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Novel Therapeutics for Relapsed or Refractory Multiple Myeloma, Part 2


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Syed Ali Abutalib, MD

Syed Ali Abutalib, MD

Kenneth C. Anderson, MD

Kenneth C. Anderson, MD

Here is an update on several different studies focusing on novel treatments for patients with relapsed or refractory multiple myeloma presented at the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition. The featured therapeutics include the oral agent selinexor in combination with low-dose dexamethasone or daratumumab and dexamethasone; immunotherapy with AMG 420, the anti–B-cell maturation antigen (BCMA) bispecific T-cell engager; venetoclax plus carfilzomib and dexamethasone; as well as the peptidase-enhanced compound melflufen. (See part 1, with more abstracts on newer treatments for patients with newly diagnosed multiple myeloma presented at the 2018 ASH Annual Meeting & Exposition.)

Novel Treatments for Relapsed or Refractory Myeloma

Abstract 598: Deep and durable responses with oral selinexor plus low-dose dexamethasone (n = 122) in patients with penta-exposed and triple-class–refractory multiple myeloma1

Mechanism of Action: Selinexor is a first-in-class selective inhibitor of nuclear export compound that binds and inactivates exportin 1, which leads to nuclear accumulation and activation of tumor-suppressor proteins, inhibition of nuclear factor kappa B, and translational suppression of several oncoprotein mRNAs (eg, c-Myc, cyclin D).

Primary Study Endpoint: Objective response rate

Key Findings: Patients were enrolled in 38 sites (United States and European Union). About 102 patients (84%) had prior transplantation, and 2 patients had prior chimeric antigen receptor (CAR) T-cell therapy. All patients had progressive disease. Grade 3 to 4 reported adverse events (> 20%) included thrombocytopenia, fatigue (21%), and anemia (28%). Eight patients remain on study, and 114 patients discontinued treatment, most commonly due to progressive disease. There were 4 deaths on treatment: sepsis, respiratory failure, pulmonary embolism, and an unrelated, unspecified cardiac event.

The objective response rate (at least a partial response) was 26.2%, with 6.5% with at least a very good partial response, including 2 stringent complete responses, and minimal residual disease (MRD) negative at 1:10-6 and at 1:10-4 sensitivity. Both patients who relapsed after CAR T-cell therapy achieved a partial response. The clinical benefit rate (at least a minimal response) was 39.3%, and 79% of patients achieved at least stable disease. Responses typically occurred within the first month. The median duration of response was 4.4 months, the progression-free survival was 3.7 months, and the overall survival was 8.0 months. Patients with at least a minimal response had significantly longer overall survival than patients with progressive disease or who were not evaluable (median not reached vs 1.9 months, P < .0001).

Clinical Implications: The results of the pivotal STORM Part 2 trial in penta-refractory multiple myeloma demonstrated that the combination of selinexor and low-dose dexamethasone was active, with an objective response rate of 26.2%. No major organ toxicity was observed, and adverse events were typically transient and reversible. Future trials will assess the therapeutic index of selinexor, especially in combination therapies. (Also, see Abstract 599, in which selinexor is combined safely with daratumumab and dexamethasone.2)

Abstract 1010: Treatment with AMG 420 induces MRD-negative (10-4) complete response in relapsed or refractory multiple myeloma (including proteasome inhibitor and immunomodulatory imide drugs): Results of a first-in-human (n = 35) phase I dose-escalation study3

Mechanism of Action: AMG 420 binds to BCMA on tumor cells and plasma cells and CD3 on T cells, resulting in T-cell–mediated lysis of BCMA-positive cells.

Study Endpoint: To access safety, tolerability, and antitumor activity

Key Findings: Patients discontinued the trial drug due to progressive disease (n = 21), adverse events (n = 7, including 2 dose-limiting toxicities), or completed 10 cycles (n = 2); 5 remain on study. After the first cycle, one patient in the 50-µg/d cohort died of acute respiratory distress due to concurrent flu and aspergillosis, which was not considered related to treatment. Of those patients who had serious adverse events (n = 17, 49%), 12 required hospitalization and another 3 had prolonged hospitalization. Serious adverse events included infections; cytokine-release syndrome; and peripheral polyneuropathy, cardiac failure, edema, pyrexia, biliary obstruction, and renal failure. Treatment-related serious adverse events included cytokine-release syndrome (2 grade 1 and 1 grade 3) and peripheral

The bispecific T-cell engager technology has already shown efficacy in leukemia and lymphoma, and this study suggests that multiple myeloma may also benefit from this off-the-shelf immunotherapy.
— Syed Ali Abutalib, MD, and Kenneth C. Anderson, MD

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polyneuropathy (1 grade 3), edema (1 grade 3), and pyrexia (1 grade 1). No anti–AMG 420 antibodies were detected at doses up to 800 μg/d. Six patients had a complete response, 1 each at 6.5, 100, and 200 µg/d, and 3 at 400 µg/d; responses were ongoing for the past 3 months. There also were 2 partial remissions, a partial response at 50 µg/d, and a very good partial response at 800 µg/d. All 3 patients treated at 400 µg/d had an MRD-negative complete response.

