median follow-up of 6 months, no progression was observed among patients with MRD-negative CR

Subgroup analysis of the CANDOR study by early (<12 months) and late relapsers (>12 months) when administered with D-Kd vs. Kd were presented (Abstract #2287):

Efficacy and safety: D-Kd vs. Kd

  • 2L RRMM, early relapsers, (n=59 vs. 33) — ORR 86.4% vs. 57.6%; ≥CR: 28.8% vs. 3.0%
  • 2L RRMM, late relapsers, (n= 82 vs. 36) — ORR 93.9% vs. 88.9%; ≥CR: 39.0% vs. 16.7%
  • 3L+ RRMM, early relapsers, (n= 81 vs. 43) — ORR 75.3% vs. 65.1%; ≥CR: 19.8% vs. 4.7%
  • 3L+ RRMM, early relapsers, (n=304 vs. 148) — mPFS: 18.5 months vs. 12.0 months
  • 3L+ RRMM, late relapsers, (n= 82 vs. 36) — ORR 82.9% vs. 86.1%; ≥CR: 28.0% vs. 16.7%
  • 3L+ RRMM, late relapsers, (n=304 vs. 148) — mPFS: NE vs. 15.8 months

Grade 3/4 TEAEs in early or late relapsers were consistent with those reported in the overall CANDOR population:

  • 2L RRMM, early relapsers, (n= 58 vs. 32) — Grade ≥3 TEAEs: 84.5% vs. 62.5%; discontinuations due to TEAEs: 24.1% vs. 21.9%; deaths due to TEAEs: 8.6% vs. 9.4%
  • 2L RRMM, late relapsers, (n=81 vs. 36) — Grade ≥3 TEAEs: 77.8% vs. 77.8%; discontinuations due to TEAEs: 23.5% vs. 30.5%; deaths due to TEAEs: 3.7% vs. 2.8%
  • 3L+ RRMM, early relapsers, (n=81 vs. 43) — Grade ≥3 TEAEs: 86.4% vs. 76.7%; discontinuations due to TEAEs: 22.2% vs. 25.6%; deaths due to
  • TEAEs: 13.6% vs. 9.3%
  • 3L+ RRMM, late relapsers, (n=81 vs. 36) — Grade ≥3 TEAEs: 79% vs. 75%; discontinuations due to TEAEs: 19.8% vs. 16.7%; deaths due to TEAEs: 11.1% vs. 0%

Insights & Implications

  • Addition of daratumumab to the SoC or approved combinations in RRMM has been shown to improve patient outcomes. A similar trend was observed when daratumumab was added to Kd for the treatment of 2L+ RRMM patients, with a reduction in disease progression and significant improvement in PFS
  • The data at additional follow-ups support the data reported earlier on efficacy and safety as the D-Kd triplet continues to provide PFS benefit in RRMM patients
  • Data from a sub-group analysis support the use of D-Kd in early as well as late relapsing patients. In general, ORR and CR or better responses were higher with D-Kd vs. Kd in early relapses; the choice of treatment, however, will be based upon the PFS benefit and depth of responses in long term
  • In another sub-group analysis, significantly higher MRD-negative CR rates and deeper MRD achieved with D-Kd in comparison to Kd support its association with improved PFS for RRMM patients
  • The D-Kd triplet will continue to provide an IMiD-free option for patients progressing on IMiDs, especially those progressing on or who are refectory to lenalidomide

Context

Selinexor (Xpovio) was granted an accelerated approval for use in combination with dexamethasone in patients with RRMM who had received four or more prior therapies based on the data from the Phase II STORM trial. BOSTON is the Phase III confirmatory trial evaluating once weekly selinexor + bortezomib + dexamethasone (SVd) in RRMM patients who have received 1-3 prior regimens. Subgroup analysis was undertaken to evaluate the treatment outcomes based on prior exposure to a PI.

