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).