Revlimid, Velcade, and Dexamethasone, Followed By Stem Cell Transplantation, Yields Deep Responses And Considerable Overall Survival In Newly Diagnosed Multiple Myeloma

A new study by U.S. researchers provides useful insights into the outcomes newly diagnosed multiple myeloma patients can expect from a common sequence of initial treatments.
Drawing on data for more than 240 patients treated between 2010 and 2017, the authors of the new study investigate treatment responses and survival outcomes for newly diagnosed myeloma patients who underwent initial treatment with Revlimid (lenalidomide), Velcade (bortezomib), and dexamethasone, followed soon thereafter with an autologous (own) stem cell transplant.
More than two thirds of the patients in the study also underwent either maintenance or consolidation therapy after their transplants.
Almost all patients in the study (99 percent) had at least a partial response to their treatment, and more than 60 percent of the patients eventually achieved either a complete response or a stringent complete response to treatment.
Across all patients, the median duration of remission was a bit more than two years, measured from when the patients had their stem cell transplants. Remissions were longer among the patients who underwent maintenance therapy, but overall survival was not affected by whether or not a patient received maintenance therapy.
Overall survival was affected, however, by whether or not a patient had high-risk chromosomal abnormalities. Across all patients in the study, estimated median overall survival was 8 years from the time of stem cell transplantation. In patients who had one or more high-risk chromosomal abnormalities, estimated median overall survival was 5 years.
The overall survival outcomes in this study are probably lower than the survival myeloma patients should expect if they just recently were diagnosed and underwent initial treatment with Revlimid, Velcade, and dexamethasone, followed by a stem cell transplant.
This is because patients in the new study had only limited access to several new myeloma therapies approved by the U.S. Food and Drug Administration (FDA) in recent years. Darzalex (daratumumab), Ninlaro (ixazomib), and Empliciti (elotuzumab) were not approved by the FDA until late 2015, and several promising myeloma therapies could be approved by the FDA in the next year or two and thus available for use in more recently diagnosed myeloma patients.
In addition, the new study includes more patients with high-risk chromosomal abnormalities than normally would be seen in a random sample of newly diagnosed myeloma patients who undergo stem cell transplants. Data for the study were collected at the Mayo Clinic’s Minnesota location, and during the time when patients in the study were being treated, the Mayo Clinic tended to reserve initial treatment with Revlimid, Velcade, and dexamethasone for patients with higher-risk disease.
The new study also is retrospective, rather than prospective, meaning that patients were not randomly assigned, for example, to receive either maintenance or no maintenance after their transplants, nor were they randomly assigned to specific kinds of maintenance therapy. There are therefore likely to be biases that need to be kept in mind when interpreting the study results.
Despite these limitations, the study provides useful insights. As already has been noted, the treatment outcomes serve as helpful benchmarks. In addition, the authors share insights into the logistics of treatment and response that accompanied the Revlimid, Velcade, and dexamethasone initial therapy and stem cell transplantation.
The authors note, for example, that patients in their study received the three-drug initial therapy for a median of four months, and patients underwent stem cell transplantation a median of five months after diagnosis. The researchers also describe how the response to initial treatment and stem cell transplantation deepens over time in many patients, even those who do not undergo any maintenance therapy.
Study Design
A total of 243 patients were included in the new study. Each patient was seen at some point at the Mayo Clinic’s Rochester, Minnesota location and started their first treatment for multiple myeloma sometime between January 2010 and April 2017.
To be included in the study, patients had to receive the three-drug combination of Revlimid, Velcade, and dexamethasone as their initial myeloma treatment, and they also had to undergo an autologous stem cell transplant within 12 months of their diagnosis.
The median age at diagnosis of the patients in the study was 61, and 62 percent of the patients were male.
More than 90 percent of the patients had standard melphalan-based high-dose chemotherapy as part of the stem cell transplant process. Eighty four percent of patients received the standard dose (200 mg/m2) of high-dose melphalan, and 7 percent received the reduced dose (140 mg/m2).
Prevalence Of High-Risk Disease
Slightly more than a third (34 percent) of the patients in the study had at least one high-risk chromosomal abnormality, defined as either deletion (17p), t(4;14), or t(14;16). This is a greater share of patients with high-risk abnormalities than normally would be expected in a random sample of newly diagnosed myeloma patients, where 15-20 percent of the patients might be expected to have one or more such abnormalities.
The higher prevalence of high-risk disease in the patients in this study most likely is due to Mayo Clinic treatment guidelines in effect for much of the time covered by this study. Those guidelines recommended three-drug therapy mainly for high-risk newly diagnosed patients. Other patients were more frequently put on two-drug initial treatment regimens, usually Revlimid and dexamethasone, or sometimes Velcade, cyclophosphamide (Cytoxan), and dexamethasone (CyBorD).