Study Highlights

Data comparing SVd (n=195) vs. Vd (n-207) in 2L+ RRMM PI-naïve vs. PI-treated patients were as follows:

Efficacy

PI-naive patients: SVd (n=47) vs. Vd (n=48)

  • ORR: 74.5% vs. 70.8% (p=0.35)
  • mPFS: NR vs. 9.7 months (p=0.0003)

PI-treated patients: SVd (n=148) vs. Vd (n=159)

  • ORR: 77% vs. 59.7% (p=0.0006)
  • mPFS: 11.7 months vs. 9.4 months (p=0.06)

Bortezomib-treated prior to ASCT as induction therapy: SVd (n=148) vs. Vd (n=159)

  • PFS: 13.1 months vs. 9.4 months

Safety

PI-naive patients: SVd (n=47) vs. Vd (n=48)

  • Grade ≥3 AEs: 71% (77% vs. 65%)
  • Grade ≥2 peripheral neuropathy: 25.5% vs. 43.8%

PI-treated patients: SVd (n=148) vs. Vd (n=156)

  • Grade ≥3 AEs: 74% (88% vs. 60%)
  • Grade ≥2 peripheral neuropathy: 19.6% vs. 31.4%%

Insights & Implications

  • The subgroup analysis supports the overall findings of high response rate and improved PFS with once-daily SVd in RRMM patients who have received at least one prior line of therapy
  • SVd demonstrated a noticeable benefit in patients who had no prior exposure to a PI, more than in PI-refractory patients, suggesting that once-weekly SVd has the potential to be adopted to treat PI-naive RRMM patients; however, its uptake in the presence of well-established daratumumab-based combinations across lines of therapies remains unclear
  • The once-weekly triplet provides the benefit of convenient dosing that is expected to reduce the number of required clinic visits by approximately 40%, while conferring a reduced rate of peripheral neuropathy due to the lower dose of bortezomib used
  • Based on the data from the BOSTON trial, an sNDA has been submitted and, if approved, could become an important alternative drug class treatment option in RRMM when viewed with respect to the need for optimal sequence strategy

Context

Iberdomide (Iber), a novel cereblon E3 ligase modulator (CELMoD), could preclinically overcome IMiD resistance and work synergistically with daratumumab, bortezomib (Velcade) and dexamethasone. It is being evaluated clinically with daratumumab/bortezomib in independent cohorts in RRMM patients who have received ≥2 prior regimens (IberDd cohort) or ≥1 prior regimen (IberVd cohort) containing at least an IMiD and a PI.

Study Highlights

Data for IberDd (n=27) and IberVd (n=23) in RRMM patients were as follows:

Iberdomide + Daratumumab+ dexamethasone (IberDd, Cohort E)

Efficacy at a median follow-up of 5 months (n= 27):

  • ORR: 42.3; VGPR: 7.7%; sCR: 3.8%; CR: 7.7%
  • CBR: 50%; DCR: 88.5%
  • PR: 23.1%; MR: 7.7%
  • mTTR: 4.1 weeks; mDoR: NR

Safety (n=27):

  • Grade 3: neutropenia: 14.8%; thrombocytopenia: 11.1%; anemia: 25.9%; Infections 11.1%
  • Grade 4: neutropenia: 51.9%; thrombocytopenia: 3.7%; anemia: 3.7%; infections: 7.4%
  • No DLTs and no deaths reported

Iberdomide + Bortezomib + dexamethasone (IberVd, Cohort F)

Efficacy at a median follow-up of 3 month (n=23):

  • ORR: 60.9%; VGPR: 21.7%; sCR: NA; CR: 4.3%
  • CBR: 69.6%; DCR: 87.0%
  • PR: 34.8%; MR: 8.7%
  • mTTR: 4.1 weeks vs. 3.6 weeks; mDoR: NR

Safety (n=23):

  • Grade 3: neutropenia: 21.7%; thrombocytopenia: 4.3%; anemia: 13.0%; infections: 13.0%
  • Grade 4: neutropenia: 4.3%; thrombocytopenia: 21.7%
  • Patient discontinuations due to AE: 8.7%
  • No deaths reported