Clinical Implications: AMG 420 showed evidence of clinical activity in patients with relapsed or refractory multiple myeloma. No major toxicities were observed up to 400 µg/d, and that is the recommended dose for further investigation; dose-limiting toxicities at 800 µg/d were cytokine-release syndrome and peripheral polyneuropathy. (Also, refer to Abstract 592, which highlights the activity of AMG 701, another anti-BCMA bispecific T-cell engager.4) The bispecific T-cell engager technology has already shown efficacy in leukemia and lymphoma, and this study suggests that multiple myeloma may also benefit from this off-the-shelf immunotherapy.

Abstract 303: Phase II study of venetoclax plus carfilzomib and dexamethasone in patients [n = 42; 8 patients with t(11;14)] with relapsed or refractory multiple myeloma5

Study Endpoint: Preliminary safety and efficacy data

Key Findings: Patients received a median of 2 prior therapies (range, 1–3), 93% had received a prior proteasome inhibitor (50% were refractory), 62% were refractory to immunomodulatory imide drugs, and 33% were double-refractory.

All patients experienced at least 1 adverse event, and grade 3 to 5 adverse events experienced by more than 10% of patients included decreased lymphocyte count (26%), decreased neutrophil count (14%), and hypertension (12%). Thirteen patients experienced at least one serious adverse event. The maximum tolerated dose was not reached, and venetoclax at 800 mg/d plus carfilzomib at 70 mg/m2 were the doses selected for expansion. The objective response rate was 78%, and the very good partial response or better rate was 56%.

Clinical Implications: The combination of venetoclax, carfilzomib, and dexamethasone appears to be tolerable, with no new safety signals observed. The subset of patients with t(11;14) had the highest response, with a very good partial response or better rate of 88%. Although venetoclax is active in patients with t(11;14) multiple myeloma, this study and prior studies in combination with bortezomib showed that its activity extends beyond this patient subset, especially in combination with proteasome inhibitors.

Abstract 600: OP-106 Horizon multicenter trial: Melflufen therapy for patients with relapsed or refractory multiple myeloma (n = 56 evaluable for response) who are refractory to daratumumab and/or pomalidomide6

Mechanism of Action: Melflufen selectively targets multiple myeloma cells through aminopeptidase-driven accumulation, leading to a 50-fold enrichment of alkylating metabolites. This enrichment results in selective cytotoxicity (with increased on-target cell potency and decreased off-target toxicity); it also overcomes resistance pathways of existing myeloma treatments (including alkylators) as well as demonstrates strong antiangiogenic properties.

Primary Study Endpoint: Objective response rate (partial response or better).

Key Findings: The objective response rate was 32%, and the clinical benefit rate (minimal response or better) was 39%. Per protocol, efficacy-evaluable patients (who received at least 2 doses of melflufen) had an objective response rate of 38% and a clinical benefit rate of 46%. No treatment-related deaths were reported.

Clinical Implications: Melflufen (40 mg intravenously every 28 days with weekly dexamethasone) has shown activity in this patient population. It was generally well tolerated, with treatment discontinuation due to adverse events in 15% of patients on the trial. Melflufen is being studied in the phase III OCEAN study and is being combined with other agents (refer to Abstract 19677). The ability to selectively enrich alkylating metabolites and increase myeloma cytotoxicity, coupled with the clinical activity (even in advanced myeloma refractory to novel agents), suggests that melflufen may play a role in myeloma management. Clinical trials will determine its efficacy in melphalan-resistant multiple myeloma, as well as its potential role as ablative therapy prior to autologous hematopoietic cell transplantation.

Supportive Care: Real-World Data

Abstract 978: Racial disparities in the utilization of recommended supportive care among older adults (age > 65 years) with multiple responses in the United States8

Methods: The study focus is on older adults diagnosed with multiple myeloma between 2008 and 2013 from the Surveillance, Epidemiology, and End Results–Medicare database. Outcomes of interest include the proportion of patients receiving guideline-concordant supportive care therapy defined as bisphosphonate therapy (zoledronic acid or pamidronate disodium) within the first 12 months after diagnosis, influenza vaccination in the first flu season after diagnosis, and receipt of antivirals (acyclovir, valacyclovir) among patients receiving bortezomib therapy. A total of 1,569 Medicare beneficiaries met the prespecified eligibility criteria.

