Three-Drug Combos Offer Hope in Myeloma

Sundar Jagannath

Sundar Jagannath, MD

The treatment options for patients with relapsed/refractory multiple myeloma are expanding rapidly, notably through clinical trial evidence supporting a number of three-drug combination regimens.

Sundar Jagannath, MD, the director of the Multiple Myeloma Program at The Tisch Cancer Institute and a professor at Mount Sinai School of Medicine in New York City, detailed many of the key research results shaping this new landscape during a presentation at the 19th Annual International Congress on Hematologic Malignancies: Focus on Leukemias, Lymphomas and Myeloma that Physicians’ Education Resource (PER) hosted February 20-21 in Miami, Florida.

“Now we have a panoply of treatment choices,” Jagannath said in an interview, adding that the field has become “more exciting.”

During his presentation, Jagannath referenced five combination regimens explored in these clinical trials:

• ASPIRE—The addition of the proteasome inhibitor carfilzomib to the immunomodulatory (IMiD) agent lenalidomide and the corticosteroid dexamethasone improved median progression-free survival (PFS) to 26.3 months versus 17.6 months for patients who received lenalidomide plus dexamethasone (HR = 0.69; CI 0.57-0.83; P <.0001), with a trend toward improved overall survival.¹Nearly 800 patients who had received one to three prior treatments were enrolled in this phase III.
• Pomalidomide Trial—The combination of the cytotoxic agent cyclophosphamide with pomalidomide, another IMiD, and dexamethasone demonstrated an improvement in overall response rate compared with pomalidomide plus dexamethasone (65% vs 39%, respectively) and a PFS benefit (9.5 months vs 4.4 months, respectively).²Seventy patients were randomized in this phase II study.
• Tourmaline-MM1—The addition of the oral proteasome inhibitor ixazomib (MLN9708) to lenalidomide and dexamethasone achieved its primary endpoint of improving PFS compared with lenalidomide plus dexamethasone at a prespecified interim analysis, the Takeda Pharmaceutical Company announced earlier this month.³Details of the phase III trial findings were not released.
• ELOQUENT-2—This phase III trial will evaluate the addition of elotuzumab, a monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAMF7), in combination with lenalidomide and dexamethasone in 640 patients. In phase Ib/II findings, the triplet was tested at dosages of either 10 or 20 mg/kg and resulted in an 84% objective response rate (92% with 10 mg/kg; 76% with 20 mg/kg).⁴
• PANORMA-1—The FDA is reviewing an application for the histone deacetylase inhibitor panobinostat in combination with the proteasome inhibitor bortezomib and dexamethasone based on the results of the phase III trial. The median PFS by investigator assessment was 12 months in the panobinostat arm compared with 8.1 months with the two-drug regimen of bortezomib and dexamethasone (HR = 0.63; 95% CI, 0.52-0.76; P < .0001).⁵

In presenting these trials. Jagannath noted that the regimen tested in the ASPIRE trial represents a &ldquo;potential new standard of care in relapsed multiple myeloma.&rdquo;

&ldquo;It clearly showed that if you use the three-drug approach, it was quite effective in improving the progression free survival and a trend toward improvement in overall survival,&rdquo; he said in the interview.

Moreover, he noted that &ldquo;these three drugs could be combined effectively without added toxicity. &hellip;. Surprisingly, the patients who got the three drugs actually stayed on the three-drug combination longer.&rdquo;

In the pomalidomide trial, the findings showed that patients who received the triplet therapy from the start of the trial experienced a better PFS rate than those who had cyclophosphamide added to their regimen at a later time.

&ldquo;Perhaps in relapsed myeloma patients, you have a window of opportunity to give the best therapy, because if you wait and they relapse, sometimes the relapse could be more aggressive or the patient may not have a good performance status,&rdquo; said Jagannath. He also noted that patients could experience renal impairment or that their disease could become more refractory.

Noting the positive results of the other trials, Jagannath observed that &ldquo;in the near future, we may have additional new agents to tackle these patients.&rdquo;

In terms of employing new regimens in the clinic, Jagannath advised practicing oncologists to remember that evidenced-based medicine is developed through clinical trials that enroll patients who likely are more fit than those physicians see in their offices.

He suggested that one way to personalized treatment for patients who are over the age of 80 years is to evaluate whether they are fit, unfit, or frail, and then adjust the dosages accordingly. &ldquo;If you use the evidence-based medicine and apply it in these patients, what is coming out is that the toxicity is prohibitive and they&rsquo;re not actually benefiting,&rdquo; said Jagannath. &ldquo;So you tailor the therapy.&rdquo;

References

1. Stewart KA, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone vs lenalidomide and dexamethasone in patients with relapsed multiple myeloma: interim results from ASPIRE, a randomized, open-label, multicenter phase 3 study. Presented at: 2014 ASH Annual Meeting; December 6-9, 2014, San Francisco, CA. Abstract: 79.
2. Baz R, Martin TG, Alsina M, et al. Pomalidomide, cyclophosphamide, and dexamethasone is superior to pomalidomide and dexamethasone in relapsed and refractory myeloma: results of a multicenter randomized phase II study. Presented at: 2014 American Society of Hematology Annual Meeting; December 6-9, 2014; San Francisco, CA. Abstract 303.
3. Takeda announces that the first interim analysis of the phase 3 study of oral ixazomib in patients with relapsed or refractory multiple myeloma met the primary endpoint of improvement in progression-free survival [press release]. Cambridge, MA and Osaka, Japan: Takeda Pharmaceutical Company Limited; February 10, 2015.
4. Richardson PG, Jagannath S, Moreau P, et al. Final Results for the 1703 Phase 1b/2 Study of Elotuzumab in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma. Presented at: 2014 ASH Annual Meeting; December 6-9, 2014; San Francisco, CA. Abstract 302.
5. Richardson PG, Hungria VTM, Yoon SS, et al. Panorama 1: A randomized, double-blind, phase 3 study of panobinostat or placebo plus bortezomib and dexamethasone in relapsed or relapsed and refractory multiple myeloma.J Clin Oncol.2014;32:5s (suppl; abstr 8510).