Insights & Implications

  • Recent advances in the molecular mechanism of IMiDs show that they bind to cereblon (CRBN) and reduced CRBN levels in the cells leads to IMiD resistance. Based on these findings, CeLMoD agents were developed to have a greater affinity for CRBN and produce a faster degradation of downstream substrate required for anti-myeloma activity, thereby achieving better anti-myeloma activity even in the presence of IMiD resistance
  • In addition to IMiD-refractory patients, Iber may have potential application in anti- CD38- and PI-refractory patients as indicated by the current study’s finding of satisfactory responses, which included anti-CD38- and PI-refractory patients
  • Encouraging results in both the cohorts evaluating Iber with daratumumab, bortezomib and dexamethasone make Iber a potential combination partner with the established SoC combinations
  • These results support the further development of Iber-based regimens in MM; the company is planning Phase III trials to evaluate these combinations
  • With the acquisition of Celgene, BMS now has a rich pipeline of anti-myeloma agents that includes CeLMoDs, BiTES and BCMA-directed ADCs

Context

AMG420, a bispecific T-cell engager that is the product of the BiTE platform technology of Amgen, is being evaluated as a monotherapy in RRMM patients who have received at least two prior therapies. Results were earlier reported for MTD, in which an ORR of 70% was achieved. Long-term outcome of those patients is now being reported.

Study Highlights

Data of AMG420 (n=23) at a median follow-up of 35 months in 3L+ RRMM patients previously treated with three prior lines of therapy including a PI, an IMiD and a CD38-directed mAb were as follows:

Efficacy
ORR at a recommended dose level of 400 µg/d: 70%

  • ORR (n=23): 43.5%
  • OS (n=23): 34.9 months
  • mOS (responders, n=10): 32 months; mOS (non-responders, n=13): 39 months
  • PFS, n=10: 23.5 months

Insights & Implications

  • With the approval of belantamab being closely followed by that of Ide-cel, BCMA has now been established as a successful target in RRMM. There is a long list of BCMA-targeting agents (including CARTs, ADCs and bispecifics) that is being evaluated in MM
  • Although AMG420 has demonstrated encouraging durable response, making it an interesting candidate requiring further evaluation, it suffers from the disadvantage of being a short-acting agent requiring continuous infusion, making it somewhat cumbersome for patients to wear an infusion pump
ABSTRACT #3206 and #3213

Novel Bispecific Antibodies in MM

Context

With advances in technology and increasing molecular understanding of the mechanism of development of myeloma, many new targets are being identified and leading to the development of novel agents directed toward them. PF-06863135 (PF-3135) and BFCR4350A are two such novel bispecifics being evaluated in RRMM patients. Preliminary data from these bispecifics are reported. With the IV formulation of PF-06863135 demonstrating a manageable safety profile in RRMM patients, the SC formulation is now being evaluated.

Study Highlights

Preliminary data of PF-06863135 (n=30) and cevostamab (BFCR4350A) (n=53) in 2L+ RRMM previously treated patients are as follows:

Efficacy and Safety data are in the table below:

Insights & Implications

  • The IV formulation of PF-3135 has shown preliminary anti-tumor activity, following which the SC formation is now being evaluated
  • With the SC administration, the peak concentration of the product reached in the blood (Cmax) can be modified to reduce Cmax-related toxicities. Considering that the CRS observed following treatment with the SC formulation was less severe than that with the IV formulation, higher doses can be administered safely to patients to achieve the desired efficacy
  • Considering the RRMM patients treated included those treated earlier with an ADC and a CART, long-term evaluation will prove the efficacy of PF-3135 in patients refractory to ADC/CART
  • Preliminary clinical data support the preclinical rationale of using BFCR4350A in RRMM. However, additional data in larger populations are needed to support the ongoing evaluation of BFCR4350A in RRMM

