Metronomic Therapy for Relapsed Refractory Multiple Myeloma

Tarek H Mouhieddine, MD1, Julia Hieulle2*, Erin Moshier, MS3*, Josh R. Richter, MD4, Hearn Jay Cho, MD, PhD4, Samir S. Parekh, MD4, Ajai Chari, MD4, Bart Barlogie, MD, PhD4, Sundar Jagannath, MD4 and Deepu Madduri, MD4

1Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
2Service des Maladies du Sang, Centre Hospitalier Régional Universitaire De Lille, Lille, France
3Department of Population Health Science and Policy, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
4Department of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY

The advent of novel therapies has led to tremendous progress in the treatment of multiple myeloma (MM). However, management of patients with high-risk disease who have failed approved agents and have rapidly progressive disease with cytopenias continues to be challenging. While palliative care is an option, many patients hope to qualify for a clinical trial option. Here we report results of a 28-day metronomic therapy (METRO-28) consisting of continuous administration of very low doses of classical chemotherapeutic agents. Sixteen-day cycles of metronomic therapy were previously shown to have a favorable response with acceptable toxicity profiles in MM patients (Papanikolaou et al. Haematologica 2013).
To investigate the efficacy and toxicity in patients with high-risk relapsed refractory MM (RRMM) ineligible for clinical trial options receiving 1 cycle of METRO-28.
We retrospectively analyzed the clinical outcomes of 106 RRMM, treated with 1 cycle of 28-day metronomic chemotherapy at the Tisch Cancer Institute – The Mount Sinai Hospital. METRO-28 consists of 6 agents: dexamethasone 8 mg on days 1 through 4, 7 through 10, 13 through 16, 19 through 22 and 25 through 28; bortezomib 1 mg/m2 on days 1, 4, 7, 10, 13, 16, 19, 22, 25, 28; cisplatin 1 mg/m2 daily; doxorubicin 1 mg/m2 daily; thalidomide 100 mg daily; and vincristine flat dose 0.06 mg daily. METRO-28 was administered through a central line in either the inpatient or outpatient setting.
Our cohort of 106 RRMM patients has a median age of 65 years (range: 35-85) and at a median of 59 months from time of diagnosis; 42% were females. They had a median of 7 prior lines of therapy (range: 1 – 25); with 73% triple- and 58% penta-refractory cases. Prior autologous transplantation was utilized in 69% of patients including tandem transplants in 30%. Moreover, 78% of patients carried high-risk cytogenetic features, including 1q21 duplication/amplification (89%), 17p deletion (49%), t(4;14) (17%), t(14;16) (17%) or t(14;20) (3%).

At the time of METRO-28 initiation, patients were cytopenic with grade 3 and 4 anemia (21%), neutropenia (8%) and thrombocytopenia (23%). Profound cytopenias in some patients led to early discontinuation of treatment; forty-three patients (41%) received the full 28-day course of METRO-28, while 11%, 17%, 20% and 11% were treated for <1 week, <2 weeks, <3 weeks or <4 weeks, respectively. Grade 3-4 cytopenia increased: anemia 66%, leucopenia 61%, neutropenia 55% and thrombocytopenia 76%.

On an intent to treat basis (106 patients), the deepest response included 2% stringent complete response (sCR), 7% near complete response (nCR), 7% very good partial response (VGPR), 28% partial response (PR), 11% minimal response (MR) and 12% stable disease (SD). Only 43 patients (41%) completed all 4 weeks of METRO-28 and had a 72% overall response rate (ORR) and 88% clinical benefit rate (CBR). Seventy-four percent of these patients were able to move on to new therapies, including novel agents and clinical trials. Their overall survival (OS) was 11.8 months (range: 6.1-NE) as opposed to an OS of 4.2 months (range: 3.4-7.2) for patients with <4 weeks of METRO-28. Sixty-three patients had their treatment interrupted: 34 due to disease progression or absence of response, 18 due to bacterial or viral infections and 11 due to hematologic toxicity.
Giving 1 cycle of METRO-28 is better tolerated in patients with good hematologic reserve and offers an opportunity for a clinical benefit and a bridge to a subsequent treatment option for these advanced refractory myeloma patients.
Richter: Takeda: Consultancy; Janssen: Speakers Bureau; Sanofi: Consultancy; AstraZeneca: Consultancy; X4 Pharmaceuticals: Consultancy; Adaptive Biotechnologies: Consultancy, Speakers Bureau; Oncopeptides: Consultancy; Secura Bio: Consultancy; Antengene: Consultancy; Karyopharm: Consultancy; Bristol Myers Squibb: Consultancy; Celgene: Consultancy, Speakers Bureau. Parekh: Karyopharm: Research Funding; Celgene: Research Funding; Foundation Medicine: Consultancy. Chari: Adaptive Biotechnology: Honoraria; The Binding Site: Honoraria; Array BioPharma: Honoraria; Novartis: Honoraria; Secura Bio: Consultancy; Glaxo Smith Kline: Consultancy; Antengene: Consultancy; Takeda: Consultancy, Research Funding; Oncopeptides: Consultancy; Seattle Genetics: Consultancy, Research Funding; Sanofi Genzyme: Consultancy; Karyopharm: Consultancy; Pharmacyclics: Research Funding; Bristol Myers Squibb: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Jagannath: Legend Biotech: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Madduri: Janssen: Consultancy; BMS: Consultancy; Takeda: Consultancy; Legend: Consultancy; Sanofi: Consultancy; GSK: Consultancy; Kinevant: Consultancy; Foundation Medicine: Consultancy.