Key Findings: A total of 66% of Medicare beneficiaries on active multiple myeloma therapy received bisphosphonates within 1 year of diagnosis, 53% of patients received influenza vaccination in the first flu season after diagnosis, and 44% received antiviral prophylaxis while receiving bortezomib therapy. In the multivariate analysis, predictors of bisphosphonate nonusage included increasing age (odds ratio for

There is significant underutilization of supportive care measures focused at bone health and infection prevention among older adults with multiple myeloma in the United States.
— Syed Ali Abutalib, MD, and Kenneth C. Anderson, MD

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85+ years = 0.37; 95% confidence interval [CI] = 0.23–0.58 compared with 66–69 years), non-Hispanic black and Hispanic ethnicity (odds ratio = 0.51; 95% CI = 0.34–0.76 and odds ratio = 0.56; 95% CI = 0.35–0.91, respectively, vs white patients), and higher comorbidity index (for Elixhauser Comorbidity Index of 3+ odds ratio = 0.41, 95% CI = 0.29–0.57 vs 0). Significant predictors of flu shot nonusage included non-Hispanic black ethnicity (odds ratio = 0.49; 95% CI = 0.34–0.70 vs white patients), living in the West (odds ratio = 0.53; 95% CI = 0.38–0.75 vs the Midwest), having Medicaid dual coverage (odds ratio = 0.66; 95% CI = 0.49–0.89) and a lower comorbidity burden (for Elixhauser Comorbidity Index of 3+ odds ratio = 1.44; 95% CI = 1.07–1.93 vs 0). Predictors of antiviral prophylaxis nonusage included earlier years of diagnosis (global P < .01, with an increasing odds ratio for more recent years) and higher comorbidity burden (for Elixhauser Comorbidity Index of 3+ odds ratio = 0.40; 95% CI = 0.24–0.67 vs 0).

Clinical Implications: There is significant underutilization of supportive care measures focused at bone health and infection prevention among older adults with multiple myeloma in the United States. Future studies should seek to identify reasons for such underutilization of supportive care during therapy for multiple myeloma, so appropriate interventions may be implemented. 

Dr. Abutalib is Associate Director, Hematology and BMT Program; Director, Clinical Apheresis Program, Cancer Treatment Centers of America, Zion, Illinois; Associate Professor, Roseland Franklin University of Medicine and Science; and Founder and Co-Editor, Advances in Cell and Gene Therapy. Dr. Anderson is Program Director, Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics; and Kraft Family Professor of Medicine, Harvard Medical School, Boston.

DISCLOSURE: Dr. Abutalib has served on an advisory board for Millennium Takeda. Dr. Anderson has served as as an advisor to Celgene, Millennium Takeda, Gilead, Bristol-Myers Squibb, and Janssen.

REFERENCES

1. Chari A, et al: Results of the pivotal STORM study (Part 2) in penta-refractory multiple myeloma (MM). 2018 ASH Annual Meeting & Exposition. Abstract 598. Presented December 3, 2018.

2. Gasparetto CJ, et al: Deep and durable responses with selinexor, daratumumab, and dexamethasone in patients with multiple myeloma previously exposed to proteasome inhibitors and immunomodulatory drugs. 2018 ASH Annual Meeting & Exposition. Abstract 599. Presented December 3, 2018.

3. Topp MS, et al: Treatment with AMG 420, an anti-B-cell maturation antigen bispecific T-cell engager antibody construct, induces minimal residual disease negative complete responses in relapsed and/or refractory multiple myeloma patients. 2018 ASH Annual Meeting & Exposition. Abstract 1010. Presented December 3, 2018.

4. Cho S-F, et al: Anti-BCMA BiTE® AMG 701 potently induces specific T cell lysis of human multiple myeloma cells and immunomodulation in the bone marrow microenvironment. 2018 ASH Annual Meeting & Exposition. Abstract 592. Presented December 3, 2018.

5. Costa LJ, et al: Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma. 2018 ASH Annual Meeting & Exposition. Abstract 303. Presented December 2, 2018.

6. Richardson P, et al: OP-106 Horizon—Melflufen therapy for RRMM patients refractory to daratumumab and/or pomalidomide. 2018 ASH Annual Meeting & Exposition. Abstract 600. Presented December 3, 2018.

7. Pour L, et al: The OP-104 Anchor study. 2018 ASH Annual Meeting & Exposition. Abstract 1967. Presented December 1, 2018.

8. Giri S, et al: Racial disparities in the utilization of recommended supportive care among patients with multiple myeloma in the United States. 2018 ASH Annual Meeting & Exposition. Abstract 978. Presented December 3, 2018.


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Here is an update on several different studies focusing on novel treatments for patients with newly diagnosed multiple myeloma presented at the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition. Featured...

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