Context

CART-ddBCMA is a BCMA-directed autologous CART therapy that has been designed using the ‘ARC-T (antigen receptor complex T cells) + sparX (soluble protein antigen-receptor X-linker)’ platform of Arcellx. sparX proteins are designed to target specific antigens on diseased cells and the ARC-T cells recognizes only those cancer cells that are tagged by sparX. This allows the ARC-T cells to be controlled by the tumor-targeting protein sparX. It is being evaluated in patients who have received ≥3 prior regimens, including a PI, an IMiD and a CD38 antibody, or who are triple refractory.

Study Highlights

At a median follow-up of 3.3 months (100 days), preliminary data from ARC-101 (n=7, median follow-up: 100 days) in 4L+ RRMM patients were as follows:

Efficacy (n=7)

  • sCR (MRD negative 10-4, n=3): 33.3%
  • sCR (n=3): 33.3%
  • sCR (MRD negative 10-6, n=3): 33.3%
  • Median time to CR/sCR = 2 months

Safety: (n=6)

  • No grade 3/4 CRS and neurotoxicity reported
  • Grade 3/4 AEs: neutropenia: 100%; lymphocytopenia: 66.7%; decreased WBC: 50%
  • No SAEs and treatment-emergent grade 3/4 infections reported

Insights & Implications

  • Preliminary efficacy results are encouraging, with all three patients achieving sCR and 2 achieving MRD at one month. Study in a larger patient population and longer follow-up will validate and establish the durability of responses observed with CART-ddBCMA
  • The ARC-T cells can be readily silenced, activated and reprogrammed by sparX; this allows for dose control to minimize toxicities and targeting of multiple antigens to improve efficacy and address relapse which may give an edge to CART-ddBCMA when compared to other CARTs
  • Potential of CART-ddBCMA is being explored in patients with prior BCMA therapies
  • CART-ddBCMA received Orphan Drug and Fast Track designations from the FDA in March 2020

Context

Recently, the CASSIOPEIA study had demonstrated the added benefit of addition of daratumumab to the frontline triplet induction and consolidation therapy consisting of a PI (bortezomib), an IMiD (thalidomide) and dexamethasone in transplant eligible NDMM. Based on this positive finding, the GRIFFIN study was undertaken to investigate if the addition of daratumumab to lenalidomide, bortezomib and dexamethasone (D-RVd) and ASCT improves depth of response in patients undergoing ASCT. Updated efficacy and safety results following 12 months of maintenance therapy with lenalidomide (R) or DARA plus R (D-R) is presented.

Study Highlights

Safety and efficacy results following a 12-month maintenance therapy with D-RVd (n=104) and RVd (n=103) are as follows:

Efficacy
D-RVd (n=104) vs. RVd (n=103)

  • sCR: 66.6% vs. 47.4%; (p=0.0253)
  • ≥CR: 77.8% (n=81) vs. 57.2% (n=59)
  • PFS rate (24 months) at median follow-up=27.4 months (ITT population): 94.5% vs. 90.8%
  • OS rate (24 months) at median follow-up=27.4 months (ITT population): 94.7% vs. 93.3%
  • mPFS: NR; mOS: NR
  • MRD-negative (10-5) (ITT population): 62.5% vs. 27.2%; (p<0.0001)
  • MRD-negative (10-6) (ITT population): 26.9% vs. 12.6%; (p=0.0140)
  • MRD-negative and ≥CR (10-5) (ITT population): 59.6% vs. 24.3%; (p<0.0001)
  • MRD-negative within ≥CR (10-5): 76.5% vs. 42.4%; (p<0.0001)
  • MRD evaluable: 79.8% (n=83) vs. 68.9% (n=71)
    • MRD-negative (10-5): 78.3% vs. 39.4%; (p<0.0001)

Safety
D-RVd (n=99) vs. RVd (n=102)

