Understanding Maintenance Therapy for Multiple Myeloma
by Dr. C.H. Weaver M.D. updated 2/2023
What is maintenance therapy?
Following the primary treatment of multiple myeloma your doctor may recommend additional treatment with “maintenance therapy.” The goal of maintenance therapy is not to cure the cancer but to “maintain” a remission or prevent or delay the cancer's return.
Clinical studies have demonstrated that Revlimid (lenalidomide), Velcade, and Ninlaro can delay the progression of multiple myeloma for certain patients but have not been shown to significantly prolong survival.1-6,8 Patients with mulitple myeloma treated with Revlimd appear to have an increased risk of developing a new or “secondary” cancer. The risk appears greatest when Revlimid is combined with oral melphalan. Patients should discuss and understand the risks of developing a new cancer resulting from their treatment with their doctor. The FDA recently made a safety announcement regarding the drug.7,9
Revlimid (lenalidomide)
Revlimid is an oral medication that can stop or slow the growth of cancerous myeloma cells within the bone marrow. Despite the increased risk of causing new cancers in some patients Revlimid continues to be widely used as maintenance therapy in multiple myeloma. Several double-blind, phase 3, multi-center, randomized trials have evaluated Revlimid maintenance therapy.
Findings from the randomized phase 3 Myeloma XI clinical trial that compared Revlimid maintenance therapy to observation without maintenance in 1917 patients following a response to initial induction therapy were released. The trial demonstrated that Revlimid maintenance significantly delays myeloma progression but does not improve overall survival duration for patients with newly diagnosed multiple myeloma.10,11
The average duration of survival without myeloma progression was 39 months for Revlimid maintenance compared to 20 months for no maintenance therapy. Transplant-eligible and transplant-ineligible patients both benefited regardless of cytogenetic risk status.
Revlimid After ASCT
Researchers assigned 614 patients under age 65 to Revlimid or placebo after transplantation.1 Maintenance therapy with Revlimid improved progression-free survival, with an average survival duration without myeloma progression of 41 months in the Revlimid group compared to 23 months for patients not receiving Revlimid. After a median follow-up of 45 months, more than 70 percent of patients in both groups survived. There was an increased rate of new cancers in the Revlimid group, 32 new cancers overall compared to 12 in the placebo group.
In a second study, 460 patients age 71 or younger were randomly assigned to Revlimid or placebo after transplantation.2 Patients in the Revlimid group had a significantly longer time to disease progression compared to those in the placebo group. Estimated median time to myeloma progression was nearly doubled for those receiving treatment, from 27 months for the placebo group to 53 months for those receiving Revlimid. After 65 months median follow-up, the median overall survival has not yet been reached for those receiving Revlimid and is 76 months for the placebo group. Among those receiving Revlimid maintenance, 25 secondary primary malignancies were observed, compared to 10 in the placebo arm. The study was unblinded at 18 months median follow-up, and 86 patients from the placebo arm who showed no evidence of disease progression chose to cross over to the treatment group.4
The accompanying NEJM editorial by Dr. Ashraf Badros observed that "while Revlimid appears to offer benefit as maintenance therapy for multiple myeloma, it does come with risks, namely the increased risk of second primary cancers" . Furthermore the benefit of progression-free survival in the absence of and improvement in overall survival was called into question.7
KRd Delays Myeloma Progression Compared to Revlimid After ASCT
Results from a phase 3 randomized trial indicate that patients with multiple myeloma may benefit from carfilzomib, lenalidomide, and dexamethasone (KRd) maintenance following ASCT. In the ATLAS study, researchers compared KRd with standard Revlimid maintenance in 180 patients after ASCT. They reported that KRd therapy led to longer progression-free survival compared with Revlimid. At a median follow-up of 33.8 months, 25% of patients treated with KRd and 44% of those treated with Revlimid saw their disease progress. Estimated survival duration without myeloma progression was 59 months for patients who received KRd, compared with 41 months for those who received Revlimid. Although KRd delayed myeloma progression there is no evidence of a survival benefit and the cost of KRd is twice that of Revlimid.
Revlimid in ASCT Ineligible Patients
Among patients with newly diagnosed multiple myeloma (MM) who are ineligible for high-dose therapy and stem cell transplant, treatment with a combination of Velcade® (bortezomib), melphalan, prednisone, and thalidomide followed by maintenance therapy with Velcade and thalidomide (VMPT-VT) resulted in better response rate and progression-free survival than treatment with Velcade, melphalan, and prednisone (VMP) without maintenance therapy. These findings were published in the Journal of Clinical Oncology.1
To evaluate the addition of a fourth drug to VMP, along with maintenance therapy, researchers in Italy conducted a Phase III clinical trial among more than 500 patients with newly diagnosed multiple myeloma.
