Thalidomide Added to Induction and Maintenance Therapy in Multiple Myeloma Boosts Long-term Survival

Adding thalidomide to induction and maintenance therapy in stem cell transplant (CST)-eligible, newly diagnosed patients with multiple myeloma improved event-free survival (EFS) and progression-free survival (PFS) compared with standard chemotherapy drugs and interferon alfa, according to a long-term follow-up analysis from a phase III open-label randomized trial.¹

This analysis found that, although bortezomib-based induction therapy followed by lenalidomide maintenance is now the standard of care for recently diagnosed patients with multiple myeloma who are eligible for SCT, thalidomide-based treatment may still have a role in lower-resource settings.

“Our data support the use of thalidomide as part of induction regimens and maintenance therapy after stem cell transplantation in countries where cost and access to bortezomib and lenalidomide represent important challenges for patients with multiple myeloma and their physicians,” the authors, led by Niels WCJ van de Donk, MD, VU University Amsterdam, Netherlands, wrote inLancet Hematology. “However, careful follow-up and timely dose adjustments are important to prevent the development of thalidomide-induced neurotoxicity.”

In the HOVON-50 trial, 268 patients were randomized to receive thalidomide, doxorubicin (adriamycin), and dexamethasone (TAD) induction therapy, followed by high-dose melphalan, autologous SCT, and thalidomide maintenance, while 268 control patients received vincristine instead of thalidomide (VAD) for induction therapy and interferon alfa instead of thalidomide for maintenance therapy.²

In the new analysis, which was based on a median follow-up of 129 months (range, 123-136), thalidomide appeared to offer substantial benefits. The overall median EFS was 33 months in the thalidomide group, compared with 22 months in the control group (Hazard Ratio [HR] 0.66; 95% Confidence Interval [CI], 0.54-0.81;P< .0001). The 10-year EFS was 20% in the thalidomide group compared with 9% in the control group.

The median progression-free survival (PFS) was 34 months in the thalidomide group and 23 months in the control group (HR, 0.64; 95% CI, 0.52-0.79;P< 0&middot;0001). The 10-year PFS was 21% in the thalidomide group versus 9% in the control group.

At the time of the earlier publication, only 5-year data were available. The 5-year EFS was 31% in the thalidomide group and 14% in the control group (95% CI, 9-19). And PFS at 5 years was 32% in the thalidomide group versus 14% (95% CI, 9-19) in the control group. The authors noted that, after a median follow-up of 52 months, they observed no OS benefit despite better EFS and PFS among patients who received the thalidomide regimen.

However, many surviving patients in both arms who had not progressed by 10 years had a complete response. That includes 10 patients (67%) in the thalidomide group and 24 patients (62%) in the control group. &ldquo;When results are adjusted for covariates, addition of thalidomide also increased overall survival compared with classical cytotoxic drugs and interferon alfa,&rdquo; the investigators wrote.

The median OS with prolonged follow-up was comparable in both groups: 75 months (range, 29-not reached) in the thalidomide group and 61 months (range, 33-not reached) in the control group (HR, 0.81; 95% CI, 0.65-1.02;P=.075).

As of Oct 31, 2017, the median duration of maintenance was 19 months for thalidomide and 11 months for interferon alfa.

After maintenance therapy began, 116 patients still received thalidomide treatment. This number represents 75% of the 155 patients who had received maintenance, and excludes the 13 patients who were switched from maintenance to allogeneic SCT at 6 months. At 12 months, 96 patients (62%) were still on thalidomide. At 3 years, 40 patients (26%) remained on therapy, along with 22 patients (14%) at 5 years. Six patients (4%) achieved the 10-year mark on thalidomide.

In the control group, 65 patients still received interferon alfa. This number represents 73% of the 89 patients who had received maintenance, and excludes the 2 patients who were switched from maintenance to allogeneic SCT) at 6 months. At 12 months, 42 patients (47%) were still on maintenance therapy. At 3 years, 17 patients (19%) remained on therapy, along with 10 patients (11%) at 5 years. Two patients (2%) still received interferon alfa at 120 months.

As of Oct 31, 2017, 5 patients in the thalidomide group and 1 patient in the control group were still receiving maintenance treatment. These treatments ranged in duration from 124 to 157 months.

The authors also included data on 2 areas of clinical concern: thalidomide toxicity and the frequency of second primary malignancies.

Toxicity concerns led to thalidomide maintenance discontinuation in 65 of 155 patients (42%). Neuropathy was the most common symptom and occurred in 49 patients (75%). Other reported symptoms included skin reactions in 4 patients (6%) and fatigue in 2 patients (3%). A total of 10 patients (15%) experienced other symptoms, including abdominal pain, pancreatitis, and dyspnea.

In the control group, 24 of 90 patients (27%) discontinued maintenance therapy with interferon alfa because of toxicity. Flulike symptoms and psychiatric side effects were the most common side effects, occurring in 5 patients each (21%). Four control patients (17%) experienced hematological toxicity like thrombocytopenia or leukocytopenia and 3 patients (13%) developed skin reactions. Seven patients (29%) experienced other symptoms, such as infections, cardiomyopathy, and headache.

The authors also tracked the occurrence of second primary malignancies in both groups, due to thalidomide&rsquo;s association with increased risk. They found that the frequency of second primary malignancies was similar in both groups. In the thalidomide group, 24 patients experienced 29 second primary cancers, while 17 control patients developed 23 additional primary malignancies.

There were 16 treatment-related deaths in the thalidomide group and 19 treatment-related deaths in the control group. No additional studies are planned from the HOVON-50 trial data.

References:

1. Van de Donk NWCJ, van der Holt B, Minnema MC et al. Thalidomide before and after autologous stem cell transplantation in recently diagnosed multiple myeloma (HOVON-50): long-term results from the phase 3, randomised controlled trial.Lancet Haematol2018;5:e479—92.
2. Lokhorst HM, van der Holt B, Zweegman S et al. A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma.Blood2010 Feb 11;115(6):1113-20. doi: 10.1182/blood-2009-05-222539. Epub 2009 Oct 30.