  • Grade 3/4 TEAEs: neutropenia: 43% vs. 24%; lymphopenia: 23% vs. 23%; thrombocytopenia: 15% vs. 9%
  • Grade 3/4 infections during maintenance (cycles 7+), n=89 vs. 71: pneumonia: 6% vs. 13%; upper respiratory tract infection: 4% vs. 3%
  • Discontinuations during maintenance: 12% vs. 17%

Insights & Implications

  • The positive data from 12-month maintenance with D-Rd build upon the safety and efficacy data obtained earlier from the GRIFFFIN study and add to the increasing body of evidence for the addition of daratumumab to PI/IMiD combination therapy in the transplant setting
  • sCR and MRD negativity rates further validate the depth of response and sustained remissions following maintenance with daratumumab-lenalidomide
  • With the current triplet SoC combinations having significant clinical outcomes in the frontline setting, oncologists may not want to use the quadruplet regimen upfront in all patients and may restrict its usage to high-risk patients
  • Due to an already established market presence in MM, D-RVd followed by DR maintenance is likely to receive a positive adoption curve with a potential to become the SoC in transplant-eligible NDMM; however, it would require data on long-term survival benefits

Context

Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CART-cell therapy, has been evaluated in heavily pretreated RRMM (4L+) patients in the pivotal KarMMa study. The analysis in high-risk patients that are often the most difficult to treat is presented from the KarMMa study.

Study Highlights

Results from the analysis of various subgroups of high-risk RRMM patients treated with ide-cel (n=128) were as follows:

Efficacy
All ide-cel-treated patients- n=128

  • ORR: 73%; VGPR: 20%; PR: 21%
  • mPFS: 8.8 months

Patients with (n=50) vs. without (n=78) extramedullary disease (EMD)

  • ORR: 70% vs. 76%
  • mPFS: 7.9 months vs. 10.4 months

Safety
Grade 3/4 TEAEs, SAEs:

  • All patients (n=128): 99%, 72%
  • Extramedullary disease (n=50): 100%, 71%
  • High cytogenetic risk (n=45): 100%, 77%
  • High tumor burden (n=65): 99%, 70%
  • Received bridging therapy (n=112): 100%, 70%
  • R-ISS disease stage III (n=21): 60%, 68%
  • >1 prior regimens/year (n=60): 99%, 67%

Insights & Implications

  • The subgroup analysis data confirm the earlier-reported efficacy data for ide-cel, based on which the BLA was submitted to the FDA for approval of ide-cel in heavily pretreated RRMM patients
  • It is important to appreciate that high-risk MM patients represent a heterogeneous group of patients with several clinical and biologic markers and, hence, the outcomes to any given therapy may be very varied. Considering that the subgroup analysis from the KarMMa study demonstrated deep and durable response in high-risk RRMM patients (including those with EMD, high-risk cytogenetics and high tumor burden treated with ide-cel), it is a promising option for these difficult-to-treat patients
  • It would of interest to note how the other BCMA-targeting CARTs that are closely following ide-cel fare in high-risk patients. Any differences in the efficacy in these subgroups may eventually become important in differentiating these CARTs
ABSTRACT #3214 and #3237

Features Phase II HORIZON Trial – Subgroup Analysis by Extramedullary Disease (EMD) and Cytogenetic Features

Context

Melflufen is a first-in-class peptide-conjugated alkylator (PDC) that is currently being evaluated with dexamethasone in the Phase II HORIZON study in RRMM patients who have received ≥2 lines of prior therapy and are refractory to pomalidomide and/or an anti-CD38 mAb. EMD is often associated with high-risk cytogenetics and resistance to therapy. Currently, there is no standard therapy for this population with a high unmet need and the prognosis is very poor, especially in RRMM settings. The trial population included patients who were triple-class refractory and/or had EMD and/or had high-risk (HR) cytogenetic features. Subgroup analyses of the patients having EMD and HR cytogenetic abnormalities are reported here.