Patients enrolled in this study were not candidates for high-dose therapy plus stem-cell transplantation due to either age or other health problems. Study participants were treated with VMPT followed by maintenance therapy with VT or VMP without maintenance therapy.
- Patients in the VMPT-VT arm experienced more frequent side effects, including neutropenia (low white blood cell counts), heart problems, and blood clots. Treatment-related deaths occurred in 4% of patients in the VMPT-VT group versus 3% in the VMP group.
- Three-year progression-free survival was 56% for patients in the VMPT-VT group and 41% in the VMP group.
- 38% of patients in the VMPT-VT group experienced a complete response compared with 24% in the VMP group.
- Three-year overall survival was 89% in the VMPT-VT group versus 87% in the VMP group. This difference in overall survival did not meet the criteria for statistical significance, suggesting that it could have occurred by chance alone.
The researchers concluded that newly diagnosed MM patients who were not candidates for high-dose therapy plus stem cell transplant experienced a progression-free survival and complete response benefit with VMPT-VT treatment compared with VMP. Individualizing treatment strategies for elderly patients and patients with other health problems is critical to optimizing health outcomes both in terms of survival and quality of life.9
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In a more recent study patients were randomly assigned to one of three groups:152 patients received oral melphalan-prednisone-Revlimid induction followed by Revlimid (MPR-R); 153 patients patients received oral melphalan-prednisone-Revlimid followed by placebo (MPR); and 154 patients received melphalan-prednisone followed by placebo (MP). The median progression-free survival was significantly longer with Revlimid maintenance therapy—the MPR-R group had a median progression-free survival of 31 months, compared to 14 months for the MPR group and 13 months for the MP group. The rate of new cancers was 7% with MPR-R, 7% with MPR, and 3% with MP.6
How long is maintenance treatment for multiple myeloma?
There is some debate about the optimal length of maintenance therapy. Most European doctors will have a fixed duration (2-3 years) of maintenance therapy but that could be related to approvals by European regulatory agencies. Most US doctors suggest "until disease progression" based on a study showing the duration of survival without myeloma progression was 38.9 months for Revlimid maintenance compared to 20 months for no maintenance therapy. It is possible the minimal residual assessment will be able to "tailor" maintenance therapy as doctors learn how to use this information.
Ninlaro
Ninlaro is referred to as a proteasome inhibitor. It produces anti-cancer effects by blocking proteins called enzymes within myeloma cells. By blocking these enzymes, the growth of the cancer cells is reduced or halted. Ninlaro appears to delay cancer progression when used following ASCT but has not been found effective following allogeneic stem cell transplant.8,13
Ninlaro Maintenance Therapy Following ASCT
The TOURMALINE-MM3 clinical trial evaluated the use of Ninlaro maintenance therapy post ASCT. Because nearly one-third of patients will ultimately discontinue Revlimed due to side effects or regarding concerns of causing a second primary cancer. Ninlaro which is taken orally and has requires less-frequent administration could be beneficial for individuals who can’t tolerate Revlimd therapy.8
The TOURMALINE-MM3 clinical trial evaluated 656 adult patients with newly diagnosed multiple myeloma who had responded to induction therapy prior to undergoing high dose chemotherapy and stem cell transplant. Patients were treated with either weekly Ninlaro or matched placebo and directly compared. The study found that Ninlaro treated patients experienced a 28 percent lower risk of disease progression compared with placebo and a higher rate of conversion from MRD-positive to MRD-negative status. Whether or not Ninlaro prolongs survival has yet to be determined and requires longer follow up.
Ninlaro in ASCT Ineligible Patients
TOURMALINE-MM2 is an international, randomized, double-blind, multicenter, placebo-controlled Phase 3 clinical trial, designed to evaluate whether the addition of Ninlaro to Revlimid could improved outcomes in myeloma patients ineligible for ASCT in 705 patients. The addition of Ninlaro resulted delayed myeloma progression by 13.5 months. Ninlaro patients survived 35 months without cancer progression compared to 22 months for those treated with Revlimid and dexamethasone without Ninlaro. This improvement however did not reach "statistical significance"
Velcade
Velcade Effective for Induction and Maintenance Treatment of Multiple Myeloma
Velcade® (bortezomib) is a type of targeted drug known as a proteasome inhibitor. It has been shown to provide benefits in the treatment of multiple myeloma and mantle cell lymphoma.