Maintenance Therapy
About two thirds (68 percent) of the patients in the study underwent maintenance therapy or some form of consolidation therapy after their stem cell transplant. Forty four percent of the patients underwent Revlimid maintenance therapy, 16 percent underwent Velcade maintenance therapy, and 9 percent received some other form of post-transplant treatment (including, in some cases, a second transplant).
Patients in the study who underwent Revlimid maintenance were much less likely to have high-risk chromosomal abnormalities than the patients who underwent Velcade maintenance; 22 percent of patients who underwent Revlimid maintenance had high-risk abnormalities, compared to 68 percent of the Velcade maintenance patients.
Timing Of Treatment
The median length of time patients in the study were treated with Revlimid, Velcade, and dexamethasone prior to their transplant was 4 months.
The median time between diagnosis and transplantation was 5 months.
The median length of maintenance therapy for the patients in the study was 12 months for those who underwent Revlimid maintenance and 15 months for those who underwent Velcade maintenance.
Study Results
Response To Treatment
Almost all patients in the study responded to the Revlimid, Velcade, and dexamethasone initial therapy combined with a subsequent stem cell transplant. At 100 days post transplant, 99 percent of the patients achieved at least a partial response to treatment.
Treatment responses also were frequently deep, with 42 percent of the patients achieving a complete response (CR) or stringent complete response (sCR) at 100 days post transplant.
Many patients also saw their treatment responses deepen with time. For example, the percent of patients who achieved a complete response or stringent complete response at some point after transplant was 62 percent, a full 20 percent more than had reached the CR or sCR marks by 100 days post transplant.
Some of the improvements in response were due, of course, to the maintenance therapy many patients on the study were on. However, responses also deepened for patients who were not on maintenance therapy. At the 100-day mark, 43 percent of patients not on maintenance therapy had achieved a complete response or stringent complete response, yet a full 61 percent reached the CR or sCR mark at some point post-transplant.
Among those patients who achieved their best response later than 100 days post transplant, the median time to best response was 11 months after transplant.
Progression-Free Survival
Across all patients in the study, median progression-free survival was 28 months, or two and a third years, from the time of each patient’s stem cell transplant.
In patients such as those in the current study, who have been recently diagnosed, progression-free survival is approximately the same as time to relapse. Thus, the median length of time patients in the study were in remission after induction therapy and stem cell transplantation was a little more than two years.
As one might expect, progression-free survival was longer for patients who underwent maintenance therapy. Progression-free survival was a median of 23 months in patients who did not receive maintenance therapy, 34 months for patients who received Revlimid maintenance, and 28 months for patients who received Velcade maintenance.
There was no statistically significant difference in progression-free survival, however, between patients with standard risk disease and patients with at least one high-risk chromosomal abnormality. This is most likely due to the fact that patients in this study who had high-risk abnormalities were much more likely to receive maintenance therapy, particularly Velcade maintenance therapy, which tended to extend the time in remission of high-risk patients.
Overall Survival
Across all patients in the study, an estimated 90 percent were still alive two years after their transplant, and 67 percent were still alive five years post transplant.
Estimated median overall survival across all patients was 96 months, or 8 years, from the time of the patients’ stem cell transplants after initial treatment with Revlimid, Velcade, and dexamethasone following diagnosis.
Maintenance therapy post transplant did not affect overall survival in the study patients. There was neither a statistical difference in overall survival, nor a trend to differences in survival, between patients who did not receive maintenance therapy after their transplant and those who received either Revlimid or Velcade maintenance therapy.
(This is a common result in studies investigating maintenance therapy. Undergoing maintenance therapy typically increases the time a patient spends in their first remission. The patient’s overall survival often is unaffected, however, because subsequent remissions are shorter.)
There was a difference in estimated overall survival between patients with standard risk disease and patients with high-risk chromosomal abnormalities. Five years from the time of transplantation, approximately 77 percent of standard risk patients were still alive, compared to 50 percent of high-risk patients.
Similarly, median overall survival has not yet been reached for standard-risk patients, compared to a median overall survival of 5 years for high-risk patients.
The researchers also investigated what patient and disease characteristics were statistically associated with longer overall survival. They found that only two variables had a statistically significant effect on estimated overall survival. Both variables have a close connection to disease biology. The first variable was whether or not the patient had a high-risk chromosomal abnormality, and the second was whether or not the patient achieved at least a complete response as their best response to treatment.
For more information, please see the study by Hasab Sidiqi, M., et al., “Bortezomib, lenalidomide, and dexamethasone (VRd) followed by autologous stem cell transplant for multiple myeloma,” Blood Cancer Journal, November 8, 2018 (full text of article).
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