Study Highlights

Subgroup analyses based on cytogenetic features and presence/absence of EMD in patients receiving melflufen plus dexamethasone overall in 3L+ RRMM were as follows:

Efficacy
Overall (n=157)

  • ORR: 29%
  • mPFS: 4.2 months: mOS:11.6 months
  • mDoR: 5.5 months

EMD vs. Non-EMD subgroup (Abstract #3214) (n=55 vs. 102)

  • ORR: 24% vs. 32%; CBR: 31% vs. 53%
  • mPFS: 2.9 months vs. 4.9 months: 6.5 months vs. 14.5 months
  • mDoR: 5.5 months vs. 5.1 months

HR vs. Non-HR cytogenetic group (Abstract #3237) (n=59 vs. 98)

  • ORR: 20% vs. 35%; CBR: 37% vs. 50%
  • mPFS: 3.1 months vs. 4.4 months: 11.5 months vs. 13.2 months
  • mDoR: 6.7 months vs. 5.1 months

Safety
EMD subgroup (n=55):

  • Grade 3/4 AEs: 78%
  • SAEs: 69%
  • TEAEs leading to discontinuation: 24%

HR vs. Non-HR cytogenetics (n=59 vs. 98):

  • Grade >3 TEAEs: 96% vs. 96%
  • SAEs: 56% vs. 48%
  • TEAEs leading to discontinuation: 19% vs. 23%

Insights & Implications

  • Considering that, in the HORIZON study, the safety profile, response rates and benefits in PFS and OS observed in EMD patients and HR cytogenetic patients were all similar to those of the overall population, melflufen seems to have the therapeutic potential in these hard-to-treat patients. A larger study with a long-term follow-up is required to validate these results
  • Oncopeptides has submitted an NDA based on the overall data from the trial to the FDA to seek approval for treatment of triple refractory RRMM patients with melflufen and has been granted a priority review

Context

Renal impairment (RI) is a frequent complication that is observed in about half of all MM patients and is associated with poor prognosis and survival. It may also complicate drug dosing, limit treatment options and lead to a higher incidence of AEs. IKEMA is a Phase III study evaluating isatuximab (Isa) with carfilzomib (K) plus dexamethasone (d) vs. Kd in RRMM patients who have undergone 1-3 prior lines of therapy (2L-4L). Subgroup analysis was undertaken to examine the efficacy, safety and renal response of Isa-Kd in patients with RI. RI was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² at baseline. Complete renal response (CrR) was defined as an improvement in eGFR from <50 mL/min/1.73 m² at baseline to ≥60 mL/min/1.73 m² (no RI) in at least one post-baseline assessment as per International Myeloma Working Group recommendations. CrR was classified as durable if lasting ≥60 days.

Study Highlights

Subgroup analysis data comparing Isa-Kd (n=179) vs. Kd (n=123) in 2L-4L RRMM patients that progressed on a PI and IMiD are given below. In patients with RI in the Isa-Kd arm, ~60% received ≥2 lines of therapy compared to 72% in the Kd arm:

Efficacy (Isa-Kd vs. Kd)
Patients with RI

  • mPFS: NR vs. 13.4 months (HR 0.27; 95% CI 0.11-0.66)
  • ORR: 93.0% vs. 61.1%
  • ≥VGPR: 79.1% vs. 44.4%
  • MRD: 30.2% vs. 11.1%
  • CrR: 52% vs. 30.8%
  • Durable CrR: 32% vs. 7.7%
  • Median number of cycles, n= 43 vs. 18: 20 vs. 9

Patients without RI

  • mPFS: NR in either arm
  • Median number of cycles, n=120 vs. 92: 19 vs. 17

Safety (Isa-Kd vs. Kd)
Patients with RI, n=61

  • Grade 5 TEAEs (n=43 vs. 18): 0% vs. 11%
  • Grade ≥3 AEs (n=43 vs. 18): 79.1% vs. 77.8%
  • Grade 3 anemia: 25.6% vs. 27.8%; thrombocytopenia: 20.9% vs. 33.3%; neutropenia: 14% vs. 0%
  • Grade 4 thrombocytopenia: 18.6% vs. 11.1%; neutropenia: 2.3% vs. 0%
  • Discontinuation due to TEAEs: 7% vs. 27.8%
  • Death due to TEAEs: 0% vs. 11.1%