A randomized phase III clinical trial evaluated the sustained use of Velcade treatment during induction and maintenance. The study included 827 patients with newly diagnosed symptomatic multiple myeloma who were randomly assigned to receive induction therapy with vincristine, doxorubicin, and dexamethasone (VAD) or Velcade, doxorubicin, and dexamethasone (PAD) followed by high-dose melphalan and autologous stem-cell transplantation. Patients in the VAD group received maintenance therapy with Thalomid® (thalidomide) once per day for two years and patients in the PAD group received maintenance therapy with Velcade once every two weeks for two years.
Complete response was superior in the patients who received PAD induction—31 percent, compared to 15 percent in the VAD group. Velcade maintenance also produced superior complete response—49 percent, compared to 34 percent in the Thalomid group. After a median follow-up of 41 months, progression-free survival (PFS) was 35 months in the PAD group compared to 28 months in the VAD group. Furthermore, overall survival was better in the PAD group.
In high-risk patients presenting with increased creatinine, Velcade significantly improved PFS from a median of 13 months to 30 months and overall survival from a median of 21 months to 54 months.
The researchers concluded that Velcade during induction and maintenance improves complete response, progression-free survival, and overall survival.
References:
- Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide Maintenance after Stem-Cell Transplantation for Multiple Myeloma. New England Journal of Medicine. 2012; 366:1782-1791.
- McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after Stem-Cell Transplantation for Multiple Myeloma. New England Journal of Medicine. 2012; 366:1770-1781.
- Dimopoulos MA, Gay F, Schjesvold FH, et al. Maintenance therapy with the oral proteasome inhibitor (PI) ixazomib significantly prolongs progression-free survival (PFS) following autologous stem cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma (NDMM): phase 3 Tourmaline-MM3 trial. Abstract #301. Presented at the 2018 ASH Annual Meeting, December 2, 2018; San Diego, CA.
- Updated analysis of CALGB/ECOG/BMT CTN 100104: Lenalidomide (Len) vs. placebo (PBO) maintenance therapy after single autologous stem cell transplant (ASCT) for multiple myeloma (MM),” is abstract 8523 and will be presented on board no. 340 during the Lymphoma and Plasma Cell Disorders poster session Sunday, May 31, from 8 a.m. to 11:30 a.m. CDT in McCormick Place, S Hall A, and will also be featured in a poster discussion session later that day, from 4:30 p.m. to 5:45 p.m. CDT in McCormick Place E354b.
- Palumbo A, Hajek R, Delforge M, et al. Continuous Lenalidomide Treatment for Newly Diagnosed Multiple Myeloma. New England Journal of Medicine. 2012; 366:1759-1769.
- Badros AZ. Lenalidomide in Myeloma — A High-Maintenance Friend New England Journal of Medicine. 2012; 366:1836-1838.
- FDA Drug Safety Communication: Safety review update of cancer drug Revlimid (lenalidomide) and risk of developing new types of malignancies [FDA Safety Announcement]. U.S. Food and Drug Administration website. Available at: fda.gov/Drugs/DrugSafety/ucm302939.htm
- Sonneveld P, Schmidt-Wolf IGH, van der Holt B, et al. Bortezomib Induction and maintenance treatment in patients with newly diagnosed multiple myeloma: Results of the randomized phase III HOVON-65/ GMMG-HD4 trial. Journal of Clinical Oncology. 2012; 30(24).
- Palumbo A, Bringhen S, Rossi D, et al. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: A randomized controlled trial. Journal of Clinical Oncology [early online publication]. October 12, 2010.
- Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial
- Jackson HG, Davies FE, Pawlyn C, et al. Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2019;20(1):57-73.
- Mateos M-V, Gonzalez de la Calle V. Lenalidomide as maintenance for every newly diagnosed patient with multiple myeloma. Lancet Oncol. 2019;20(1):5-6.
Nishihori T, Bashir Q, Pasquini MC, et al. The results of multicenter phase II, double-blind placebo-controlled trial of maintenance ixazomib after allogeneic hematopoietic cell transplantation (alloHCT) for high-risk multiple myeloma (MM) from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 1302). J Clin Oncol. 2021;39:(suppl 15; abstr 7003). doi:10.1200/JCO.2021.39.15_suppl.7003
https://meetings.asco.org/abstracts-presentations/207304/video