Patients without RI, n=212

  • Grade ≥3 AEs (n=120 vs. 92): 77.5% vs. 65.2%
  • Grade 3 anemia: 19.2% vs. 15.2%; thrombocytopenia: 15.8% vs. 13.0%; neutropenia: 19.2% vs. 8.7%
  • Grade 4 thrombocytopenia: 8.3% vs. 6.5%; neutropenia: 1.7% vs. 0%
  • Grade 5 TEAEs (n=43 vs. 18): 4.2% vs. 1.1%
  • Discontinuation due to TEAEs: 10.0% vs. 9.8%

Insights & Implications

  • Adding isatuximab to Kd was shown to have a significant improvement in PFS with clinically meaningful depths of response in the overall population. Similar trends are observed in patients with RI, which is indicative of a potential opportunity to address an unmet need in this RRMM subgroup
  • Isa-Kd emerges as a safe option in RI patients, considering the lower discontinuation rates despite greater treatment exposure (almost twice the number of cycles received) than with Kd
  • Patients treated with Isa-Kd showed reversal of RI and durable renal responses compared to those treated with Kd. A detailed analysis supported by real-world evidence can make isatuximab-based regimens the preferred treatment in patients with impaired RI
ABSTRACT #3215 and #3245

Phase III BOSTON Trial – SVd vs. Vd, Subgroup Analysis by Age and Frailty

Context

Selinexor (Xpovio) was granted an accelerated approval for use in combination with dexamethasone in patients with RRMM who had received four or more prior therapies based on data from the Phase II STORM trial. The Phase III confirmatory BOSTON trial is evaluating once weekly selinexor + bortezomib + dexamethasone (SVd) in RRMM patients who have received 1-3 prior regimens. Subgroup analysis was conducted based on the age (>75 years), prior number of therapies and prior lenalidomide (len) exposure.

Study Highlights

Subgroup analysis data comparing SVd (n=109) vs. Vd (n=132) in frail and aged ≥75 years, len-treated (n=154) vs. len-naïve (n=248) 2L-4L RRMM patients from the BOSTON study (n=402) were as follows:

Overall efficacy (Abstracts #3215 and #3245)

  • mPFS: 13.93 months vs. 9.46 months
  • ORR: 76.6% vs. 62.3%; ≥VGPR: 44.6% vs. 32.4%; DoR: 20.3 months vs. 12.9 months

Efficacy (Abstract #3215)

<65 years age [SVd (n=86) vs. Vd (n=75)]

  • ORR: 76.7% vs. 58.7%; VGPR: 26.7% vs. 24.0%; PR: 30.2% vs. 24.0%; sCR: 10.5% vs. 5.3%; CR: 9.3% vs. 5.3%
  • PFS: 12.2 months vs. 9.4 months (HR, 0.74; 95% CI, 0.41-1.10; P=0.07)

≥65 years age [SVd (n=109) vs. Vd (n=132)]

  • ORR: 76.1% vs. 64.4%; VGPR: 28.4% vs. 20.5%; PR: 33.0% vs. 33.3%; sCR: 9.2% vs. 6.8%; CR: 5.5% vs. 3.8%
  • PFS: 21.0 months vs. 9.4 months (HR, 0.55; 95% CI, 0.37-0.83; P=0.02)

Fit patients [SVd (n=129) vs. Vd (n=143)]

  • ORR: 79.8% vs. 62.9%; VGPR: 30.2% vs. 23.1%; PR: 31.0% vs. 29.4%; sCR: 10.1% vs. 5.6%; CR: 8.5% vs. 4.9%
  • PFS: 13.2 months vs. 9.4 months (HR, 0.66; 95% CI, 0.47-0.93; P=0.008)

Frail patients [SVd (n=66) vs. Vd (n=64)]

  • ORR: 69.7% vs. 60.9%; VGPR: 22.7% vs. 18.8%; PR: 33.3% vs. 31.3%; sCR: 9.1% vs. 7.8%; CR: 4.5% vs. 3.1%
  • PFS: 13.9 months vs. 9.4 months (HR, 0.69; 95% CI, 0.40-1.17; P=0.08)
  • OS: NA vs. 23.5 mos

Safety

  • Most common grade ≥3 AEs were thrombocytopenia, anemia, and fatigue
  • Deaths during the study
    • Age <65 years: 26% vs. 20%
    • Age ≥65 years: 23% vs. 36%
    • Fit: 23% vs. 24%
    • Frail: 26% vs. 44%

Efficacy (Abstract #3245)

Len-treated patients [SVd (n=77) vs. Vd (n=77)]

  • ORR: 67.5% vs. 53.2%, (p=0.035); VGPR: 24.7% vs. 19.5%; PR: 31.2% vs. 26.0%; sCR: 7.8% vs. 2.6%; CR: 3.9% vs. 5.2%
  • PFS: 9.59 months vs. 7.2 months (HR, 0.63; 95% CI, 0.41-0.97; P=0.017)

Len-naïve [SVd (n=118) vs. Vd (n=130)]

  • ORR: 82.2% vs. 67.7%, (p=0.004); VGPR: 29.7% vs. 23.1%; PR: 32.2% vs. 32.3%; sCR: 11.0% vs. 8.5%; CR: 9.3% vs. 3.8%
  • PFS: 16.62 months vs. 10.61 months (HR, 0.66; 95% CI, 0.45-0.96; P=0.015)

Patients with 1 prior therapy [SVd (n=99) vs. Vd (n=99)]

  • ORR: 80.8% vs. 65.7%, (p=0.008); VGPR: 24.2% vs. 18.2%; PR: 28.3% vs. 36.4%; sCR: 15.2% vs. 6.1%; CR: 13.1% vs. 5.1%
  • PFS: 16.62 months vs. 10.68 months (HR, 0.63; 95% CI, 0.41-0.96; P=0.015)

Patients with ≥2 prior therapies [SVd (n=96) vs. Vd (n=108)]

  • ORR: 71.9% vs. 59.3%, (p=0.029); VGPR: 31.3% vs. 25.0%; PR: 35.4% vs. 24.1%; sCR: 4.2% vs. 6.5%; CR: 1.0% vs. 3.7%
  • PFS: 11.76 months vs. 9.43 months (HR, 0.69; 95% CI, 0.48-1.01; P=0.029)

Safety

  • Grade ≥3 AEs: Len-treated: 83% vs. 57%; Len-naïve: 76% vs. 55%; 1 prior therapy: 77% vs. 56% and ≥2 prior therapies: 81% vs. 56%

Insights & Implications

  • The results demonstrate that once-weekly SVd is a potent and convenient treatment option for RRMM patients who are aged ≥65 years and/or frail, irrespective of the number of prior treatments or whether patients had previous exposure to Len compared to doublet Vd
  • The subgroup analysis supports the overall findings of high response rate and improved PFS with the once-daily triplet SVd in RRMM patients who have received at least one prior line of therapy
  • The once-weekly triplet comes with the benefit of convenient dosing that is expected to reduce clinic visits by approximately 40%, while conferring a reduced rate of peripheral neuropathy due to the lower dose of bortezomib used
  • Based on the data from the BOSTON trial, an sNDA has been submitted and an approval based on the same will help selinexor move up the treatment ladder and capture a greater market share in RRMM
The commentary included in this newsletter has been generated by the disease and market experts within Prescient’s dedicated Analytics function following analysis of publicly available sources of information.

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